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| Title: | DHHS Letter to Chuck Rosenberg |
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| Body: | DEPARTMENT OF HEALTH & HUMAN SERVICES
Office of the Secretary
Office of the Assistant Secretary for" Health
Washington, D.C. 20201
JUN 2 5 2015
The Hon.orable Chuck Rosenberg
Acting Admiliistrator
Drug Enforcement Administration
U.S. Department of
Justice
8701 MmTissette Drive
Springfield, VA 22152
Dear Mr. Rosenberg:
Pursuant to the Controlled Substances Act (CSA, 21 U.S.C. § 811(b), (c), and (f)), the
Department of
Health and Human Services (HHS) is recommending that marijuana continue to
be maintained in Schedule I of
the CSA.
The Food and Drug Administration (FDA) has considered the abuse potential and dependence-
producing characteristics of marijuana.
Marijuana meets the three criteria for placing a substance in Schedule I of
the CSA under 21
U.S.C 812(b)(l). As discussed in the enclosed analyses, marijuana has a high potential for
abuse, no currently accepted n1edical use in treatment in the United States, and a lack of
accepted
safety for use under medical supervision. Accordingly, HHS recommends that marijuana be
maintained in Schedule I ofthe CSA. Enclosed are two documents prepared by FDA'
s
Controlled Substance Staff (in response to petitions filed in 2009 by Mr. Bryan Krumm and in
2011 by Governors Lincoln D. Chafee and Christine 0. Gregoire) that form the basis for the
recommendation. Pursuant to the requests in the petitions, FDA broadly evaluated marijuana,
and did not focus its evaluation on pruticular strains ofmarijuana or components or derivatives
of
marijuana.
FDA's Center for Drug Evaluation ru1d Research'
s current review of
the available evidence and
the published clinical studies on marijuana demonstrated that since our 2006 scientific and
medical evaluation and scheduling recommendation responding to a previous DEA petition,
research with marijuana has progressed. However, the available evidence is not sufficient to
.
determine that marijuana has an accepted medical use. Therefore, more research is needed into
marijuana's effects, including potential medical uses for marijuana and its derivatives. Based on
the current review, we identified several methodological challenges in the marijuana studies
published in the literature. We recommend they be addressed in future clinical studies with
marijuana to ensure that valid scientific data are generated in studies evaluating marijuana's
safety and efficacy for therapeutic use. For exrunple, we recommend that studies need to focus
on consistent administration and reproducible dosing of mru.ijuana, potentially through the use of
U.S. Public Health Service
Page 2-
The Honorable Chuck Rosenberg
administration methods other than smoking. A summary of
our review of
the published
literature on the clinical uses of marijuana, including recommendations for future studies, is
attached to this document.
FDA and the National Institutes of Health's National Institute on Drug Abuse (NIDA) also
believe that work continues to be needed.to ensure support by the federal government for the
efficient conduct of clinical research using marijuana. Concerns have been raised about whether
. the existing federal regulatory system-
is flexible enough to respond to increased interest in
research into the potential therapeutic uses ofmarijuana and marijuana-derived drugs. HHS
. welcomes an opportunity to continue to explore these concerns with DEA.
Should you have any questions regarding these recommendations, please contact
-Corinne P.
Moody, Science Policy Analyst, Controlled Substance Staff, Center for Drug Evaluation and
Research, FDA, at (301) 796-3152.
Karen B. DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health
Enclosures
DEPARTMENT OF HEALTH & HUMAN SERVICES Office of the Secretary
Office of the Assistant Secretary for Health
Washington, D.C. 20201
JUN-
3 2015
The Honorable Chuck Rosenberg
Acting Administrator
Drug Enforcement Administration
I
U.S. Department of
Justice
8701 Morrissette Drive
Springfield, VA 22152
Dear Mr. Rosenberg:
Pursuant to the Controlled Substances Act (CSA, 21 U.S.C. § 8ll(b), (c), and (t)), the
Department of
Health and Human Services (HHS) is recommending that marijuana continue to
be maintained in Schedule I of
the CSA.
The Food and Drug Administration (FDA) and the National Institutes of
Health's National
Institute on Drug Abuse (NIH!NIDA) have also considered the abuse potential and dependence-
producing characteristics of
marijuana.
Marijuana meets the three criteria for placing a substance in Schedule I of
the CSA under 21
U.S.C 812(b)(l). As discussed in the enclosed analyses, marijuana has a high potential for
abuse, no currently accepted medical use in treatment in the United States, and a lack of
accepted
safety for use under medical supervision. Accordingly, HHS recommends that marijua.D.a be
maintained in Schedule I of the CSA. Enclosed are two documents prepared.by FDA's
Controlled Substance Staff (in response to petitions filed in 2009 by Mr. Bryan Krumm and in
2011 by Governors Lincoln b. Chafee and Christine 0. Gregoire) that form the basis for the
recommendation. Pursuant to the requests in the petitions, FDA broadly evaluated marijuana,
and did not focus its evaluation on particular strains ofmarijuana or components or derivatives
of
marijuana.
FDA's Center for Drug Evaluation and Research's current review of
the available evidence and
the published clinical studies on marijuana d.emonstrated that since our 2006 scientific and
medical evaluation and scheduling recommendation responding to a previous DEA petition,
research with marijuana has progressed. However, the available evidence is not sufficient to
determine that marijuana has an accepted medical use. Therefore, more research is needed into
marijuana's effects, including potential medical uses for marijuana and its derivatives. Based on
the current review, we identified several methodological challenges in the marijuana studies
published in the literature. We recommend they be addressed in future clinical studies with
marijuana to ensure that valid scientific data are generated in studies evaluating marijuana's
safety and efficacy for therapeutic use. For example, we recommend that studies need to focus
on consistent administration and reproducible dosing of
marijuana, potentially through the use of
U.S. Public Health Service
Page 2 -
The Honorable Chuck Rosenberg
administration methods other than smoking. A summary of
our review ofthe published
literature on the clinical uses ofmarijuana, including recommendations for future studies, is
attached to this document.
FDA and NIDA also believe that work continues to be needed to ensure support by the federal
government for the efficient conduct of clinical research using marijuana. Concerns have been
raised about whether the existing federal regulatory system is flexible enough to respond to
increased interest in research into the potential therapeutic uses of marijuana and marijuana-
derived drugs. HHS welcomes an opportunity to continue to explore these concerns with DBA.
Should you have any questions regarding these recommendations, please contact Corinne P.
Moody, Science Policy Analyst, Controlled Substance Staff, Center for Drug Evaluation and
Research, FDA, at (30 1) 796-3152.
Sincerely yours,
Karen . vo, MD, MPH, MSc
Acting Assistant Secretary for Health
Enclosures
ENCLOSURE 1
BASIS FOR THE RECOMMENDATION FOR
MAINTAINING MARIJUANA IN SCHEDULE I
OF THE CONTROLLED SUBSTANCES ACT
On November 30, 2011, Governors Lincoln D. Chafee of Rhode Island and Christine 0.
Gregoire of Washington submitted a petition to the Drug Enforcement Administration (DEA)
requesting that proceedings be initiated to repeal the rules and regulations that place marijuana in
Schedule I of
the Controlled Substances Act (CSA). The petition contends that marijuana has an
accepted medical use in the United States, is safe for use under medical supervision, and has a
relatively low abuse potential compared to other Schedule II drugs. The petition requests that
marijuana and "related items" be rescheduled in Schedule II of the CSA. In June 2013, the DEA
Administrator requested that the U.S. Department of
Health and Human Services (HHS) provide
a scientific and medical evaluation of
the available information and a scheduling
recommendation for marijuana, in accordance with the provisions of21 U.S.C. 81l(b).
In accordance with 21 U.S.C. 811(b), DEA has gathered information related to the control of
marijuana (Cannabis sativa)
1
under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary of
HHS is required to consider in a scientific and medical evaluation eight factors determinative of
control under the CSA. Following consideration of
the eight factors, if it is appropriate, the
Secretary must make three fmdings to recommend scheduJing a substance in the CSA or
transferring a substance from one schedule to another. The findings relate to a substance's abuse
potential, legitimate medical use, and safety or dependence liability.
Administrative responsibilities for evaluating a substance for control under the CSA are
performed by the Food and Drug Administration (FDA), with the concurrence of
the National
Institute on Drug Abuse (NIDA), as described in the Memorandum of
Understanding (MOU) of
March 8, 1985 (50 FR 9518-20).
In this document, FDA recommends continued control of
marijuana in Schedule I of the CSA.
Pursuant to 21 U.S.C. 811 (c), the eight factors pertaining to the scheduling of
marijuana are
considered below. .
1
The CSA defines marihuana (marijuana) as the following:
All parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin
extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture,
or preparation of
such plant, its seeds or resin. Such tenn does not include the mature stalks of
such plant, fiber produced from such stalks, oil or cake made from the seeds of
such plant, any
other compound, manufacture, salt, derivative, mixture, or preparation of
such mature stalks
(except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of
such plant which
is incapable of
gennination (21 U.S.C. 802(16)).
1
1. ITS ACTUAL OR RELATIVE POTENTIAL FOR ABUSE
Under the first factor, the Secretary must consider marijuana's actual or relative potential for
abuse. The CSA does not define the term "abuse." However, the CSA's legislative history .
suggests the following in determining whether a particular drug or substance has a potential
for abuse
2
: .
a.
There is evidence that individuals are taking the drug or drugs containing such a
substance in amounts sufficient to create a hazard to their health or to the safety of
other individuals or to the community.
b.
There is a significant diversion ofthe drug or drugs containing such a substance .
from legitimate drug channels.
c.
Individuals are taking the drug or drugs containing such a substance on their own
initiative rather than on the basis of medical advice from a practitioner licensed by
law to administer such drugs in the course of his professional practice.
d.
The drug or drugs containing such a substance are new drugs so related in their
action to a drug or drugs already listed as having a potential for abuse to make it
likely that the drug will have the same potentiality for abuse as such drugs, thus
making it reasonable to assume that there may be significant diversions from
legitimate channels, significant use contrary to or without medical advice, or that
it has a substantial capability of
creating hazards to the health of
the user or to the
safety of the community.
In the development of this scientific and medical evaluation for the purpose of
scheduling,
the Secretary analyzed considerable data related to the substance's abuse potential. The data
include a discussion ofthe prevalence and frequency of
use, the amount of
the substance
available for illicit use, the ease of
obtaining or manufacturing the substance, the reputation
or status of
the substance "on the street," and evidence relevant to at-risk populations.
Importantly, the petitioners define marijuana as including all Cannabis cultivated strains.
Different marijuana samples derived from various cultivated strains may have very different
chemical constituents, thus the analysis is based on what is known about the range of these
constituents across all cultivated strains.
Determining the abuse potential of a substance is complex with many dimensions, and no
single test or assessment provides a complete characterization. Thus, no single measure of
abuse potential is ideal. Scientifically, a comprehensive evaluation ofthe relative abuse
potential of a substance can include consideration of
the following elements: receptor binding
affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects,
dependence producing potential, pharmacokinetics, route ofadministration, toxicity, data on
2
Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 9lst Cong., Sess. 1
(1970) reprinted in U.S.C.C.A.N. 4566,4603.
2
actual abuse, clinical abuse potential studies, and public health risks. Importantly, abuse can
exist independently from tolerance or physical dependence because individuals may abuse
drugs in doses or patterns that do not induce these phenomena. Additionally, evidence of
clandestine production and illicit trafficking of a substance can shed light on both the demand
for a substance as well as the ease of
obtaining a substance. Animal and human laboratory
data and epidemiological data are all used in determining a substance's abuse potential.
Moreover, epidemiological data can indicate actual abuse.
The petitioners compare the effects of
marijuana to currently controlled Schedule II
substances and make repeated claims about their comparative effects. Comparisons between
marijuana and the diverse array of
Schedule II substances is difficult, because of
the
pharmacologically dissimilar actions of
substances in Schedule II of
the CSA. For example,
Schedule II substances include stimulant-like drugs (e.g., cocaine, methylphenidate, and
amphetamine), opioids (e.g., oxycodone, fentanyl), sedatives (e.g., pentobarbital,
amobarbital), dissociative anesthetics (e.g., PCP), and naturally occurring plant components
(e.g., coca leaves and poppy straw). The mechanism(s) of
action ofthe above Schedule II
substances are wholly different from one another, and they are different from
tetrahydrocannabinol (THC) and marijuana as well. For example, Schedule II stimulants
typically function by increasing monoaminergic tone via an increase in dopamine and
norepinephrine (Schmitt et al., 2013). In contrast, opioid analgesics function via mu-opioid
receptor agonist effects. These differing mechanism(s) of action result in vastly different
behavioral and adverse effect profiles, making comparisons across the range of
pharmacologically diverse C-II substances inappropriate.
In addition, many substances scheduled under the CSA are reviewed and evaluated within the
context of
commercial drug development, using data submitted in the form of a new drug
application (NDA). A new analgesic drug might be compared to a currently scheduled
analgesic drug as part ofthe assessment of
its relative abuse potential. However, because the
petitioners have not identified a specific indication for the use of
marijuana, identifying an
appropriate comparator based on indication cannot be done.
a. There is evidence that individuals are taking the substance in amounts sufficient to
create a hazard to their health or to the safety of other individuals or to the community.
Evidence shows that some individuals are taking marijuana in amounts sufficient to create a
hazard to their health and to the safety ofother individuals and the community. A large
number of
individuals use marijuana. HHS provides data on the extent of
marijuana abuse
through NIDA and the Substance Abuse and Mental Health Services Administration
(SAMHSA). According to the most recent data from SAMHSA's 2012 National Survey on
Drug Use and Health (NSDUH), which estimates the number of individuals who have used a
substance within the month prior to the study (described as "current use"), marijuana is the
most commonly used illicit drug among Americans aged 12 years and older, with an
estimated 18.9 million Americans having used marijuana within the month prior to the 2012
NSDUH. Compared to 2004, when an estimated 14.6 million individuals reported using
marijuana Within the month prior to the study, the estimated rates in 2012 show an increase
of approximately 4.3 million individuals. The 2013 Monitoring the Future (MTF) survey of
3
8th, 1Oth, and 12th grade students also indicates that marijuana is the most widely used illicit
substance in this age group. Specifically, current monthly use was at 7.0 percent of8th
graders, 18.0 percent of 1 0
1
h, graders and 22.7 percent of 12th graders. Additionally, the 2011
Treatment Episode Data Set (TEDS) reported that primary marijuana abuse accounted for
18.1 percent of non-private substance-abuse treatment facility admissions, with 24.3 percent
ofthose adm~tted reporting daily use. However, ofthese admissions for primary marijuana
abuse, the criminal justice system referred 51.6 percent to treatment. SAMHSA' s Drug
Abuse Warning Network (DAWN) was a national probability survey of
U.S. hospitals wi.th
emergency departments (EDs), and was designed to obtain information on ED visits where
recent drug use was implicated. In 2011, there were 455,668 ED visits in which marijuana
was In:entioned, accounting for 36.4 percent of
illicit drug related ED visits. There are some
limitations related to DAWN data on ED visits, which are discussed in detail in Factor 4, "Its
History and Current Patterns ofAbuse." For more information, refer to Factor 4, "Its History
and Current Pattern of
Abuse;" Factor 5,."The Scope, Duration, and Significance ofAbuse;"
and Factor 6, "What, if
any, Risk There is to the Public Health." These factors contain
detailed discussions of
these data.
A number ofrisks can occur with both acute and chronic use ofmarijuana. Detailed
discussions ofthe risks are addressed in Factor 2, "SCientific Evidence ofits Pharmacological
Effect, if
Known," and Factor 6, "What, if
any, Risk There is to the Public Health."
b. .There is significant diversion of the substance from legitimate drug channels.
There is a lack ofevidence of
significant diversion of
marijuana from legitimate drug
channels, but this is likely due to the fact that marijuana is more widely available from illicit
sources rather than through legitimate channels. Marijuana is not an FDA-approved drug
product, as an NDA or biologics license application (BLA) has not been approved for
marketing in the United States. Numerous states and the District ofColumbia have state-
level medical marijuana laws that allow for marijuana use within that state. These state-level
drug channels do not ~ave sufficient and complete data to allow for an analysis of diversion,
nor is there sufficient collection ofdata related to medical treatment, including efficacy and
safety.
Marijuana is used by researchers for nonclinical researc}:t as well as clinical research under
investigational new drug (IND) applications; this represents the only legitimate drug channel
in the United States. However, marijuana used for research represents a very small
contribution of
the total amount ofmarijuana available in the United States, and thus
provides limited information about diversion .. In addition, the lack of
significant diversion of
investigational supplies is likely because ofthe widespread availability ofillicit marijuana of
equal or greater amounts of delta
9
-
THC. The data originating from the DBA on seizure .
statistics demonstrate the magnitude of
the av~lability for illicit marijuana. DEA's. System .
to Retrieve Information from, Drug Evidence (STRIDE) provides information on total
domestic drug seizures. STRIDE reports a total domestic seizure of
573,195 kg ofmarijuana
in 2011, the most recent year with complete data that is currently publically available (DEA
Domestic Drug Seizures, n.d.).
4
c. Individuals are taking the substance on their own initiative rather than on the basis of
medical advice from a practitioner licensed by law to administer such substances. .
Because the FDA has not approved an NDA or BLA for a marijuana drug product for any
therapeutic indication, the only way an individual can take marijuana on the basis of
medical
advice through legitimate channels at the federal level is by participating in research under an
IND application. That said, numerous states and the District of Columbia have passed state-
level medical marijuana laws allowing for individuals to use marijuana under certain
circumstances. However, data are not yet available to determine the number ofindividuals
using marijuana under these state..:level medical marijuana laws. Regardless, according to the
2012 NSDUH data, 18.9 million American adults currently use marijuana (SAMHSA, 2013).
Based on the large number of individuals reporting current use of marijuana and the lack of
an FDA-approved drug product in the United States, one can assume that it is likely that the
majority of
individuals using marijuana do so on their own initiative rather than on the basis
of
medical advice from a licensed practitioner.
d. The substance is so related in its action to a substance already listed as having a
potential for abuse to make it likely that it will have the same potential for abuse as such
substance, thus making it reasonable to assume that there may be significant diversions
from legitimate channels, significant use contrary to or without medical advice, or that it
has a substantial capability of creating hazards to the health of the user or to the safety of
the community.
FDA has approved two drug products containing cannabinoid compounds that are
structurally related to the active components in marijuana. These two marketed products are
controlled under the CSA. Once a specific drug product containing cannabinoids becomes
approved, that specific drug product may be moved from Schedule I to a different Schedule
(II -
V) under the CSA. Firstly, Marinol-generically known as dronabinol-is a Schedule
III drug product containing synthetic delta
9
-
THC. Marino I, which is formulated in sesame
oil in
soft gelatin capsules, was first placed in Schedule II under the CSA following its
approval by the FDA. Marino! was later rescheduled to Schedule III under the CSA because
of
low numbers of
reports of
abuse relative to marijuana. Dronabinol is listed in Schedule I
under the CSA. FDA approved Marino! in 1985 for the treatment of
nausea and vomiting
associated with cancer chemotherapy in patients who failed to respond adequately to
conventional anti-emetic 'treatments. In 1992, FDA approved Marinol for anorexia
associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS).
Secondly, in 1985, FDA approved Cesamet, a drug product containing the Schedule II
substance nabilone, for the treatment of
nausea and vomiting associated with cancer
chemotherapy. Besides the two cannabinoid-containing drug products FDA approved for
marketing, other naturally occurring cannabinoids and their derivatives (from Cannabis) and
their synthetic equivalents with similar chemical structure and pharmacological activity are
included in the CSA as Schedule I substances.
5
2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN
Under the second factor, the Secretary must consider the scientific evidence of
marijuana's
pharmacological effects. Abundant scientific data are available on the neurochemistry,
toxicology, and pharmacology of
marijuana. This section inclucles a scientific evaluation of
marijuana's neurochemistry; pharmacology; and human and animal behavioral, central
nervous system, cognitive, cardiovascular, autonomic, endocrinological and immunological
system effects. The overview presented below relies upon the current research literature on
cannabinoids available in the public domain.
Neurochemistry and Pharmacology of Marijuana
Marijuana is a plant that contains numerous natural constituents, such as cannabinoids, that
have a variety of
pharmacological actions. The petition defines marijuana as including all
Cannabis cultivated strains. Different marijuana samples derived from various cultivated
strains may have very different chemical constituents including delta
9
-THC and other
cannabinoids (Appendino et al., 2011). As a consequence, marijuana products from different
strains will have different biological and pharmacological profiles.
According to ElSohly and Slade (2005) and Appendino et al. (2011), marijuana contains
approximately 525 identified natural constituents, including approximately 100 compounds
classified as cannabinoids. Cannabinoids primarily exist in Cannabis, and published data
suggests that most major cannabinoid compounds occurring naturally have been identified
chemically. New and minor cannabinoids and other new compounds are continuously being
characterized (Pollastro et al., 2011). So far, only two cannabinoids (cannabigerol and its
corresponding acid) have been obtained from a non-Cannabis source. A South African
Helichrysum (H umbraculigerum) accumulates these compounds (Appendino et al., 2011).
The chemistry of
marijuana is described in more detail in Factor 3, "The State of
Current
Scientific Knowledge Regarding the Drug or Other Substance."
The site of cannabinoid action is at the cannabinoid receptors. Cloning of
cannabinoid
receptors, first from rat brain tissue (Matsuda et al., 1990) and then from human brain tissue
(Gerard et al., 1991), has verified the site of action. Two cannabinoid receptors, CB1 and
CB
2
, were characterized (Battista et al., 2012; Piomelli, 2005). Evidence ofa third
cannabinoid receptor exists, but it has not been identified (Battista et al., 2012).
The cannabinoid receptors, CB
1 and CB2, belong to the family of
G-protein-coupled
receptors, and present a typical seven transmembrane-spanning domain structure.
Cannabinoid receptors link to an inhibitory G-protein (Gi), such that adenylate cyclase
activity is inhibited when a ligand binds to the receptor. This, in turn, prevents the
conversion of
ATP to the second messenger, cyclic AMP (cAMP). Examples of
inhibitory-
coupled receptors include opioid, muscarinic cholinergic, alpha2-adrenoreceptors, dopamine
(D
2
), and serotonin (5-HT~).
Cannabirioid receptor activation inhibits N-and P/Q-type calcium channels and activates
inwardly rectifying potassium channels (Mackie et al., 1995; Twitchell et al., 1997). N-type
6
calcium channel inhibition decreases neurotransmitter release from several tissues. Thus,
calcium channel inhibition may be the mechanism by which cannabinoids inhibit
acetylcholi~e, norepinephrine, and glutamate release from specific areas of
the brain. These
effects may represent a potential cellular mechanism underlying cannabinoids'
antinociceptive and psychoactive effects (Ameri, 1999).
CB
1
receptors are found primarily in the central nervous system, but are also present in
peripheral tissues. CB
1
receptors are located mainly in the basal ganglia, hippocampus, and
cerebellum of
the brain (Howlett eta!., 2004). The localization of
these receptors may
explain cannabinoid interference with movement coordination and effects on memory and
cognition. Additionally, CB
1 receptors are found in the immune system and numerous other
peripheral tissues (Petrocellis and DiMarzo, 2009). However, the concentration ofCB1
receptors is considerably lower in peripheral tissues than in the central nervous system
(Herkenham et a!., 1990 and 1992).
CB
2
receptors are found primarily in the immune system, but are also present in the central
nervous system and other peripheral tissues. In the immune system, CB2 receptors are found
predominantly in B lymphocytes and natural killer cells (Bouaboula eta!., 1993). CB
2
receptors may mediate cannabinoids' immunological effects (Galiegue eta!., 1995).
Additionally, CB
2
receptors have been localized in the brain, primarily in the cerebellum and
hippocampus (Gong et al., 2006). The distribution of CB
2 receptors throughout the body is
less extensive than the distribution of
CB
1 receptors (Petrocellis and Di Marzo, 2009).
However, both CB
1
and CB
2 receptors are present in numerous tissues of
the body.
Cannabinoid receptors have endogenous ligands. In 1992 and 1995, two endogenous
cannabinoid receptor agonists, anandamide and arachidonyl glycerol (2-AG), respectively,
were identified (DiMarzo, 2006). Anandamide is a low efficacy agonist (Brei vogel and
Childers, 2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000). Cannabinoid
endogenous ligands are present in central as well as peripheral tissues. A combination of
uptake and hydrolysis terminate the action of
the endogenous ligands. The endogenous
cannabinoid system is a locally active signaling system that, to help restore homeostasis, is
activated "on demand" in response to changes to the local homeostasis (Petrocellis and Di
Marzo, 2009). The endogenous cannabinoid system, including the endogenous cannabinoids .
and the cannabinoid receptors, demonstrate substantial plasticity in response to several
physiological and pathological stimuli (Petrocellis and Di Marzo, 2009). This plasticity is
particularly evident in the central nervous system.
Delta
9
-THC and cannabidiol (CBD) are two abundant cannabinoids present in marijuana.
Marijuana's major psychoactive cannabinoid is delta
9
-THC (Wachtel eta!., 2002). In 1964,
Gaoni and Mechoulam first described delta
9
-THC's structure and function. In 1963,
Mechou1am and Shvo first described CBD's structure. . The pharmacological actions ofCBD
have not been fully studied in humans.
Delta
9
-THC and CBI) have varying affinity and effects at the cannabinoid receptors. Delta
9
-
THC displays similar affinity for CB 1 arid CBz receptors, but behaves as a weak agonist for
CB2 receptors. The identification of synthetic cannabinoid ligands that selectively bind to
7
CB2 receptors but do not have the typical delta
9
-THC-like psychoactive properties suggests
that the activation ofCB
1
-receptors mediates cannabinoids' psychotropic effects (Hanus et
al., 1999). CBD has low affinity for both CB 1 and .CB
2 receptors (Mechoulam et al., 2007).
According to Mechoulam et al. (2007), CBD has antagonistic effects at CB
1
receptors and
some inverse agonistic properties at CB2 receptors. When cannabinoids are given subacutely
to rats, CB1 receptors down-regulate and the binding of
the second messenger system
coupled to CB1 receptors, GTPgammaS, decreases (Breivogel et al., 2001).
Animal Behavioral Effects
Self-Administration
Self-administration is a method that assesses the ability of
a drug to produce rewarding
effects. The presence ofrewarding effects increases the likelihood of
behavioral responses to
obtain additional drug. Animal self-administration of
a drug is often useful in predicting
rewarding effects in humans, and is indicative of
abuse liability. A good correlation is often
observed between those drugs that rhesus monkeys self-administer and those drugs that
humans abuse (Balster and Bigelow, 2003). Initially, researchers could not establish self-
administration of
crumabinoids, including delta
9
-
THC, in animal models. However, self-
.
administration of
delta
9
-
THC can now be established in a variety of
animal models under
specific training paradigms (Justinova et al., 2003, 2004, 2005).
Squirrel monkeys, with and-without prior exposure to other drugs of
abuse, self-administer
delta
9
-THC under specific conditions. For instance, Tanda et al. (2000) observed that when
squirrel monkeys are initially trained to self-administer intravenous cocaine, they will
continue to bar-press delta
9
-
THC at the same rate as they would with cocaine. The doses
were notably comparable to those doses used by humans who smoke marijuana. SR141716,
a CB
1
cannabinoid receptor agonist-antagonist, can block this rewarding effect. Other
studies show that naYve squirrel monkeys can be successfully trained to self-administer
delta
9
-THC intravenously (Justinova et al., 2003). The maximal responding rate is 4 )lg/kg
per injection, which is 2-3 times greater than observed in previous studies using cocaine-
experienced monkeys. Naltrexone, a mu-opioid antagonist, partially antagonizes these
1
rewarding effects of
delta
9
-
THC (Justinova et al., 2004 ).
Additionally, data demonstrate that under specific conditions, rodents self-administer
cannabinoids. Rats will self-administer delta
9
-
THC when applied intracerebroventricularly
(i.c.v.), but only at the lowest doses tested (0.01-0.02 J.Lg /infusion) (Braida et al., 2004).
SR141716 and the opioid antagonist naloxone can antagonize this effect. However, most
studies involve rodents self-administrating the synthetic cannabinoid WIN 55212, a CB1
receptor agonist with a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007;
Martellotta et al., 1998; Mendizabal et al., 2006).
Aversive effects, rather than reinforcing effects, occur in rats that received high doses of
WIN 55212 (Chaperon et al., 1998) or delta
9
-
THC (Sanudo-Pena et al., 1997), indicating a
possible critical dose-dependent effect. In both studies, SR141716 reversed these aversive
effects.
8
Conditioned Place Preference
Conditioned place preference (CPP) is a less rigorous method than self-administration for
determining whether or not a drug has rewarding properties. In this behavioral test, animals
spend time in two distinct environments: one where they previously received a drug and one
where they received a placebo. If
the drug is reinforcing, animals will choose to spend more
time in the environment paired with the drug, rather than with the placebo, when presented
with both options simultaneously.
Animals show CPP to delta
9
-THC, but only at the lowest doses tested (0.075-1.0 mg!kg,
intraperitoneal (i.p.)) (Braida et al., 2004). SR141716 and naloxone antagonize this effect
(Braida et al., 2004). As a partial agonist, SR141716 can induce CPP at doses of 0.25, 0.5, 2
and 3 mg/kg (Cheer et al., 2000). In knockout mice, those without Jl-opioid receptors do not
develop CPP to de1ta
9
-THC (Ghozland et al., 2002).
Drug Discrimination Studies
Drug discrimination is a method where animals indicate whether a test drug produces
physical or psychic perceptions similar to those produced by a known drug of
abuse. In this
test, an animal learns to press one bar when it receives the known drug of
abuse and another
bar when it receives placebo. To determine whether the test drug is like the known drug of
abuse, a challenge session with the test drug demonstrates which ofthe two bars the animal
presses more often.
In addition to humans (Lile et al., 2009; Lile et al., 2011 ), it has been noted that animals,
including monkeys (McMahon, 2009), mice (McMahon et al., 2008), and rats (Gold et al.,
1992), are able to discriminate cannabinoids from other drugs or placebo. Moreover, the
major active metabolite of
delta
9
-
THC, 11-hydroxy-delta
9
-
THC, also generalizes (following
oral administration) to the stimulus cues elicited by delta
9
-THC (Browne and Weissman,
1981). Twenty-two other cannabinoids found in marijuana also fully substitute for delta
9
-
THC. However, CBD does not substitute for delta
9
-THC in rats (Vann et al., 2008).
Discriminative stimulus effects of delta
9
-
THC are pharmacologically specific for marijuana-
containing cannabinoids (Balster and Prescott, 1992; Browne and Weissman, 1981 ; Wiley et
al., 1993, I 995). The discriminative stimulus effects of the cannabinoid group appear to
provide unique effects because stimulants, h~Iucinogens, opioids, benzodiazepines, .
barbiturates, NMDA antagonists, and antipsychotics do not fully substitute for delta
9
-THC.
Central Nervous System Effects
Human Psychological and Behavioral Effects
Psychoactive Effects
Below is a list of the common subjective responses to cannabinoids (Adams and Martin,
1996; Gonzalez, 2007; Hollister 1986, 1988; Institute of Medicine, 1982). According to
Maldonado (2002), these responses to marijuana are pleasurable to many humans and are
9
often associated-with drug-seeking and drug-taking. High levels of
positive psychoactive
effects are associated with increased marijuana use, abuse, and dependence (Scherrer et al.,
2009; Zeiger et al., 201 0).
1) Disinhibition, relaxation, increased sociability, and talkativeness.
2) Increased merriment and appetite, and even exhilaration at high doses.
3) Enhanced sensory perception, which can generate an increased appreciation of
music,
art, and touch.
4) Heightened imagination, which can lead to a subjective sense of increased creativity.
5) Initial dizziness, nausea, tachycardia, facial flushing, dry mouth, and tremor.
6) Disorganized thinking, inability to converse logically, time distortions, and short-term
memory impairment.
7) Ataxia and impaired judgment, which can impede driving ability or lead to an increase
in risk-tasking behavior.
8) Illusions, delusions, and hallucinations that intensify with higher doses.
9) Emotional lability, incongruity of
affect, dysphoria, agitation, paranoia, confusion,
drowsiness, and panic attacks, which are more common in inexperienced or high-dosed
users.
As with many psychoactive drugs, a person's medical, psychiatric, and drug-taking history .
can influence the individual's response to marijuana. Dose preferences to marijuana occur in
that marijuana users prefer higher concentrations ofthe principal psychoactive substance
(1.95 percent delta
9
-THC) over lowe~ concentrations (0.63 percent delta
9
-THC) (Chait and
Burke, 1994). Nonetheless, frequent mariJuana users (>I 00 times of
use) were able to
identify a drug effect from low-dose delta -THC better than occasional users.(<IO times of
use) while also experiencing fewer sedative effects from marijuana (Kirk and deWit, 1999).
The petitioners contend that many ofmarijuana's naturally occurring cannabinoids mitigate
the psychoactive effects of
delta
9
-THC, and therefore that marijuana lacks sufficient abuse
potential to warrant Schedule I placement, because Marinol, which is in Schedule III,
contains only delta
9
-
THC. This theory has not been demonstrated in controlled studies.
Moreover, the concept of
abuse potential encompasses all properties of
a substance,
including its chemistry, pharmacology, and pharmacokinetics, as well as usage patterns and
diversion history. The abuse potential of
a substance is associated with the repeated or
sporadic use of
a substance in nonmedical situations for the psychoactive effects the
substance produces. These psychoactive effects include euphoria, perceptual and other
cognitive distortions, hallucinations, and mood changes. However, as stated above, the abuse
potential not only includes the psychoactive effects, but also includes other aspects related to
a substance.
DEA's final published rule entitled "Rescheduling of
the Food and Drug Administration
Approved Product Containing Synthetic Dronabinol [(-)-delta
9
-(trans)-
Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From
Schedule II to Schedule III" (64 FR 35928, July 2, 1999) rescheduled Marino! from Schedule
II to Schedule III. The HHS assessment of
the abuse potential and subsequent scheduling
recommendation compared Marino} to marijuana on different aspects related to abuse
10
potential. Major differences in formulation, availability, and usage between marijuana and
the drug product, Marino!, contribute to their differing abuse potentials.
Hollister and Gillespie (I 973) estimated that delta
9
-
THC by smoking is 2.6 to 3 times more
potent than delta
9
-THC ingested orally. The intense psychoactive drug effectachieved .
rapidly by smoking is generally considered to produce the effect desired by the abuser. This
effect explains why abusers often prefer to administer certain drugs by inhalation,
intravenously, or intranasally rather than orally. Such is the case with cocaine, opium,
heroin, phencyclidine, methamphetamine, and delta
9
-THC from marijuana (0.1-9.5 percent
delta
9
-THC range) or hashish (1 0-30 percent delta
9
-TIIC range) (Wesson and Washburn,
I 990). Thus, the delayed onset and longer duration of action for Marinol may be
contributing factors limiting the abuse or appeal of Marino! as a drug of
abuse relative to
marijuana.
The formulation of Marino! is a factor that contributes to differential scheduling ofMarinol
and marijuana. For example, extraction and purification of
dronabinol from the encapsulated
sesame oil mixture of
Marino I is highly complex and difficult. Additionally, the presence of
sesame oil mixture in the formulation may preclude the smoking ofMarinol-Iaced cigarettes.
Additionally, there is a dramatic difference between actual abuse and illicit trafficking of
Marinol and marijuana. Despite Marinol's availability in the United States, there have been
no significant reports of
abuse, diversion, or public health problems due to Marino!. By
comparison, 18.9 million American adults report currently using marijuana (SAMHSA,
2013).
In addition, FDA's approval of
an NDA for Marino! allowed for Marinoi to be rescheduled to
Schedule II, and subsequently to Schedule III of
the CSA. In conclusion, marijuana and
Marino! differ on a wide variety of
factors that contribute to each substance's abuse potential.
These differences are major reasons distinguishing the higher abuse potential for marijuana
and the different scheduling determinations ofmarijuana and Marinol.
In terms ofthe petitioners' claim that diffet:ent cannabinoids present in marijuana mitigate
the psychoactive effects of
delta
9
-
THC, only three of
the cannabinoids present in marijuana
were simultaneously administered with delta
9
-
THC to examine how the combinations of
these cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN) influence
delta
9
-THC's psychoactive effects. Dalton et al. (1976) observed that smoked administration
of placebo marijuana cigarettes containing injections of 0.15mg/kg CBD combined with
0.025mg/kg of
delta
9
-
THC, in a 7:1 ratio of
CBD to delta
9
-
THC, significantly decreased
ratings of
acute subjective effects and "high" when compared to smoking delta
9
-
TIIC alone.
In contrast, Ilan et al. (2005) calculated the naturally occurring concentrations of
CBC and
CBD in a batch of marijuana cigarettes with either 1.8 percent or 3.6 percent delta
9
-
THC
concentration by weight. For each strength of delta
9
-
THC in marijuana cigarettes, the
~oncentrations of
CBC and CBD were classified in groups of
either low or high. The study
varied the amount of
CBC and CBD within each strength of
delta
9
-
THC marijuana cigarettes,
with administrations consisting of
either low CBC (between 0.1-0.2 percent CBC
concentration by weight) and low CBD (between 0.1-0.4 percent CBD concentration by
11
weight), high CBC (>0.5 percent CBC concentration by weight) and low CBD, or low CBC
and high CBD (> 1.0 percent CBD concentration by weight). Overall, all combinations
scored significantly greater than placebo on ratings of subjective effects, and there was no
significant difference between any combinations.
The oral administration of a combination of either 15, 30, or 60 mg CBD with 30 mg delta
9
-
.
THC dissolved in liquid ~n a ratio of at least I :2 CBD to delta
9
-
THC) reduced the subjective
effects produced by delta -THC alone (Karniol et al., 197 4 ). Additionally, orally
administering a liquid mixtUre combining 1 mg/kg CBD with 0.5 mg!k:g of
delta
9
-
THC(ratio
of 2: I CBD to delta
9
-
THC) decreased scores of anxiety and mar~uana drug effect on the
Addiction Research Center Inventory (ARCI) compared to delta -THC alone (Zuardi et al.,
I 982J. Lastly, oral administration of
either I 2.5, 25, or 50 mg CBN combined ~ith 25 mg
delta -THC dissolved in liquid (ratio of
at least I :2 CBN to delta
9
-
THC) significantly
increased subjective ratings of"drugged," "drowsy," "dizzy," and "drunk," compared to
delta
9
-THC alone (Karniol et al., 1975).
Even though some studies suggest that CBD may decrease some of
delta
9
-
THC's
psychoactive effects, the ratios of CBD to delta
9
-
THC administered in these studies are not
present in marijuana used by most people. For example, in one study, researchers used
smoked marijuana with ratios of CBD to delta
9
-THC naturally present in marijuana plant
material and they found out that varying the amount of
CBD actually had no effect on delta
9
~
THC's psychoactive effects (llan et al., 2005). Because most marijuana currently available
on the street has high amounts of delta
9
-
THC with low amounts of
CBD and other
cannabinoids, most individuals use marijuana with low levels of CBD present (Mehmedic et
al., 201 0). Thus, any possible mitigation of delta
9
-
THC
's psychoactive effects by CBD will
not occur for most marijuana users. In contrast, one study indicated that another cannabinoid
present in marijuana, CBN, may enhance delta
9
-
THC's psychoactive effects (Kamiol et al.,
I 975).
Behavioral Impairment
Marijuana induces various psychoactive effects that can lead to behavioral impairment.
Marijuana's acute effects can significantly interfere with a person's ability to learn in the
classroom or to operate motor vehicles. Acute administration of smoked marijuana impairs
performance on learning, associative processes, and psychomotor behavioral tests (Block et
al., 1992). Ramaekers et al. (2006a) showed that acute administration of250 Jlg/kg and 500
Jlg/kg of
delta
9
-THC in smoked marijuana dose-dependently impairs cognition and motor
control, including motor impulsivity and tracking impairments (Ramaekers et al., 2006b).
Similarly, administration of
290 ~g!k:g delta
9
-
THC in a smoked marijuana cigarette resulted
in impaired perceptual motor speed and accuracy: two skills which are critical to driving
ability (Kurzthaler et al., 1999). Lastly, administration of 3.95 percent delta
9
-
THC in a
smoked marijuana cigarette not only increased disequilibrium measures, but also increased
the latency in a task of
simulated vehicle braking at a rate comparable to an increase in
stopping distance of
five feet at 60 mph (Liguori et al., 1998). However, acute
administration ofmarijuana containing 2.1 percent delta
9
-
THC does not produce "hangover
effects" (Chait, 1990).
12
In addition to measuring the acute effects immediately following marijuana administration,
researchers have conducted studies to determine how long behavioral impairments last after
abstinence. Some of
marijuana's acute effects may not fully resolve until at least one day
after the acute psychoactive effects have subsided. Heishman et al. (1990) showed that
impairment on memory tasks persists for 24 hours after smoking marijuana cigarettes
containing 2.57 percent delta
9
-THC. However, Fant et al. (1998) showed that the morning
after exposure to 1.8 percent or 3.6 percent smoked delta
9
-
THC, subjects had minimal
residual alterations in subjective or performance measures.
A number of
factors may influence marijuana's behavioral effects including the duration of
use (chronic or short term), frequency of use (daily, weekly, or occasionally), and amount of
use (heavy or moderate). Researchers also have examined how long behavioral impairments
last following chronic marijuana use. These studies used self-reported histories ofpast
duration, frequency, and amount ofpast marijuana use, and administered a variety of
performance and cognitive measures at different time points following marijuana abstinence.
In chronic marijuana users, behavioral impairments may persist for up to 28 days of
abstinence. Solowij et al. (2002) demonstrated that after 17 hours of
abstinence, 51 adult
heavy chronic marijuana users performed worse on memory and attention tasks than 33 non-
using controls or 51 heavy, short-term users. Another study noted that heavy, frequent
marijuana users, abstinent for at least 24 hours, performed significantly worse than the
controls on verbal memory and psychomotor speed tests (Messinis et al., 2006).
Additionally, after at least 1 week of
abstinence, young adult frequent marijuana users, aged
18-28, showed deficits in psychomotor speed, sustained attention, and cognitive inhibition
(Lisdahl and Price, 2012). Adult heavy, chronic marijuana users showed deficits on memory
tests after ?days of supervised abstinence (Pope et al., 2002). However, when these same
individuals were again tested after 28 days of
abstinence, they did not show significant
memory deficits. The authors concluded, "cannabis-associated cognitive deficits are
reversible and related to recent cannabis exposure, rather than irreversible and related to
cumulative lifetime use."
3
However, other researchers reported neuropsychological deficits
in memory, executive functioning, psychomotor speed and manual dexterity in heavy
marijuana users abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up study of
heavy marijuana users noted decision-making deficits after 25 days of
supervised abstinence.
(Bolla et al., 2005). However, moderate marijuana users did not show decision-making
deficits after 25 days of
abstinence, suggesting the amount of
marijuana use may impact the
duration of
residual impairment.
The effects of chronic marijuana use do not seem to persist after more than 1 to 3 months of
abstinence. After 3 months of
abstinence, any deficits observed in IQ, immediate memory,
delayed memory, and information-processing speeds following heavy marijuana use
compared to pre-drug use scores were no longer apparent (Fried et al., 2005). Marijuana did
not appear to have lasting effects on performance of a comprehensive neuropsychological
battery when 54 monozygotic male twins (one of)Vhom used marijuana, one of
whom did
not) were compared 1-20 years after cessation ofmarijuana use (Lyons et al., 2004).
Similarly, following abstinence for a year or more, both light and heavy adult marijuana
In this quotation the term Cannabis is used interchangeably for marijuana.
13
3
users did not show deficits on scores of
verbal memory compared to non-using controls (Tait
et al., 2011). According to a recent meta~analysis looking at non-acute and long-lasting
effects of
marijuana use on neurocognitive performance, any deficits seen within the first
month following abstinence are generally not present after about 1 month of abstinence
(Schreiner and Dunn, 20 12). .
Another aspect that may be a critical factor in the intensity and persistence of
impairment
resulting from chronic marijuana use is the age of
first use. Individuals with a diagnosis of
marijuana misuse or dependence who were seeking treatment for substance use, who initiated
marijuana use before the age of 15 years, showed deficits in performance on tasks assessing
sustained attention, impulse control, and general executive functioning compared to non-
using controls. These deficits were not seen in individuals who initiated marijuana use after
the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic marijuana users who
began using marijuana before the age of 16 years had greater decrements in executive
functioning tasks than heavy, chronic marijuana users who started using after the age of 16
years and non-using controls (Gruber et al., 2012). Adoitionally, in a prospective
longitudinal birth cohort study of 1,037 individuals, marijuana dependence or chronic
marijuana use was associated with a decrease in IQ and general neuropsychological
performance compared to pre-marijuana exposure levels in adolescent onset users (Meier et
al., 2012). The decline in adolescent-onset user's IQ persisted even after reduction or
abstinence of
marijuana use for at least 1 year. In contrast, the adult-onset chronic marijuana
users showed no significant changes in IQ compared to pre-exposure levels whether they
were current users or abstinent for at least 1 year (Meier et al., 2012).
In addition to the age of
onset of use, some evidence suggests that the amount of
marijuana
used may relate to the intensity of
impairments. In the above study by Gruber et al. (2012),
where early-onset users had greater deficits than late-onset users, the early-onset users
reported using marijuana twice as often and using three times as much marijuana per week
than the late-onset users. Meier et al. (2012) showed that the deficits in IQ seen in
adolescent-onset users increased with the amount of
marijuana used. Moreover, when
comparing scores for measures of IQ, immediate memory, delayed memory, and
information-processing speeds to pre-drug-use levels, the current, heavy, chronic marijuana
users showed deficits in all three measures while current, occasional marijuana users did not
(Fried et al., 2005).
Behavioral Effects of
Prenatal Exposure
Studies with children at different stages of
development are used to examine the impact of
prenatal marijuana exposure on performance in a series of
cognitive tasks. However, many
pregnant women who reported marijuana use were more likely to also report use of
alcohol,
tobacco, and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure to multiple
drugs, it is difficult to determine the specific impact of
prenatal marijuana exposure.
Most studies assessing the behavioral effects of
prenatal marijuana exposure included women
who, in addition to using marijuana, also reported using alcohol and tobacco. However,
some evidence suggests an association between heavy prenatal marijuana exposure and
deficits in some cognitive domains. In both 4-year-old and 6-year-old children, heavy
14
prenatal marijuana use is negatively associated with performance op tasks assessing memory,
verbal reasoning, and quantitative reasoning (Fried and Watkinson, 1987; Goldschmidt et al.,
2008). Additionally, heavy prenatal marijuana use is associated with deficits in measures of
sustained attention in children at the ages of
6 years and 13-16 years (Fried et al., 1992;
Fried, 2002). In 9-
to 12-year-old children, prenatal marijuana exposure is negatively
associated with executive functioning tasks that require impulse control, visual analysis, and
hypothesis (Fried et al., 1998).
Association of Marijuana Use with Psychosis
This analysis evaluates only the evidence for a direct link between prior marijuana use and
the subsequent development of
psychosis. Thus, this discussion does not consider issues
such as whether marijuana's transient effects are similar to psychotic symptoms in healthy
individlials or exacerbate psychotic symptoms in individuals already diagnosed with
schizophrenia.
Extensive research has been conducted to investigate whether exposure to marijuana is
associated with the development of schizophrenia or other psychoses. Although many
studies are small and inferential, other studies in the literature use hundreds to thousands of
subjects. At present, the available data do not suggest a causative link between marijuarui
use and the development of psychosis (Minozzi et al., 201 0). Numerous large, longitudinal
studies show that subjects who used marijuana do not have a greater incidence of
psychotic
diagnoses compared to those who do not use marijuana (Fergusson et al., 2005; Kuepper et
al., 2011; Van Os et al., 2002).
When analyzing the available evidence of the connection between psychosis and marijuana,
it is critical to determine whether the subjects in the studies are patients who are already
diagnosed with psychosis or individuals who demonstrate a limited number of
symptoms
associated with psychosis without qualifying for a diagnosis of
the disorder. For example,
instead of
using a diagnosis of
psychosis, some researchers relied on non-standard methods
ofrepresenting symptoms ofpsychosis including "schizophrenic cluster" (Maremmani et al.,
2004), "subclinical psychotic symptoms" (VanGastel et al., 2012), "pre-psychotic clinical
high risk" (VanderMeer et al., 2012), and symptoms related to "psychosis vulnerability"
(Griffith-Lendering et al., 2012). These groupings do not conform to the criteria in the
Diagnostic and Statistical Manual (DSM-5) or the International Classification of
Diseases
(ICD-1 0) for a diagnosis of
psychosis. Thus, these groupings are not appropriate for use in
evaluating marijuana's impact on the development of
actual psychosis. Accordingly, this
analysis includes only those studies that use subjects diagnosed with a psychotic disorder.
In the largest study evaluating the link between psychosis and drug use, 274 of
the
approximately 45,500 Swedish conscripts in the study population ( <0.01 percent) received a
diagnosis of
schizophrenia within the 14-year period following military induction from 1969
to 1983 (Andreasson et al., 1987). Of
the conscripts diagnosed with psychosis, 7.7 percent
(21 .ofthe 274 conscripts with psychosis) had used marijuana more than 50 times at
induction, while 72 percent (197 of
the 274 conscripts with psychosis) had never used
marijuana. Although high marijuana use increased the relative risk for schizophrenia to 6.0,
15
the authors note that substantial marijuana use history "accounts for only a minority of all
cases" ofpsychosis (Andreassen et al., 1987). Instead, the best predictor for whether a
conscript would develop psychosis was a non-psychotic psychiatric diagnosis upon
induction. The authors concluded that marijuana use increased the risk for psychosis only
among individuals predisposed to develop the disorder. In addition, a 35-year follow up to
this study reported very similar results (Manrique-Garcia et al., 2012). In this follow up
study, 354 conscripts developed schizophrenia; of these 354 conscripts, 32 used marijuana
more than 50 times at induction (9 percent, an odds ratio of 6.3), while 255 had never used
marijuana (72 percent).
Additionally, the conclusion that the impact of
marijuana may manifest only in individuals
likely to develop psychotic disorders has been shown in many other types of
studies. For
example, although evidence shows that marijuana use may precede the presentation of
symptoms in individuals later diagnosed with psychosis (Schimmelmann et al., 2011), most
reports conclude that prodromal symptoms of
schizophrenia appear prior to marijuana use
(Schiffman et al., 2005). Similarly, a review of
the gene-environment interaction model for
marijuana and psychosis concluded that some evidence supports marijuana use as a factor
that may influence the development ofpsychosis, but only in those individuals with
psychotic liability (Pelayo-Teran et al., 20 12).
A similar conclusion was drawn when the prevalence of
schizophrenia was modeled against
marijuana use across eight birth cohorts in Australia in individuals born between the years
1940 to 1979 (Degenhardt et al., 2003 ). Although marijuana use increased over time in
adults born during the four-decade period, there was not a corresponding increase in
diagnoses for psychosis in these individuals. The authors conclude that marijuana may
precipitate schizophrenic disorders only in those individuaJs who are vulnerable to
developing psychosis. Thus, marijuana per se does not appear to induce schizophrenia in the
majority of
individuals who have tried or continue to use marijuana. However, in individuals
with a genetic vulnerability for psychosis, marijuana use may influence the development of
psychosis. .
Cardiovascular and Autonomic Effects
Single smoked or oral doses of
delta
9
-THC produce tachycardia and may increase blood
pressure (Capriotti et al., 1988; Benowitz andJones, 1975). Some evidence associates the
tachycardia produced by delta
9
-
THC with excitation of
the sympathetic and depression of
the
parasympathetic nervous systems (Malinowska et al., 2012). During chronic marijuana.
ingestion, a tolerance to tachycardia develops (Malinowska et al., 2012).
However, prolonged delta
9
-
THC ingestion produces bradycardia and hypotension (Benowitz
and Jones, 1975). Plant-derived cannabinoids and endocannabinoids elicit hypotension and
bradycardia via activation ofperipherally-located CB1 receptors (Wagner et al., 1998).
Specifically, the mechanism of
this effect is through presynaptic CB1 receptor-mediated
inhibition ofnorepinephrine release from peripheral sympathetic nerve terminals, with
possible additional direct vasodilation via activation of vascular cannabinoid receptors
(Pacher et al., 2006). In humans, tolerance can develop to orthostatic hypotension (Jones,
16
2002; Sidney, 2002) possibly related to plasma volume expansion, but tolerance does not
develop to the supine hypotensive effects (Benowitz and Jones, 1975). Additionally,
electrocardiographic changes are minimal, even after large cumulative doses of
delta
9
-THC
are administered. (Benowitz and Jones, 197 5)
Marijuana smoking by individuals, particularly those with some degree of coronary artery or
cerebrovascular disease, poses risks such as increased cardiac work, catecholamines and
carboxyhemoglobin, myocardial infarction, and postural hypotension (Benowitz and Jones,
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 2012).
Respiratory Effects
After acute exposure to marijuana, transient bronchodilation is the most typical respiratory
effect (Gong et al., 1984). A recent 20-year longitudinal study with over 5,000 individuals
collected information on the amount ofmarijuana use and pulmonary function data at years
0, 2, 5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000 individuals who
participated in the study, almost 800 ofthem reported current marijuana use but not tobacco
use at the time of
assessment. Pletcher et al. (20 12) found that the occasional use of
marijuana is not associated with decreased pulmonary function. However, some preliminary
evidence suggests that heavy marijuana use may be associated with negative pulmonary
effects (Pletcher et al., 2012). Long-term use of
marijuana can lead to chronic cough and
increased sputum, as well as an increased frequency of
chronic bronchitis and pharyngitis. In
addition, pulmonary function tests reveal that large-airway obstruction can occur with
chronic marijuana smoking, as can cellular inflammatory histopathological abnormalities in
bronchial epithelium (Adams and Martin 1996; Hollister 1986).
Evidence regarding marijuana smoking leading to caricer is inconsistent, as some studies
suggest a positive correlation while others do not (Lee and Hancox, 2011; Tashkin, 2005).
Several lung cancer cases have been reported in young marijuana users with no tobacco
smoking history or other significant risk factors (Fung et al., 1999). Marijuana use may
dose-dependently interact with mutagenic sensitivity, cigarette smoking, and alcohol use to
increase the risk of
head andneck cancer (Zhang et al., 1999). However, in a large study
with 1,650 subjects, a positive association was not found between marijuana and lung cancer
(Tashkin et al., 2006). This fmding remained true, regardless of
the extent of
marijuana use,
when controlling for tobacco use and other potential confounding variables. Overall, new
evidence suggests that the effects of
marijuana smoking on respiratory function and
carcinogenicity differ from those oftobacco smoking (Lee and Hancox, 2011).
Endocrine S;rstem
Experimental marijuana administration to humans does not consistently alter many endocrine
parameters. In an early study, male subjects who experimentally received smoked marijuana
showed a significant depression in luteinizing hormone and a significant increase in cortisol
(Cone et al., 1986). However, two later studies showed no changes in hormones. Male
subjects experimentally exposed to smoked delta
9
-THC (18 mg/marijuana cigarette) or oral
delta
9
-THC (10 mg three times per day for 3 days and on the morning ofthe fourth day)
showed no changes in plasma adrenocorticotropic hormone (ACTH), cortisol, prolactin,
17
luteinizing hormone, or testosterone levels (Dax et al., 1989). Similarly, a study with 93 men
and 56 women showed that chronic marijuana use did not significantly alter concentrations
of
testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, or.cortisol
(Blocket al., 1991). Additionally, ch!onic marijuana use did not affect serum levels of
thyrotropin, thyroxine, and triiodothyronine (Bonnet, 2013). However, in a double-blind,
placebo-controlled, randomized clinical trial of
HIV -positive men, smoking marijuana dose-
dependently increased plasma levels of
ghrelin and leptin, and decreased plasma levels of .
peptide YY (Riggs et al., 2012).
The effects of
marijuana on female reproductive system functionality differ between humans
and animals. In monkeys, delta
9
-
THC administration suppressed ovulation (Asch et al., .
1981) and reduced progesterone levels (Almirez et al., 1983). However, in women, smoked
marijuana did not alter hormone levels or the menstrual cycle (Mendelson and Mello, 1984).
Brown and Dobs (2002) suggest that the development oftolerance in humans may be the
cause ofthe discrepancies between animal and human hormonal response to cannabinoids.
The presence ofin vitro delta
9
-THC reduces binding ofthe corticosteroid, dexamethasone, in
hippocampal tissue from adrenalectomized rats, suggesting an interaction with the
glucocorticoid receptor (Eldridge et al., 1991 ). Although acute delta
9
-
THC presence releases
corticosterone, tolerance develops in rats with chronic administration (Eldridge et al., 1991).
Some studies support a possible association between frequent, long-term marijuana use and
increased risk of
testicular germ cell tumors (Trabert et al., 201 1). On the other hand, recent
data suggest that cannabinoid agonists may have therapeutic value in the treatment of .
prostate cancer, a type of
carcinoma in which growth is stimulated by androgens. Research
with prostate cancer cells shows that the mixed CB
1
/CB
2
agonist, WIN-55212-2, induces
apoptosis in prostate cancer cells, as well as decreases the expression of
androgen receptors
and prostate-specific antigens (Sarfaraz et al., 2005).
Immune System
Cannabinoids affect the immune system in mari.y different ways. Synthetic, natural, and
endogenous cannabinoids often cause different effects in a dose-dependent biphasic manner
(Croxford and Yamamura, 2005; Tanasescu and Constantinescu, 2010).
Studies in humans and animals give conflicting results about cannabinoid effects on immune
functioning in subjects with compromised immune systems. Abrams et al. (2003)
investigated marijuana's effect on immunological furlctioning in 62 AIDS patients taking.
protease inhibitors. Subjects received one of
the following three times a day: a smoked
marijuana cigarette containing 3.95 percent delta
9
-
THC, an oral tablet containing delta
9
-
THC
(2.5 mg oral dronabinol), or an oral placebo. The results showed no changes in CD4+ and
CD8+ cell counts, HIV RNA levels, or protease inhibitor levels between groups. Thus, the
use of
cannabinoids showed no short-term adverse virologic effects in individuals with
compromised immune systems. However, these human data contrast with data generated in
immunodeficient mice, which demonstrated that exposure to delta
9
-THC in vivo suppresses
18
immune function, increases HIV co-receptor expression, and acts as a cofactor to enhance
HIV replication (Roth et al., 2005).
3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE DRUG OR
OTHER SUBSTANCE
Under the third factor, the Secretary must consider the state of
current scientific knowledge
regarding marijuana. Thus, this section discusses the chemistry, human pharmacokinetics,
and medical uses of
marijuana.
Chemistry
Marijuana is one of
the common names of Cannabis sativa L. in the family Cannabaceae.
Cannabis is one ofthe oldest cultivated crops, providing a source of
fiber, food, oil, and
drug. Botanists still debate whether Cannabis should be considered as a single (The Plant
List, 201 0) or three species, i.e., C. sativa, C. indica, and C. ruderalis (Hillig, 2005).
Specifically, marijuana is developed as sativa and indica cultivated varieties (strains) or
various hybrids.
The petition defines marijuana as including all Cannabis cultivated strains. Different
marijuana samples derived from various cultivated strains may have very different chemical
constituents including delta
9
-THC and other cannabinoids (Appendino et al., 2011). As a
consequence, marijuana products from different strains will have different safety, biological,
pharmacological, and toxicological profiles. Thus, all Cannabis strains cannot be considered
together because of
the varying chemical constituents between strains.
Marijuana contains numerous naturally occurring constituents including cannabinoids.
Overall, various Cannabis strains contain more than 525 identified natural constituents.
Among those constituents, the most important ones are the 21 (or 22) carbon terpenoids
found in the plant, as well as their carboxylic acids, analogues, and transformation products,
known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 1973; Appendino et al.,
2011). Thus far, more than 100 compounds classified as cannabinoids have been
characterized (ElSohly and Slade, 2005; Radwan, ElSohly et al., 2009; Appendino et al.
2011 ).
Cannabinoids primarily exist in Cannabis, and published data suggest that most major
cannabinoid compounds occurring naturally have been chemically identified. New and
minor cannabinoids and other new compounds are continuously being characterized
(Pollastro et al., 2011). So far, only two cannabinoids (cannabigerol and its corresponding
acid) have been obtained from a non-Cannabis source. A South African Helichrysum (H
umbraculigerum) accumulates these compounds (Appendino et al. 2011 ).
Among the cannabin~ids found in marijuana, delta
9
-THC (alternate name delta
1
-THC) and
delta-8-tetrahydrocannabinol ( delta
8
-
THC, alternate name delta
6
-THC) produce marijuana's
characteristic psychoactive effects. Because delta
9
-
TH C is more abundant than delta
8
-THC,
19
marijuana's psychoactivity is lar~ely attributed to the former. Only a few varieties of
marijuana analyzed contain delta-THC at significant amounts (Hively et al., 1966). Delta
9
-
THC is an optically active resinous substance, insoluble in water, and extremely lipid-
soluble. Chemically, delta
9
-11IC is ( 6aR-trans )-6a, 7 ,8, 1 Oa-tetrahydro-6,6,9-trimethy 1-3-
pentyl-6H-dibenzo-[b,d]pyran-1-ol, or ( -)-delta9-(trans)-tetrahydrocannabinol. The (-)-trans
isomer ofdelta
9
-
THC is pharmacologically 6-100 times more potent than the (+)-trans
isomer (Dewey et al., 1984).
Other cannabinoids present in marijuana include CBD, CBC, and CBN. CBD, a major
cannabinoid of
marijuana, is insoluble in water and lipid-soluble. Chemically, CBD is 2-
[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD .
does not have cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al., 1984,
1986; Hollister, 1986). CBC is another major cannabinoid in marijuana. Chemically, CBC
is 2-methyl-2-( 4-methylpent-3-enyl)-7-pentyl:-5-chromenol. CBN, a major metabolite of
delta
9
-THC, is also a minor naturally-occurring cannabinoid with weak psychoactivity.
Chemically, CBN is 6,6,9-trimethyl-3-pentyl-benzo[ c ]chromen-1-ol.
Different marijuana samples derived from various cultivated strains may differ in chemical
constituents including delta
9
-
THC and other cannabinoids (Appendino et al. 2011 ). As a
consequence, marijuana products from different strains may have different safety, biological,
pharmacological, and toxicological profiles. In addition to differences between cultivated
strains, the concentration of
delta
9
-11IC and other cannabinoids in marijuana may vary with
growing conditions and processing after harvest. In addition to genetic differences among
Cannabis species, the plant parts collected-for example, flowers, leaves, and stems--can
influence marijuana's potency, quality, and purity (Adams and Martin, 1996; Agurell et al.,
1984; Mechoulam, 1973). All these variations produce marijuana with potencies, as
indicated by cannabinoid content, on average from as low as 1-2 percent to as high as 17
percent.
Overall, these variations in the concentrations of
cannabinoids and other chemical
constituents in marijuana complicate the interpretation of
clinical data using marijuana. The
lack of consistent concentrations of
delta
9
-
THC and other substances in marijuana from
diverse sources makes interpreting the effect of
different marijuana constituents difficult. In
addition to different cannabinoid concentrations having different pharmacological and
toxicological.profiles, the non~cannabinoid components in maiijuana, such as other
terpe~oids and flavonoids, might also contribute to the overall pharmacological and
toxicological profiles of various marijuana strains and products derived from those strains.
The term marijuana is often used to refer to a mixture of
the dried flowering tops and leaves
from Cannabis. Marijuana in this limiting definition is one of
three major derivatives sold as
separate illicit products, which also include hashish and hash oil. According to the DEA,
Cannabis sativa is the primary species of Cannabis currently marketed illegally in the United
States.
Marijuana can vary in cannabinoid content and potency (Agurell et al., 1984, 1986;
Mechoulam 1973, Cascini et al., 2012). In the usual mixture of
leaves and stems distributed
20
as marijuana, the concentration of
delta
9
-THC averages over 12 percent by weight.
However, specially grown and selected marijuana can contain 15 percent or greater delta
9
-
THC (Appendino et al. 2011). Thus, a 1-gram marijuana cigarette might contain delta
9
-THC
in a range from as little as 3 milligrams to as much as 150 milligrams or more. Additionally,
a recent systematic review and meta-analysis found that marijuana's delta
9
-
THC content has
increased significantly from 1979-2009 (Cascini et al., 2012). In addition to smoking
marijuana, individuals ingest marijuana through food made with butter or oil infused with
marijuana and its extracts. These marijuana butters are generally made by adding marijuana
to butter and heating it. The resultant butter is then used to cook a variety of foods. There
are no published studies measuring the concentrations of cannabinoids in these marijuana
food products.
Hashish consists ofthe dried and compressed cannabinoid-rich resinous material of
Cannabis
and comes in a variety of forms (e.g. balls and cakes). Individuals may break off
pieces,
place it into a pipe and smoke it. DEA reports that cannabinoid content in hashish averages
six percent (DEA, 2005). With the development and cultivation of more high potency
Cannabis strains, the average cannabinoid content in hashish will likely increase.
Hash oil is produced by solvent extraction ofthe cannabinoids from plant material. The
extract's color and odor vary, depending on the solvent type used. Hash oil is a viscous
brown-
or amber-colored liquid containing approximately 50 percent cannabinoids. One or
two drops ofthe liquid placed on a cigarette purportedly produce the equivalent of
a single
marijuana cigarette (DEA, 2005).
In conclusion, marijuana has hundreds of
cultivars containing variable concentrations of
delta
9
-THC, cannabinoids, and other compounds. Thus, marijuana is not a single chemical
with a consistent and reproducible chemical profile or predictable and consistent clinical
effects. A guidance for industry, entitled Botanical Drug Products,
4
provides information on
the approval of botanical drug products. To investigate marijuana for medical use in a
manner acceptable as support for marketing approval under an NDA, clinical studies under
an IND of
consistent batches of
a particular marijuana product for particular disease
indications should be conducted. In addition, information and data regarding the marijuana
product's chemistry, manufacturing and control, pharmacology, and animal toxicology data,
among others must be provided and meet the requirements for new drug approval (See 21
CFR 314.50).
Human Pharmacokinetics
Marijuana can be taken in a variety of formulations by multiple routes of
administration.
Individuals smoke marijuana as a cigarette, weighing between 0.5 and 1.0 gram, or in a pipe.
Additionally, individuals take marijuana orally in foods or as an extract in ethanol or other
solvents. More recently, access to vaporizers provides another means for abusers to inhale
marijuana,
This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
21
4
The absorption, metabolism, and pharrnacokinetic profile of delta
9
-
THC, cannabinoids, and
drug products containing delta
9
-
THC vary with route of administration and formulation
(Adams and Martin, 1996; Agurell et al., 1984, 1986).
Pharmacokinetics of Smoked Administration of Cannabinoids
Characterization ofthe pharmacokinetics of delta
9
-THC and other cannabinoids from smoked
marijuana is difficult because a subject's smoking behavior during an experiment varies
(Agurell et al., 1986; Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a
discrete dose of
delta
9
._THC. An experienced marijuana smoker can titrate and regulate the
dose to obtain the desired acute psychological effects and minimize undesired effects. For
example, under naturalistic conditions, users hold marijuana smoke in their lungs for an
extended period of
time which causes prolonged absorption and.increases psychoactive
effects. The effect of experience in the psychological response may explain why delta
9
-
THC
venous blood levels correlate poorly with intensity of effects and intoxication level (Agurell
et al. 1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation volumes should be
recorded in studies as the concentration (dose) of cannabinoids administered can vary at
different stages of
smoking.
Smoked marijuana results in absorption of
delta
9
-
11-IC in the form of
an aerosol within
seconds. Psychoactive effects occur immediately following absorption, with mental and
behavioral effects measurable for up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988).
Delta
9
-
THC is delivered to the brain rapidly and efficiently as expected of
a very lipid-
soluble drug.
The bioavailability of
the delta
9
-
THC, from marijuana in a cigarette or pi.pe, can range from 1
to 24 percent with the fraction absorbed rarely exceeding I 0 to 20 percent (Agurell et al.,
1986; Hollister, 1988). The relatively low and variable bioavailability results from
significant loss of
delta
9
-
THC in side-stream smoke, variation in individual smoking
behaviors, cannabinoid pyrolysis, incomplete absorption of inhaled smoke, and metabolism
in the lungs. An individual's experience and technique with smoking marijuana also
determines the dose absorbed (Heming et al., 1986; Johansson et al., 1989). After smoking,
delta
9
-THC venous levels decline precipitously within minutes, and continue to go down to
about 5 to 10 percent ofthe peak level within an hour (Agurell et al., 1986, Huestis et al.,
1992a, 1992b ).
Pharmacokinetics for Oral Administration of Cannabinoids
After oral administration of
delta
9
-
THC or marijuana, the onset of effects starts within 30 to
90 minutes, reaches its peak after 2 to 3 hours and then remains for 4 to 12 hours
(Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984, 1986). Due to the
delay in onset of
effects, users have difficulty in titrating oral delta
9
-
THC doses compared to
smoking marijuana. Oral bioavailability of delta
9
-
THC, whether pure or in marijuana, is low
and extremely variable, ranging between 5 and 20 percent (Agurell et al., 1984, 1986).
Following oral administration of
radioactive-labeled delta
9
-
THC, de
lta
9
-THC plasma levels
are low relative to plasma levels after smoking or intravenous administration. Inter-
and
22
intra-subject variability occurs even with repeated dosing under controlled conditions. The
low and variable oral bioavailability of
delta
9
-
THC is a consequence of
its first-pass hepatic
elimination from blood and erratic absorption from stomach and bowel.
Cannabinoid Metabolism and Excretion
Cannabinoid metabolism is complex. Delta
9
-
THC is metabolized via microsomal
hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, 1972b;
Agurell et al., 1986; Hollister, 1988). The primary active metabolite of
delta
9
-THC
following oral ingestion is 11-hydroxy-delta
9
-
THC. This metabolite is approximately
equipotent to delta
9
-THC in producing marijuana-like S'!lbjective effects (Agurell et al., 1986,
Lemberger and Rubin, 1975). After oral administration, metabolite levels may exceed that of
delta
9
-THC and thus contribute greatly to the pharmacological effects of oral delta
9
-THC or
marijuana.
Plasma clearance of delta
9
-
THC approximates hepatic blood flow at about 950 ml/rnin or
greater. The rapid disappearance of delta
9
-
THC from blood is largely due to redistribution to
other tissues in the body, rather than to metabolism (Agurell et al., 1984, 1986). Metabolism
in most tissues is relatively slow or absent. Slow release of delta
9
-
THC and other
cannabinoids from tissues and subsequent metabolism results in a long elimination half-life.
The terminal half-life of
delta
9
-
THC ranges from approximately 20 hours to as long as 10 to
13 days, though reported estimates vary as expected with any slowly cleared substance and
the use of assays with variable sensitivities (Hunt and Jones, 1980). Lemberger et al. (1970)
determined the half-life of
delta
9
-THC to range from 23 to 28 hours in heavy marijuana users
to 60 to 70 hours in naive users. In addition to 11-hydroxy-delta
9
-THC, some inactive
carboxy metabolites have terminal half-lives of
50 hours to 6 days or more. The latter
substances serve as long-term markers in urine tests for earlier marijuana use.
The majority ofthe absorbed delta
9
...THC dose is eliminated in feces, and about 33 percent in
urine. Delta
9
-THC enters enterohepatic circulation and undergoes hydroxylation and
oxidation to 11-nor-9-carboxy-delta
9
-
THC. The glucuronide is excreted as the major urine
metabolite along with about 18 non-conjugated metabolites. Frequent and infrequent
marijuana users metabolize delta
9
-
THC similarly (Agurell et al., 1986).
Status of
Research into the Medical Uses for Marijuana
State-level public initiatives, including laws and referenda in support ofthe medical use of
marijuana, have generated interest in the medical community and the need for high quality
clinical investigation as well as comprehensive safety and effectiveness data. In order to
address the need for high quality clinical investigations, the state of California established the
Center for Medicinal Cannabis Research (CMCR, www.cmcr.ucsd.edu) in 2000 "in response
to scientific evidence for therapeutic possibilities of
cannabis
5
and local legislative initiatives
in favor of
compassionate use" (Grant, 2005). State legislation establishing the CMCR
called for high quality medical research that would "enhance understanding of
the efficacy
and adverse effects of
marijuana as a pharmacological agent," but stressed the project
5
In this quotation the term cannabis is interchangeable with marijuana
23
"should not be construed as encouraging or sanctioning the social or recreational use of
marijuana." The CMCR funded many of
the published studies on marijuana's potential use
for treating multiple sclerosis, neuropathic pain, appetite suppression and cachexia.
However, aside from the data produced by CMCR, no state-level medical marijuana laws
have produced scientific data on marijuana's safety and effectiveness.
FDA approves medical use of a drug following a submission and review of
an NDA or BLA.
The FDA has not approved any drug product containing marijuana for marketing. Even so,
results of
small clinical exploratory studies have been published in the current medical
literature. Many studies describe human research. with marijuana in the United States under
FDA-regulated IND applications.
However, FDA approval of
an NDA is not the only means through which a drug can have a
currently accepted medical use in treatment in the United States. In general, a drug may have
a "currently accepted medical use" in treatment in the United States if
the drug meets a five-
part test. Established case law (Alliance forCannabis Therapeutics v. DEA, 15 F.3d 1131,
1135 (D.C. Cir. 1994)) upheld the Administrator ofDEA's application of
the five-part test to
determine whether a drug has a "currently accepted medical use." The following describes
the five elements that characterize "currently accepted medical use" for a drug
6
:
i. the drug's chemistry must be known and reproducible
"The sub!?tance's chemistry must be scientifically established to permit it to be
reproduced into dosages which can be standardized. The listing of
the substance
in a current edition ofone of
the official compendia, as defmed by section 201(j)
of
the Food, Drug and Cosmetic Act, 21 U.S.C. 3210), is sufficient to meet this
requirement."
11. there must be adequate safety studies
"There must be adequate pharmacological and toxicological studies, done by all
methods reasonably applicable, on the basis of
which it could fairly and
responsibly be concluded, by experts qualified by scientific training and
experience to evaluate the safety and effectiveness ofdrugs, that the substance is
safe for treating a specific, recognized disorder."
iii. there must be adequate and well-controlled studies proving efficacy
. "There must be adequate, well-controlled, well-designed, well-conducted, and
well-documented studies, including clinical investigations, by experts qualified by
scientific training and experience to evaluate the safety and effectiveness of
drugs,
on the basis ofwhich it could be fairly and responsibly concluded by such experts
that the substance will have the intended effect in treating a specific, recognized
disorder."
6
57 FR 10499, 10504-06 (March 26, 1992).
24
IV. the drug must be accepted by qualified experts
"The drug has a New Drug Application (NDA) approved by the Food and Drug
Administration, pursuant to the Food, Drug and Cosmetic Act, 21 U.S.C. 355. Or,
a consensus of
the national coiil.l11unity ofexperts, qualified by scientific training
and experience to evaluate the safety and effectiveness of drugs, accepts the
safety and effectiveness of
the substance for use in treating a specific, recognized
disorder. A material conflict of
opinion among experts precludes a finding of
consensus." and
v. the scientific evidence must be widely available.
"In the absence ofNDA approval, information concerning the chemistry,
pharmacology, toxicology, and effectiveness of
the substance must be reported,
published, or otherwise widely available, in sufficient detail to permit experts,
qualified by scientific training and experience to evaluate the safety and
effectiveness ofdrugs, to fairly and responsibly conclude the substance is safe and
effective for use in treating a specific, recognized disorder."
Marijuana does not meet any of
the five elements necessary for a drug to have a "currently
accepted medical use."
Firstly, the chemistry of marijuana, as defined in the petition, is not reproducible in terms of
creating a standardized dose. The petition defines marijuana as including all Cannabis
cultivated strains. Different marijuana samples derived from various cultivated strains may
have very different chemical constituents including delta
9
-
THC and othercannabinoids
(Appendino et al., 2011). As a consequence, marijuana products from different s:trains will
have different safety, biological, pharmacological, and toxicological profiles. Thus, when
considering all Cannabis strains together, because of
the varying chemical constituents,
reproducing consistent standardized doses is not possible. Additionally, smoking marijuana
currently has not been shown to allow delivery of
consistent and reproducible doses.
However, if
a specific Cannabis strain is grown and processed under strictly controlled
conditions, the plant chemistry may be kept consistent enough to produce reproducible and
standardized doses.
As to the second and third criteria; there are neither adequate safety studies nor adequate and
well:..controlled studies proving marijuana's efficacy. To support the petitioners' assertion
that marijuana has accepted medical use, the petitioners cite the American Medical
Association's (AMA) 2009 report entitled "Use of Cannabis for Medicinal Purposes." The
petitioners claim the AMA report is evidence the AMA accepts marijuana's safety and
efficacy. However, the 2009 AMA report clarifies that the report "should not be viewed as
an endorsement of state-based medical cannabis programs, the legalization of
marijuana, or
25
that scientific evidence on the therapeutic use of
cannabis meets the same and current
standards for a prescription drug product."
7
Currently, no published studies conducted with marijuana meet the criteria of
an adequate
and well-controlled efficacy study. The criteria for an adequate and well-controlled study for
purposes of
determining the safety and efficacy of a human drug are defined under the Code
of
Federal Regulations (CFR) in 21 CPR 314.126. In order to assess this element, FDA
conducted a review of clinical studies published and available in the public domain before
February, 2013. Studies were identified through a search ofPubMed
8
for articles published
from inception to February 2013, for randomized controlled trials using marijuana to assess
marijuana's efficacy in any therapeutic indication. Additionally, the review included studies
identified through a search of
bibliographic references in relevant systematic reviews and
identified studies presenting original research in any language. Selected studies needed to be
placebo-controlled and double-blinded. Additionally, studies needed to encompass
administered marijuana plant material. There was no requirement for any specific route of
administration, nor any age limits on study subjects. Studies were excluded that used
placebo marijuana supplemented by the addition of
specific arriounts of
THC or other
cannabinoids. Additionally, studies administering marijuana plant extracts were excluded.
The PubMed search yielded a total of
566 abstracts of
scientific articles. Ofthese abstracts, a
full-text review was conducted with 85 papers to assess eligibility. Of
the studies identified
through the search ofthe references and the 566 abstracts from the PubMed search, only 11
studies met all the criteria for selection (Abrams et al., 2007; Corey-Bloom et al., 2012;
Crawford and Merritt, 1979; Ellis et al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt
et al., 1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008; Wilsey et al., 2013).
These 11 studies were published between 1974 and 2013. Ten of
these studies were
conducted in the United States and one study was conducted in Canada. The identified
studies examine the effects of
smoked and vaporized marijuana for the indications ofchronic
neuropathic pain, spasticity related to Multiple Sclerosis (MS), appetite stimulation in human
immunodeficiency virus (HIV) patients, glaucoma, and asthma. All studies used adult
subjects. .
The 11 identified studies were individually evaluated to determine if
they successfully meet
accepted scientific standards. Specifically, they were evaluated on study design including
subject selection criteria, sample size, blinding techniques, dosing paradigms, outcome
measures, and the statistical analysis of
the results. The analysis relied on published studies,
thus information available about protocols, procedures, and results were limited to
documents published and widely available in the public domain. The review found that all
11 studies that examined effects ofinhaled marijuana do not currently prove efficacy of
marijuana in any therapeutic indication based on a number of limitations in their study
design; however, they may be considered proof
of concept studies. Proof ofconcept studies
provide preliminary evidence on a proposed hypothesis involving a drug's effect. For drugs
under development, the effect often relates to a short-term clinical outcome being
7
In this quotati9n the term cannabis is used interchangeably for marijuana.
8
The following search strategy was used, "(cannabis OR marijuana) AND (therapeutic use OR therapy) AND (RCT
OR randomized controlled trial OR "systematic review" OR clinical trial OR clinical trials) NOT ("marijuana
abuse"[Mesh] OR addictive behavior OR substance related disorders)."
26
investigated. Proof of
concept studies often serve as the link between preclinical studies and
dose ranging clinical studies. Thus, proof
of
concept studies generally are not sufficient to
prove efficacy of
a drug because they provide only preliminary information about the effects
of a drug.
In addition to the lack ofpublished adequate and well-controlled efficacy studies proving
efficacy, the criteria for adequate safety studies has also not been met. Importantly, in its
discussion of the five-part test used to determine whether a drug has a "currently accepted
medical use," DEA said, "No drug can be considered safe in the abstract. Safety has
meaning only whenjudged against the intended use of the drug, its known effectiveness, its
known and potential risks, the severity of
the .illness to be treated, and the availability of
alternative remedies" (57 FR 1 0504). When determining whether a drug product is safe and
effective for any indication, FDA performs an extensive risk-benefit analysis to determine
whether the risks posed by the drug product's side effects are outweighed by the drug
product's potential benefits for a particular indication. Thus, contrary to the petitioner's
assertion that marijuana has accepted safety, in the absence of an accepted therapeutic
indication which can be weighed against marijuana's risks, marijuana does not satisfy the
element for having adequate safety studies such that experts may conclude that it is safe for
treating a specific, recognized disorder.
The fourth of the five elements for determining "currently accepted medical use" requires
that the national community of experts, qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of
the
substance for use in treating a specific, recognized disorder. A material conflict of
opinion
among experts precludes a finding of
consensus. Medical practitioners who are not experts
in evaluating drugs are not qualified to determine whether a drug is generally recognized as
safe and effective or meets NDA requirements (57 FR 10499, 1 0505).
There is no evidence that there is a consensus among qualified experts that marijuana is safe
and effective for use in treating a specific, recognized disorder. As discussed above, there
are not adequate scientific studies that show marijuana is safe and effective in treating a
specific, recognized disorder. In addition, there is no evidence that a consensus of qualified
experts have accepted the safety and effectiveness of marijuana for use in treating a specific,
recognized disorder. Although medical practitioners are not qualif1ed by scientific training
and experience to evaluate the safety and effectiveness of
drugs, we also note that the AMA's
report, entitled "Use of
Cannabis for Medicinal Purposes," does not accept that marijuana
currently has accepted medical use. Furthermore, based on the above definition of a
"qualified expert", who is an individual qualified by scientific training and experience to
evaluate the safety and effectiveness of
a drug, state-level medical marijuana laws do not
provide evidence of a consensus among qualified experts that marijuana is safe and effective
for use in treating a specific, recognized disorder.
As to the fifth part ofthe test, which requires that information concerning the chemistry,
pharmacology, toxicology, and effectiveness of
marijuana to be reported in sufficient detail,
the scientific evidence regarding all ofthese aspects is not available in sufficient detail to
allow adequate scientific scrutiny. Specifically, the scientific evidence regarding marijuana's
27
chemistry in terms of a specific Cannabis strain that could produce standardized and
reproducible doses is not currently available.
Alternately, a drug can be considered to have a "currently accepted medical use with severe
restrictions" (21 U.S.C. 812(b)(2)(B)), as allowed under the stipulations for a Schedule II
drug. Yet, as stated above, currently marijuana does not have any accepted medical use,
even under conditions where its use is severely restricted.
In conchision, to date, research on marijuana's medical use has not progressed to the point
where marijuana is considered to have a "currently accepted medical use" or a "currently
accepted medical use with severe restrictions."
4. ITS IDSTORY AND CURRENT PATTERN OF ABUSE
Under the fourth factor, the Secretary must consider the history and current pattern of
marijuana abuse. A variety of
sources provide data necessary to assess abuse patterns and
trends of
marijuana. The data indicators of
marijuana use include the NSDUH, MTF,
DAWN, and TEDS. The following briefly describes each data source, and summarizes the
.data from each source.
National Survey on Drug Use and Health (NSDUH)
9
According to 2012 NSDUH
10
data, the most recent year with complete data, the use of
illicit
drugs, including marijuana, is increasing. The 2012 NSDUH estimates that 23.9 million
individuals over 12 years of
age (9.2 percent of
the U.S. population) currently use illicit
drugs, which is an increase of4.8 million individuals from 2004 when 19.1 million
individuals (7.9 percent of
the U.S. population) were current illicit drug users. NSDUH
reports marijuana as the most commonly used illicit drug, with 18.9 million individuals (7.3
percent of
the U.S. population) currently using marijuana in 2012. This represents an
increase of
4.3 million individuals from 2004, when 14.6 million individuals (6.1 percent of
the U.S. population) were current marijuana users.
The majority of individuals who try marijuana at least once in their lifetime do not currently
use marijuana. The 2012 NSDUH estimates that 111.2 million individuals (42.8 percent of
the U.S. population) have used marijuana at least once in their lifetime. Based on this
estimate and the estimate for the number of individuals currently using marijuana,
approximately 16.9 percent ofthose who have tried marijuana at least once in their lifetime
9
NSDUH provides national estimates of
the prevalence and incidence ofillicit drug, alcohol and tobacco use in the
United States. NSDUH is an annual study conducted by SAMHSA. Prior to 2002, the database was known as the
National Household Survey on Drug Abuse (NHSDA). NSDUH utilizes a nationally representative sample of
United States civilian, non-institutionalized population aged 12 y.ears and older. The survey excludes homeless
people who do not use shelters, active military persormel, and residents of institutional group quarters such as jails
and hospitals. The survey identifies whether an individual used a drug within a specific time period, but does not
identify the amount of
the drug used on each occasion. NSDUH defines "current use" as having used the substance
within the month prior to the study.
.
10
2013; http://www.samhsa.gov/data/NSDUH.aspx
28
currently use marijuana; conversely, 83.1 percent do not currently use marijuana. In terms of
the frequency of
marijuana use, an estimated 40.3 percent of
individuals who used marijuana
in the past month used marijuana on 20 or more days within the past month. This amount
corresponds to an estimated 7.6 million individuals who used marijuana on a daily or almost
daily basis.
Some characteristics of
marijuana users are related to age, gender, and criminal justice
system involvement. In observing use among different age cohorts, the majority of
individuals who currently use marijuana are shown to be between the ages of 18-25, with
1K7 percent of
this age group currently using marijuana. In the 26 and older age group, 5.3
percent of
individuals currently use marijuana. Additionally, in individuals aged.12 years
and older, males reported more current marijuana use than females.
NSDUH includes a series of
questions aimed at assessing the prevalence of
dependence and
abuse of
different substances in the past 12 months.
11
In 2012, marijuana was the most
common illicit drug reported by individuals with past year dependence or abuse. An
estimated 4.3 million individuals meet the NSDUH criteria for marijuana dependence or
abuse in 2012. The estimated rates and number of
individuals with marijuana dependence or
abuse has remained similar from 2002 to 2012. In addition to data on dependence and abuse,
NSDUH includes questions aimed at assessing treatment for a substance use problem.
12
In
2012, an estimated 957,000 persons received treatment for marijuana use during their most
recent treatment in the year prior to the survey.
Monitoring the Future CMTF)
13
According to MTF,
14
rates of
marijuana and illicit drug use declined for all three grades from
2005 through 2007. However, starting around 2008, rates of annual use of illicit drugs and
11
"These questions are used to classify persons as dependent on or abusing specific substances based on criteria
specified in the Diagnostic and Statistical Manual ofMental Disorder, 4th edition (DSM-IV). The questions related
to dependence ask about health and emotional problems associated with substance use, unsuccessful attempts to cut
down on use, tolerance, withdrawal, reducing other activities to use substances, spending a lot of
time engaging in
activities related to substance use, or using the substance in greater quantities or for longer time than intended. The
questions on abuse ask about problems at work, home, and school; problems with family or friends; physical danger;
and trouble with the law due to substance use. Dependence is considered to be a more severe substance use problem
than abuse because it involves the psychological and physiological effects oftolerance and withdrawal." (NSDUH,
2013)
12
"Estimates ... refer to treatment received for illicit drug or alcohol use, or for medical problems associated with the
use of
illicit drugs or alcohol. This inciudes treatment received in the past year at any location, such as a hospital
(inpatient), rehabilitation facility (outpatient or inpatient), mental health center, emergency room, private doctor's
office, prison or jail, or a self-help group, such as Alcoholics Anonymous or Narcotics Anonymous." (NSDUH,
2013).
13
Monitoring the Future is a national survey that tracks drug use prevalence and trends among adolescents in the
United States. MTF is reported annually by the Institute for Social Research at the University of
Michigan under a
grant from NIDA. Every spring, MTF surveys 8
1
\ lOu., and 12th gmders in randomly selected U.S. schools. MTF
has been conducted since 1975 for 12"' graders and since !991 for 8th and 10
111
graders. The MTF survey presents
data in tenns of
prevalence among the sample interviewed. For 4012, the latest year with complete data, the sample
sizes were 15,200
-
8 graders; 13,300 -
IOth gmders; and 13,200-
12m graders. In all, a total of
about 41,700
students of389 schools participated in the 2013 MTF.
14
20
13; http://www.monitoringthefuture.org/index.html
29
marijuana increased through 2013 for all three grades. Marijuana remained the most widely
used illicit drug during all time periods. The prevalence of
annual and past month marijuana
use in 10
1
h and 12th graders in 2013 is greater than in 2005. Table llists the lifetime, annual,
and monthly prevalence rates ofvanous drugs for 8th, lOth and 12th graders in 2013.
Table 1: Trends in lifetime, annual, and monthly prevalence of use of various drugs
for eighth, tenth, and twelfth graders. Percentages represent students in survey
responding that they had used a drug at least once in their lifetime, in the past year,
or in the past 30 days.
Lifetime Annual 30-Day
2011 2012 2013 2011 2012 2013 2011 2012 2013
Any illicit Dru2 (a)
8
111
Grade 20.1 18.5 20.3 14.7 13.4 14.9 8'.5
7.7 8.5
!Om Grade 37.7 36.8 38.8 3l.l 30.1 31.8 19.2 18.6 19.4
12m Grade 49.9 49.1 50.4 40.0 39.7 40.3 25.2 25.2 25.5
Marijuana/Hashish
8
111
Grade 16.4 15.2 16.5 12.5 11.4 12.7 7.2 6.5 7.0
10
1
" Grade 34.5 33.8 35.8 28.8 28.0 29.8 17.6 17.0 18.0
12m Grade 45.5 45.2 45.5 36.4 36.4 36.4 22.6 22.9 22.7
SOURCE: The Monitoring the Future Study, the University of Michigan
a. For 12th graders only: "any illicit drug" includes any use ofmarijuana, LSD, other hallucinogens, crack,
other cocaine, or heroin; or any narcotics use other than heroin, amphetamines, sedatives (barbiturates), or
tranquilizers not under a doctor'
s orders. For 8th andl0
1
h graders only: the use of narcotics other than
heroin and sedatives (barbiturates) was excluded.
Drug Abuse Warning Network (DAWN)
15
Importantly, many factors crui influence the estimates ofED visits, including trends in
overall use of
a substance as well as trends in the reasons for ED usage. For instance, some
drug users may visit EDs for life-threatening issues while others may visit to seek care for
. detoxification because they needed certification before entering treatment. Additionally,
DAWN data do not distinguish the drug responsible for the ED visit from other drugs that
may have been used concomitantly. As stated in aDAWN report, "Since marijuana/hashish
is frequently present in combination with other drugs, the reason for the ED visit may be
more relevant to the other drug(s) involved in the episode."
For 2011, DA WN
16
estimates a total of5,067,374 (95 percent confidence interval [CI]:
4,616,753 to 5,517,995) drug-related ED visits from the entire United States. Ofthese,
approximately 2,462,948 ([CI]: 2,112,868 to 2,813,028) visits involved drug misuse or abuse.
15
DAWN is a national probability survey of the U.S. hospitals with ED designed to obtain infonnation on drug-
related ED visits. DAWN is sponsored by SAMHSA. The DAWN system provides information on the health
consequences ofdrug use in the United States, as manifested by drug-related visits to ED. The ED data from a
representative sample of
hospital emergency departments are weighted to produce national estimates. Importantly,
. DAWN data and estimates, starting in 2004, are not comparable to those for prior years because of vast changes in
the methodology used to collect the data. Furthermore, estimates for 2004 are the flrst to be based on a redesigned
sample of hospitals, which ended in 20 II .
16
2011; http://www.samhsa.gov/data/dawn.aspx
30
During the same period, DAWN estimates that 1,252,500 (CI: 976,169 to 1,528,831) drug-
related ED visits involved illicit drugs. Thus,. over half
of
all drug-related ED visits
associated with drug misuse or abuse involved an illicit-drug. For ED visits involving illicit
drugs, 56.3 percent involved multiple drugs while 43.7 percent involved a single drug.
Marijuana was involved in 455,668 ED visits (CI: 370,995 to 540,340), while cocaine was
involved in 505,224 (CI: 324,262 to 686,185) ED visits, heroin was involved in 258,482 (CI:
205,046 to 311,918) ED visits and stimulants including amphetamine and methamphetamine
were involved in 159,840 (CI: 100,199 to 219,481) ED visits. Other illicit drugs, such as
PCP, MDMA, GHB and LSD were much less frequently associated with ED visits. The
number of
ED visits involving marijuana has increased by 62 percent since 2004.
Marijuana-related ED visits were most frequent among young adults and minors. Individuals
under the age of 18 accounted for 13.2 percent of
these marijuana-related visits, whereas this
age group accounted for approximately 1.2 percent of
ED visits involving cocaine, and less
than 1 percent of
ED visits involving heroin. However, the age group with the most
marijuana-related ED visits was between 25 and 29 years old. Yet, because populations
differ between age groups, a standardized measure for population size is useful to make
comparisons. For marijuana, the rates ofED visits per 100,000 population were highest for
patients aged 18 to 20 (443.8 ED visits per 100,000) and for patients aged 21 to 24 (446.9 ED
visits per 100,000).
While DAWN provides estim&tes for ED visits associated with the use of medical marijuana
for 2009-2011, the validity ofthese estimates is questionable. Because the drug is not
approved by the FDA, reP.orting medical marijuana may be inconsistent and reliant on a
number of
factors including whetherthe patient self-reports the marijuana use as medicinal,
how the treating health care provider records the marijuana use, and lastly how the SAMHSA
coder interprets the report. All ofthese aspects will vary greatly between states with medical
marijuana laws and states without medical marijuana laws. Thus, even though estimates are
reported for medical marijuana related ED visits, medical marijuana estimates cannot be
assessed with any acceptable accuracy at this time, as FDA has not approved marijuana
treatment of
any medical condition. These data show the difficulty in evaluating abuse of a
product that is not currently approved by FDA, but authorized for medical use, albeit
inconsistently, at the state level. Thus, we believe the likelihood of the treating health care
provider or SAMHSA coder attributing the ED visit to "medical marijuana" versus
"marijuana" to be very low. Overall, the available data are inadequate to characterize its
abuse at the community level.
Treatment Episode Data Set (TEDS)
17
17
The TEDS system is part of
SAMHSA
's Drug and Alcohol Services Information System (Office of
Applied
Science, SAMHSA). The TEDS report presents information on the demographic and substance use characteristics
ofthe 1.8 million annual admissions to treatment for alcohol aitd drug abuse in facilities that report to individual
state administrative data systems. Specifically, TEDS includes facilities licensed or certified by the states to provide
substance abuse treatment and is required by the states to provide TEDS client-level data. Facilities that report
TEDS data are those receiving State alcohol and drug agency funds for the provision of alcohol and drug treatment
services. Since TEDS is based only on reports from these facilities, TEDS data do not represent the total national
demand for substance abuse treatment or the preValence ofsubstance abuse in the general population. The primary
31
. Primary marijuana abuse accounted for 18.1 percent of all 2011 TEDS
18
admissions.
Individuals admitted for primary marijuana abuse were nearly three-quarters (73.4 percent)
male, and almost half (45.2 percent) were white. The average age at admission was 24 years
old, and 31.1 percent of
individuals admitted for primary marijuana abuse were under the age
of 18. The reported frequency of
marijuana use was 24.3 percent reporting daily use.
Almost all (96.8 percent) primary marijuana users utilized the substance by smoking.
Additionally, 92.9 percent reported using marijuana for the first time before the age of 18.
An important aspect of TEDS admission data for marijuana is ofthe referral source for
treatment. Specifically, primary marijuana admissions were less likely than all other
admissions to either be self-referred or referred by an individual for treatment. Instead, the
criminal justice system referred more than half(51.6 percent) ofprimary marijuana
admissions.
Since 2003, the percent of
admissions for primary marijuana abuse increased from 15.5
percent of all admissions in 2003 to 18.1 percent in 2011. This increaSe is less than the
increase seen for admissions for primary opioids other than heroin, which increased from 2.8
percent in 2003 to 7.3 percent in 2011. In contrast, the admissions for primary cocaine abuse
declined from 9.8 percent in 2003 to 2.0 percent in 2011.
5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE
Under the fifth factor, the Secretary must consider the scope, duration, and significance of
marijuana abus~. According to 2012 data from NSDUH and 2013 data from MTF, marijuana
remains the most extensively used illegal drug in the United States, with 42.8 percent ofU.S.
individuals over age 12 (111.2 million) and 45.5 percent of
12th graders having used .
marijuana at least once in their lifetime. Although the majority of
individuals over age 12
(83.1 percent) who have ever used marijuana in their lifetime do not use the drug monthly,
18.9 million individuals (7.3 percent of
the U.S. population) report that they used marijuana
within the past 30 days. An examination ofuse among various age cohorts through NSDUH
demonstrates that monthly use occurs primarily among college-aged individuals, with use
dropping off sharply after age 25. Additionally, NSDUH data show the number of
individuals reporting past-month use of
marijuana has increased by 4.3 million individuals
since 2004. Data from MTF shows that annual prevalence ofmarijuana use declined for all
three grades from 2005 through 2007, then began to rise through 2013. Additionally, in
2013, 1.1 percent of
8th graders, 4.0 percent of 1oth graders, and 6.5 percent of 1ih graders
reported daily use ofmarijuana, defined as use on 20 or more days within the past 30 days.
goal for TEDS is to monitor the characteristics of
treatment episodes for substance abusers. Importantly, TEDS is
an admissions-based system, where admittance to treatment is counted as an anonymous tally. For instance, a given
individual who is admitted to treatment twice within a given year would be counted as two admissions. The most
recent year with complete data is 2011.
18
2011; http://www.samhsa.gov/data/DASIS.aspx?qr=t#TEDS
32
The 2011 DAWN data show that marijuana use was mentioned in 455,668 ED visits, which
amounts to approximately 36.4 percent of
all illicit drug~related ED visits.
19
TEDS data for 2011 show that 18.1 percent of
all admissions were for primary marijuana
abuse.
20
Between 2003 and 2011, there was a 2.6 percent increase in the number ofTEDS
admissions for primary marijuana use. Approximately 61.5 percent of primary marijuana
admissions in 20 11 were for individuals under the age of 25 years.
6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC HEALTH
Under the sixth factor, the Secretary must consider the risks posed to the public health by
marijuana. Factors 1, 4, and 5 include a. discussion of the risk to the public health as
measured by emergency room episodes and drug treatment admissions. Additionally, Factor
2 includes a discussion of
marijuana's central nervous system, cognitive, cardiovascular,
autonomic, respiratory, and immune system effects. Factor 6 focuses on the health risks to
the individual user in terms of
the risks from acute and chronic use of marijuana, as well as
the "gateway hypothesis."
Risks from Acute Use of Marijuana
Acute use of marijuana impairs psychomotor performance, including complex task
performance, which makes operating motor vehicles or heavy equipment after using
marijuana inadvisable (Ramaekers et al., 2004; Ramaekers et al., 2006a). A meta-analysis
conducted by Li et al. (2011) showed an association between marijuana use by the driver and
a significantly increased risk of involvement in a car accident. Additionally, in a minority of
individuals who use marijuana, some potential responses include dysphoria and
psychological distress, including prolonged anxiety reactions (Haney et al., 1999).
Risks from Chronic Use of Marijuana
A distinctive marijuana withdrawal syndrome following long term or chronic use has been
identified. The withdrawal syndrome indicates that marijuana produces physical dependence
that is mild, short~lived, and comparable to tobacco withdrawal (Budney et al., 2008).
Marijuana withdrawal syndrome is described in detail below under Factor 7.
19
Many factors can influence the estimates of
ED visits, including trends in the reasons for ED usage. For instance,
some drug users may visit EDs for life-threatening issues while others may visit to seek care for detoxification
because they needed certification before entering tre~tment. Additionally, DAWN data do not distinguish the drug
responsible for the ED visit from other drugs that may have been used concomitantly. As stated in a l)AWN report,
"Since marijuana/hashish is
.frequently present in combination with other drugs, the reason for the ED visit may be
more relevant to the other drug(s) involved in the episode."
20
An important aspect ofTEDS admission data for marijuana is of
the referral source for treatment. Specifically,
primary marijuana admissions were less likely than all other admissions to either be self~referred or referred by an
individual for treatment. Instead, the criminaljustice system referred more than half(51.6 percent) of
primary
marijuana admissions.
33
The following states how the DSM-V (2013) ofthe American Psychiatric Association
describes the consequences of Cannabii
1
abuse:
Individuals with cannabis use disorder may use cannabis throughout the day
over a period of months or years, and thus may spend many hours a day under
the influence. Others may use less frequently, but their use causes recurrent
problems related to family, school, work, or other important activities (e.g.,
repeated absences at work; neglect of family obligations). Periodic cannabis
use and intoxication can negatively affect behavioral and cognitive functioning
and thus interfere with optimal performance at work or school, or place the
individual at increased physical risk when performing activities that could be
physically hazardous (e.g:, driving a car; playing certain sports; performing
manual work activities, including operating machinery). Arguments with
spouses or parents over the use of
cannabis in the home, or its use in the
presence of
children, can adversely impact family functioning and are common
features of
those with cannabis use disorder. Last, individuals with cannabis
use disorder may continue using marijuana despite knowledge of
physical
problems (e.g., chronic cough related to smoking) or psychological problems
(e.g., excessive sedation or exacerbation of other inental health problems)
associated with its use.
Marijuana as a "Gateway Drug"
Kandel (1975) proposed nearly 40 years ago the hypothesis that marijuana is a
"gateway drug'' that leads to the use or abuse of
other illicit drugs. Since that time,
epidemiological research explored this premise. Overall, research does not support a
direct causal relationship between regular marijuana use and other illicit drug use.
The studies examining the gateway hypothesis are limited. First, in general, studies
recruit individuals influenced by a myriad of
social, biological, and economic factors
that contribute to extensive drug abuse (Hall & Lynskey, 2005). Second, most studies
that test the hypothesis that marijuana use causes abuse of illicit drugs use the
determinative measure any u~ ofan illicit drug, rather than DSM-5 criteria for drug
abuse or dependence on an illicit drug (DSM-5, 2013). Consequently, although an
individual who used marijuana may try other illicit drugs, the individual may not
regularly use drugs, or have a diagnosis of
drug abuse or dependence.
Little evidence supports the hypothesis that initiation of
marijuana use leads to an
abuse disorder with other illicit substances. For example, one longitudinal study of
708 adolescents demonstrated that early onset marijuana use did not lead to
problematic drug use (Kandel & Chen, 2000). Similarly, Nace et al. (1975) examined
Vietnam-era soldiers who extensively abused marijuana and heroin while they were
in the military, and found a lack of correlation of
a causal relationship demonstrating
marijuana use leading to heroin addiction. Additionally, in another longitudinal study
21
Cannabis is the term used in the DSM-V to refer to marijuana. In the following excerpt the term Cannabis is
interchangeable for the term marijuana.
34
of 2,446 adoles~;ents, marijuana dependence was uncommon but when it did occur,
the common predictors of
marijuana dependence were the following: parental death,
deprived socio-economic status, and baseline. illicit drug use other than marijuana
(von Sydow et al., 2002).
When examining the association between marijuana and illicit drugs, focusing on
drug use versus abuse or dependence, different patterns emerge. For example, a study
examining the possible causal relationship of
the gateway hypothesis found a
correlation between marijuana use in adolescents and other illicit drug use in early
adulthood and, adjusting for age-linked experiences, did not effect this correlation
(Van Gundy and Rebellon, 2010). However, when examining the association in
terms ofdevelopment of
drug .abuse; age-linked stressors and social roles moderated
the correlation between marijuana use in adolescents and other illicit drug abuse.
Similarly, Degenhardt et al. (2009) examined the development of
drug dependence
and found an association that did not support the gateway hypothesis. Specifically,
drug dependence was significantly associated with the use of other illicit drugs prior
to marijuana use.
Interestingly, the order of
initiation of
drug use seems to depend on the prevalence of
use ofeach drug, which varies by country. Based on the World Health Organization
(WHO) World Mental Health Survey that includes data from 17 different countries,
the order of drug use initiation varies by country and relates to prevalence of
drug use
in each country (Degenhardt et al., 2010). Specifically, in the countries with the
lowest prevalence of
marijuana use, use of other illicit drugs before marijuana was
common. This sequence of initiation is less common in countries with higher
prevalence of
marijuana use. A study of9,282 households in the United States found
that marijuana use often preceded the use of
other illicit drugs; however, prior non-
. marijuana drug dependence was also frequently correlated with higher levels of
illicit
drug abuse (Degenhardt et al., 2009). Additionally, in a large 25-year longitudinal
study of I ,256 New Zealand children, the author concluded that marijuana use
correlated to an increased risk of abuse of other drugs, including cocaine and heroin
(Fergusson et al., 2005).
Although many individuals with a drug abuse disorder may have used marijuana as
one oftheir first illicit drugs, this fact does. not correctly lead to the reverse inference
that most individuals who used marijuana will inherently go on to try or become
regular users of
other illicit drugs. Specifically, data from the 2011 NSDUH survey
illustrates this issue (SAMHSA, 2012). NSDUH data estimates 107.8 million
individuals have a lifetime history of
marijuana use, which indicates use on at least
one occasion, compared to approximately 36 million individuals having a lifetime
history of
cocaine use and approximately 4 million individuals having a lifetime
history of heroin use. NSDUH data do not provide information about each
individual's specific drug history. However, even if
one posits that every cocaine and
heroin user previously used marijuana, the NSDUH data show that marijuana use at
least once in a lifetime does not predict that an individual will also use another illicit
drug at least once.
35
Finally, a review ofthe gateway hypothesis by Vanyukov et al. (20 12) notes that
because the gateway hypothesis only addresses the order of
drug use initiation, the
gateway hypothesis does not specify any mechanistic connections between drug
"stages" following exposure to marijuana and does not extend to the risks for
addiction. This concept contrasts with the concept of
a common liability to addiCtion
that involves mechanisms and biobehavioral characteristics pertaining to the entire
course of
drug abuse risk and disorders.
7. ITS PSYCIDC OR PHYSIOLOGIC DEPENDENCE LIABILITY
Under the seventh factor, the Secretary must consider marijuana's psychic or physiological
dependence liability.
P~ychic or psychological dependence has been shown in response to marijuana's
.psychoactive effects. Psychoactive responses to marijuana are pleaswable to many humans
and are associated with drug-seeking and drug-taking (Maldonado, 2002). Moreover, high
levels of
psychoactive effects, notably positive reinforcement, are associated with increased
marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010).
Epidemiological data support these findings through 20
12 NSDUH statistics that show that
of
individuals years 12 or older who used marijuana in the past month, an estimated 40.3
percent.used marijuana on 20 or more days within the past month. This equates to
approximately 7.6 million individuals aged 12 or older who used marijuana on a daily or
almost daily basis. Additionally, the 2013 MrF data report the prevalence of
daily marijuana
use, defined as use on 20 or more days within the past 30 days, in 8
1
\ 1Oth, and 1 ih graders is
1.1 percent, 4.0 percent, and 6.5 percent, respectively.
Tolerance is a state of adaptation where exposure to a drug induces changes that result in a
diminution of
one or more ofthe drug's effects over time (American Academy of
Pain .
Medicine, American Pain Society and American Society of
Addiction Medicine consensus
document, 2001). Tolerance can develop to some, but not all, of
marijuana's effects.
Specifically, tolerance does not seem to develop in response to many ofmarijuana's
psychoactive effects. This lack oftolerance may relate to electrophysiological data
demonstrating that chronic delta
9
-
THC administration does not affect increased neuronal
firing in the ventral tegmental area, a region .known to play a critical role in drug
reinforcement and reward (Wu and French, 2000). In
the absence of
other abuse indicators,
such as rewarding properties, the presence oftolerance or physical dependence does not
determine whether a drug has abuse potential.
However, humans can develop tolerance to marijuana's cardiovascular, autonomic, and
behavioral effects (Jones et al., 1981). Tolerance to some ofmarijuana's behavioral effects
seems to develop after heavy marijuana use, but not after occasional marijuana use. For
instance, following acute administration of
marijuana, heavy marijuan~ users did not exhibit
impairments in tracking and attention tasks, as were seen in occasional marijuana users
(Ramaekers et al., 2009). Furthermore, a neurophysiological assessment administered
36
through an electroencephalograph (EEG) which measures event-related potentials (ERP)
conducted in the same subjects as the previous study, found a corresponding effect in the
P100
22
component ofERPs. Specifically, corresponding to performance on tracking and
attention tasks, heavy marijuana users showed no changes in P 100 amplitudes following
acute marijuana administration, although occasional users showed a decrease in P1 00
amplitudes (Theunissen et al., 20 12). A possible mechanism underlying tolerance to
marijuana's effects may be the down-regulation of
cannabinoid receptors (Hirvonen et al.,
2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993).
Importantly, pharmacological tolerance alone does not indicate a drug's physical dependence
liability. In order for physical dependence to exist, evidence of
a withdrawal syndrome is
needed. Physical dependence is a state of
adaptation, manifested by a drug-class specific
withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood
level of the drug, and/or administration of
an antagonist (ibid). Many medications not
associated with abuse or addiction can produce physical dependence and withdrawal
symptoms after chronic use.
Discontinuation of
heavy, chronic marijuana use has been shown to lead to physical
dependence and withdrawal symptoms (American Psychiatric Association DSM-V, 2013;
Budney and Hughes, 2006; Haney et al., 1999). In heavy, chronic marijuana users, the most
commonly reported withdrawal symptoms are sleep difficulties, decreased appetite or weight
loss, irritability, anger, anxiety or nervousness, and restlessness. Some less commonly
reported withdrawal_ symptoms are depressed mood, sweating, shakiness, physical
discomfort, and chills (Budney and Hughes, 2006; Haney et al., 1999). The occurrence of
marijuana withdrawal symptoms in light or non-daily marijuana users has not been
established. The American Psychiatric Association's DSM-V (2013) includes a list of
symptoms of"cannabis withdrawal." Most marijuana withdrawal symptoms begin within
24-48 hours of discontinuation, peak within 4-6 days, and last for 1-3 weeks. Marijuana
withdrawal syndrome has been reported in adolescents and adults admitted for substance
abuse treatment.
Based on clinical descriptions, this syndrome appears to be mild compared to classical
alcohol and barbiturate withdrawal syndromes, which can include more serious symptoms
such as agitation, paranoia, and seizures. Multiple studies comparing marijuana and tobacco
withdrawal symptoms in humans demonstrate that the magnitude and time course of
the two
withdrawal syndromes are similar (Budney et al., 2008; Vandrey et al., 2005, 2008).
8. WHETIIER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE
ALREADY CONTROLLED UNDER THIS ARTICLE
Under the eight factor analysis, the Secretary must consider whether marijuana is an
immediate precursor of a controlled substance. Marijuana is not .an immediate precursor of
another controlled substance.
The PIOO component ofERPs are thought to relate to the visual processing of
stimuli and can be modulated by
attention.
37
22
RECOMMENDATION
After consideration of the eight factors discussed above, FDA recommends that marijuana
remain in Schedule I ofthe.CSA. NIDA concurs with this scheduling recommendation.
Marijuana meets the three criteria for placing a substance in Schedule I of
the CSA under 21
U.S.C. 812(b)(l):
1) Marijuana has a high potential for abuse:
A number of
factors indicate marijuana's highabuse potential, including the large number of
individuals regularly using marijuana, marijuana's widespread use, and the vast amount of
marijuana available for illicit use. Approximately 18.9 million individuals in the United
States (7.3 percent of the U.S. population) used marijuana monthly in 2012. Additionally,
approximately 4.3 million individuals met diagnostic criteria for marijuana dependence or
abuse in the year prior to the 2012 NSDUH survey. A 2013 survey indicates that by lih
grade, 36.4 percent of
students report using marijuana within the past year, and 22.7 percent
report using marijuana monthly. In 2011, 455,668 ED visits were marijuana-related,
representing 36.4 percent of
all illicit drug-related episodes. Primary marijuana use
accounted for 18.1 percent of admissions to drug treatment programs in 2011. Additionally,
marijuana has dose-dependent reinforcing effects, as demonstrated by data showing that
humans prefer relatively higher doses to lower doses. Furthermore, marijuana use can result
in psychological dependence.
2) Marijuana has no currently accepted medical use in treatment in the United States:
FDA has not approved a marketing application for a marijuana drug product for any
indication. The opportunity for scientists to conduct clinical research with marijuana exists,
and there are active INDs for marijuana; however, marijuana does not have a currently
accepted medical use for treatment in the United States, nor does marijuana have an accepted
medical use with severe restrictions.
A drug has a"currently
accepted medical use" if
all of the following five elements have been
satisfied:
a. the drug's chemistry is known and reproducible;
b. there are adequate safety studies;
c. there are adequate and well-controlled studies proving efficacy;
d. the drug is accepted by qualified experts; and
e. the scientific evidence is widely available.
[57 FR 10499, March 26, 1992]
Marijuana does not meet any of
the elements for having a "currently accepted medical use."
First, FDA broadly evaluated marijuana, and did not focus its evaluation on particular strains
of
marijuana or components or derivatives of
marijuana. Since different strains may have
different chemical constituents, marijuana, as identified in this petition, does not have a
38
known and reproducible chemistry, which would be needed to provide standardized doses.
Second, there are not adequate safety studies on marijuana in the medical literature in
relation to a specific, recognized disorder. Third, there are no published adequate and well-
controlled studies proving efficacy of marijuana. Fourth, there is no evidence that qualified
experts accept marijuana for use in treating a specific, recognized disorder. Lastly, the
scientific evidence regarding marijuana's chemistry in terms of
a specific Cannabis strain
that could produce standardized and reproducible doses is not currently available, so the
scientific evidence on marijuana is not widely available.
Alternately, a Schedule II drug can be considered to have a "currently accepted medical use
with severe restrictions" (21 U.S.C. 812(b)(2)(B)). Yet as stated above, the lack of
accepted
medical use for a specific, recognized disorder precludes the use of
marijuana even under
conditions where its use is severely restricted.
In conclusion, to date, research on marijuana's medical use has not developed to the point
where marijuana is considered to have a "currently accepted medical use" or a "currently
accepted medical use with severe restrictions."
3) There is a lack of accepted safety for use of marijuana under medical supervision:
There are currently no FDA-approved marijuana drug products. Marijuana does not have a
currently accepted medical use in treatment in the United States or a currently accepted
medical use with severe restrictions. Thus, FDA has not determined that marijuana is safe
for use under medical supervision.
In addition, FDA cannot conclude that marijuana has an acceptable level of safety relative to
. its effectiveness in treating a specific, recognized disorder without evidence that the
substance is contamination free, and assurance of a consistent and predictable dose.
Investigations into the medical use of marijuana should include information and data
regarding the chemistry, manufacturing, and specifications of marijuana. Additionally, a
procedure for delivering a consistent dose of marijuana should also be developed.
Therefore, FDA concludes marijuana does not currently have an accepted level of safety for
use under medical supervision.
39
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56
ENCLOSURE 2
The Medical Application of Marijuana: A Review of Published Clinical Studies
The Medical Application of
Marijuana: A Review of Published
Clinical Studies
March 19, 2015
Prepared by:
U.S. Food and Drug Administration
Center for Drug Evaluation and Research (FDA/CDER)
Controlled Substance Staff (CSS)
Food and Drug Administration 1 March 19, 2015
The Medical Application of Marijuana: A Review ofPublished Clinical Studies
Table of Contents
1. Introduction
............................................................................................................................... 7
2. Methods...................................................................................................................................... 9
2.1 Define the Objective ofthe Review
..........-..................
........................................................... 9
2.2 Define "Marijuana" ........................
...................................................
.......
....
.......................... 9
2.3 Define "Adequate and Well-Controlled Clinical Studies"......
.............................................10
2.4 Search Medical Literature Databases and Identify Relevant Studies .................................. 10
2.5 Review and Analyze Qualifying Clinical Studies..........................
...............
....................... 13
3. Results and Discussion ............................................................................................................ 13
3.! Neuropathic Pain.........................................................................................................
......... 13
3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy .................................................... 13
3.1.2 Central and Peripheral Neuropathic Pain .............................................
.......................................
17
3.2 Appetite Stimulation in HIV .....
...............
............................................................................ 21
3.3 Spasticity in Multiple Sclerosis............................................................................................ 24
3.4 Asthma .........
.......
.........
.............
.......................................................................................
.... 25
3.5 Glaucoma .................................................
...........................................................................
. 27
3.6 Conclusions..
...................................................................................................
...
.........
...
...... 27
3.6.1 Conclusions for Chronic Neuropathic Pain ..................................................................
.......... 28
3.6.2 Conclusions for Appetite Stimulation in HIV ........................................................................ 28
3.6.3 Conclusions for Spasticity in M$........................................................................................... 28
3.6.4 Conclusions for Asthma ........................ , ................................................................................ 28
3.6.5 Conclusions for Glaucoma .................................................................................................... 29
3.7 Design Challenges for Future Studies .................................................
.................................. 29
3.7.1 Sample Size ............................................................................................................................. 29
.
3.7.2 Marijuana Dose Standardization ..............................................................
..............................30
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use ..................................................................... .31
3.7.4 Smoking as a Route of Administration ........................................
...........................................32
3.7.5 Difficulty in Blinding ofDrug Conditions ............................................................................. 32
3.7.6 Prior Marijuana Experience ................................................................................................... 33
3.7.7 Inclusion and Exclusion Criteria ............................................................................................ 34
3.7.8 Number of Female Subjects .........
............................................
..............................................35
Appendix (Tables) ....................................................................................................................... 39
Food and Drug Administration 2 March 19,2015
The Medical Application of Marijuana: A Review of Publi.shed ClinicaJ Studies
List of Figure
Figure 1: Identification of Studies from PubMed Search ........................................... 12
List of Tables
Table I: Randomized, controlled, double-blind trials examining smoked marijuana in
treatment of neuropathic pain ........................................................................................... 39
Table 2: Randomized, controlled, double-blind trials examining smoked marijuana in
treatment of appetite stimulation in HIVIAIDS .......... ; ..................................................... 44
Table 3: Randomized, controlled, double-blind trails examining smoked marijuana in
treatment of spasticity in Multiple Sclerosis .................................................................... : 47
Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in
treatment of intraocular pressure in Glaucoma ................................................................. 48
Table 5: Randomized, controlled, double-blind trails examining smoked marijuana in
treatment of asthma.... , ...................................................................................................... 49
Food and Drug Administration 3 March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Executive Summary
Marijuana is a Schedule I substance Wlder the Controlled Substances Act.
Schedule I indicates a high potential for abuse, no currently accepted medical use
in the United States, and a lack of accepted safety for use Wlder medical
supervision. To date, marijuana has not been subject to an approved new drug
application that demonstrates its safety and efficacy for a specific indication under
the Federal Food, Drug, and Cosmetic Act.
Nevertheless, as of October 2014, twenty-three states and the District of
Columbia have passed state-level medical marijuana laws that allow for marijuana
use within that state; similar bills are pending in other states.
The present review was undertaken by the Food and Drug Administration (FDA)
to analyze the clinical studies published in the medical literature investigating the
use of marijuana in any therapeutic areas. First, we discuss the context for this
scientific review. Next, we describe the methods used in this review to identify
adequate and well-controlled studies evaluating the safety and efficacy of
marijuana for particular therapeutic uses.
The FDA conducted a systematic search for published studies in the medical
literature that meet the described criteria for study design and outcome measures
prior to February 2013
. While not part of
our systematic review, we have
routinely continued to follow the literature beyond that date for subsequent
studies. Studies were considered to be relevant to this review if
the investigators
administered marijuana to patients with a diagnosed medical condition in a well-
controlled, double-blind, placebo-controlled clinical trial. Ofthe eleven studies
that met the criteria for review, five different therapeutic areas were investigated:
.
Five studies examined chronic neuropathic pain.
.
Two studies examined appetite stimulation in human immunodeficiency
virus (HIV) patients.
.
Two studies exam1ned glaucoma.
.
One study examined spasticity and pain in multiple sclerosis (MS).
.
One study examined asthma.
For each ofthese eleven clinical studies, information is provided regarding the
subjects studied, the drug conditions tested (including dose and method of
administration), other drugs used by subjects during the study, the physiological
and subjective measures collected, the outcome ofthese measures comparing
treatment with marijuana to placebo, and the reported and observed adverse
events. The conclusions drawn by the investigators are then described, along with
potential limitations ofthese conclusions based on the study design. A brief
Food and Drug Administration 4
March 19, 2015
The Medical Application of Marijuana: A Review ofPublished Clinical Studies
summary of each study'
s findings and limitations is provided at the end of the
section.
The eleven clinical studies that met the criteria and were evaluated in this review showed
positive signals that marijuana may produce a desirable therapeutic outcome, under the
specific experimental conditions tested. Notably, it is beyond the scope of this review to
determine whether these data demonstrate that marijuana has a currently accepted
medical use in the United States. However, this review concludes that these eleven
clinical studies serve as proof-of-concept studies, based on the limitations of their study
designs, as described in the study summaries. Proof-of-concept studies provide
preliminary evidence on a proposed hypothesis regarding a drug's effect. For drugs
under development, the effect often relates to a short-term clinical outcome being
investigated. Proof-of-concept studies serve as the link between preclinical studies and
dose ranging clinical studies. Therefore, proof-of-concept studies are not sufficient to
demonstrate efficacy of a drug because they provide only preliminary information about
the effects of a drug. However, the studies reviewed produced positive results,
suggesting marijuana should be further evaluated as an adjunct treatment for neuropathic
pain, appetite stimulation in IDV patients, and spasticity in MS patients.
The main limitations identified in the eleven studies testing the medical applications of
marijuana are listed below:
.
The small numbers of subjects enrolled in the studies, which limits the statistical
analyses of safety and efficacy.
.
The evaluation of
marijuana only after acute administration in the studies, which
limits the ability to determine efficacy following chronic administration.
.
The administration of marijuana typically through smoking, which exposes ill
patients to combusted material and introduces problems with determining the
doses delivered.
.
The potential for subjects to identify whether they received marijuana or placebo,
which breaks the blind ofthe studies.
.
The small number of
cannabinoid-nai've subjects, which limits the ability to
determine safety and tolerability in these subjects.
.
The low number of female subjects, which makes it difficult to generalize the
study findings to subjects of both genders.
Thus, this review discusses the following methodological changes that may be .
made in order to resolve these limitations and improve the design of future studies
which examine the safety and efficacy of marijuana for specific therapeutic
indications:
Food and Drug Administration 5
March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
.
Determine the appropriate number of
subjects studied based on
recommendations in various FDA guidances for industry regarding the
conduct of
clinical trials for specific medical indications.
.
Administer consistent and reproducible doses of
marijuana based on
recommendations in FDA's 2004 guidance for industry entitled Botanical
Drug Products.
1
.
Evaluate the effects of marijuana under therapeutic conditions following
both acute and chronic administration.
.
Consider alternatives to smoked marijuana (e.g., vaporization).
.
Address and improve, whenever possible, the difficulty in blinding of
m<rrijuana and placebo treatments in clinical studies.
.
Evaluate the effect of
prior experience with marijuana with regard to the
safety and tolerability of
marijuana.
.
Strive for gender balance in the subjects used in studies.
In conclusion, the eleven clinical studies conducted to date do not meet the
criteria required by the FDA to determine if
marijuana is safe and effective in
specific therapeutic areas. However, the studies can serve as proof-of-concept
studies and support further research into the use ofmarijuana in these therapeutic
indications. Additionally, the clinical outcome data and adverse event profiles
reported in these published studies can beneficially inform how future research in
this area is conducted. Finally, application ofthe recommendations listed above
by investigators when designing future studies could greatly improve the available
clinical data that can be used to determine if marijuana has validated and reliable
medical applications.
1
This guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance
(Drugs).
Food and Drug Administration 6
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The Medical Application of
Marijuana: A Review of Published Clinical Studies
J. Introduction
In response to citizen petitions submitted to the Drug Enforcement Administration
(DEA) requesting DEA to reschedule marijuana, the DEA Administrator
requested that the U.S. Department of
Health and Human Services (HHS) provide
a scientific and medical evaluation of
the available information and a scheduling
recommendation for marijuana, in accordance with 21 U.S.C. 8ll(b). The
Secretary ofHHS is required to consider in a scientific and medical evaluation
eight factors determinative ofcontrol under the Controlled Substance Act (CSA).
Administrative responsibilities for evaluating a substance for control under the
CSA are performed by the Food and Drug Administration (FDA), with the
. concurrence of
the National Institute on Drug Abuse (NIDA). Part ofthis
evaluation includes an assessment of
whether marijuana has a currently accepted
medical use in the United States. This assessment necessitated a review of the
available data from published clinical studies to determine whether there is
adequate scientific evidence ofmarijuana's effectiveness. .
Under Section 202 of
the GSA, marijuana is currently controlled as a Schedule I
substance (21 U.S.C § 812). Schedule I includes those substances that have a
high potential for abuse, have no currently accepted medical use in treatment in
the United States, and lack accepted safety for use under medical supervision (21
U.S.C. § 812(b)(1)(A)-(C)). .
A drug product which has been approved by FDA for marketing in the United
States is considered to have a "currently accepted medical use." Marijuana is not
an FDA-approved drug product, as a New D,rug Application (NDA) or Biologics
License application (BLA) for marijuana has not been approved by FDA.
However, FDA approval of
an NDA is not the only means through which a drug
can have a currently accepted medical use in the United States.
In general, a drug may have a "currently accepted medical use" in the United States ifthe
drug meets a five-part test. Established case law (Alliance for Cannabis Therapeutics v.
DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the Administrator ofDEA's
application ofthe five-part test to determine whether a drug has a "currently accepted
medical use." The following describes the five elements that characterize "currently
accepted medical use" for a drug
2
:
i. the drug's chemistry must be known and reproducible
"The substance's chemistry must be scientifically established
to permit it to be reproduced into dosages which can be
standardized. The listing of
the substance in a current edition
of
one of
the official compendia, as defined by section 201(j)
2
57 FR 10499, 10504-06 (March 26, 1992).
Food and Drug Administration 7 March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
of
the Food, Drug and Cosmetic Act, 21 U.S.C. 3210), is
sufficient to meet this requirement."
ii. there must be adequate safety studies
"There tnust be adequate pharmacological and toxicological
studies, done by all methods reasonably applicable, on the
basis of
which it could fairly and responsibly be concluded, by
experts qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs, that the
substance is safe for treating a specific, recognized disorder."
iii. there must be adequate and well-controlled studies proving efficacy
"There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical
investigations, by experts qualified by scientific training and
experience to evaluate the safety and effectiveness of
drugs, on
the basis of
which it could be rairly and responsibly concluded
by such experts that the substance will have the intended effect
in treating a specific, recognized disorder."
iv. the drug must be accepted by qualified experts
"The drug has a New Drug Application (NDA) approved by
the Food and Drug Administration, pursuant to the Food, Drug
and Cosmetic Act, 21 U.S.C. 355. Or, a consensus of the
national community ofexperts, qualified by scientific training
and experience to evaluate the safety and effectiveness of
drugs, accepts the safety and effectiveness of
the substance for
use in treating a specific, recognized disorder. A material
conflict of
opinion among experts precludes a finding of
consensus." and
v. the scientific evidence must be widely available.
"In the absence ofNDA approval, information concerning the
chemistry, pharmacology, toxicology, and effectiveness ofthe
substance must be reported, published, or otherwise widely
available, in sufficient detail to permit experts, qualified by
scientific training and experience to evaluate the safety and
effectiveness of
drugs, to fairly and responsibly conclude the
substance is safe and effective for use in treating a specific,
recognized disorder."
One way to pass the five-part test for having a "currently accepted medical use" is
through submission of
an NDA or BLA which is approved by FDA. However,
Food and Drug Administration 8 March 19,2015
The Medical Application of Marijuana: A Review of
Published Clinical Studies
FDA approval of an NDA or BLA is not required for a drug to pass the five-part
test.
This review focuses on FDA's analysis of one element of
the five-part test for
determining whether a drug bas a "currently accepted medical use." Specifically,
the present review assesses the
3rd criterion that addresses whether marijuana has
"adequate and well-controlled studies proving efficacy." Thus, this review
evaluates published clinical studies that have been conducted using marijuana in
subjects who have a variety of
medical conditions by assessing the adequacy of
the summarized study designs and the study data. The methodology for selecting
the studies that were evaluated is delineated below.
FDA's evaluation and conclusions regarding the remaining four criteria for
whether marijuana has a "currently accepted medical use," as well as the eight
factors pertaining to the scheduling of
marijuana, are outside the scope of
this
review. A detailed discussion of
these factors is contained in FDA's scientific
and medical evaluation of marijuana.
2. Methods
The methods for selecting the studies to include in this review involved the
following steps, which are described in detail in the subsections below:
1.
Define the objective of
the review,
2.
Define "marijuana" in order to facilitate the medical literature search for
studies that administered the substance,
3.
Define "adequate and well-controlled studies" in order to facilitate the
search for relevant data and literature,
4.
Search medical literature databases and identify relevant adequate and
well-controlled studies, and
5.
Review and analyze the adequate and well-controlled clinical studies to
determine ifthey demonstrate efficacy of marijuana for any therapeutic
indication.
2.1 Define the Objective ofthe Review
The objective of
this review is to assess the study designs and resulting data from
clinical studies published in the medical literature that were conducted with
marijuana (as defined below) as a treatment for any therapeutic indication, in
order to determine if they meet the criteria of "adequate and well-controlled
studies proving efficacy."
2.2 Define."Marijuana"
In this review, the term "marijuana" refers to
.the flowering tops or leaves of
the
Cannabis plant. There were no restrictions on the route of administration used for
marijuana in the studies.
Food and Drug Administration
9
March 19,2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Studies which administered individual cannabinoids (whether experimental
substances or marketed drug products) or marijuana extracts were excluded from
this review. Additionally, studies of
administered neutral plant material or
placebo marijuana (marijuana with all cannabinoids extracted) that had
subsequently been supplemented by the addition of
specific amounts of
tetrahydrocannabinol (THC) or other cannabinoids were also excluded (Chang et
al., 1979).
2.3 Define uAdequate and Well-Controlled Clinical Studies"
The criteria for an "adequate and well-controlled study" for purposes of
determining the safety and efficacy of a human drug is defined under the Code of
Federal Regulations (CFR) in 21 CFR 314.126. The elements of an adequate and
well-controlled study as described in 21 CFR 314.126 can be smnmarized as
follows: .
1.
The main objective must be to assess a therapeutically relevant outcome.
2.
The study must be placebo-controlled.
3.
The subjects must qualify as having the medical condition being studied.
4.
The study design permits a valid comparison with an appropriate control
condition.
5.
The assignment of
subjects to treatment and control groups must be
randomized.
6.
There is minimization ofbias through the use of
a double-blind study
design.
7.
The study report contains a full protocol and primary data.
8.
Analysis ofthe study data is appropriately conducted.
As noted above, the current review examines only those data available in the
public domain and thus relies on clinical studies published in the medical .
literature. Published studies by their nature are summaries that do not include the
level of
detail required by studies submitted to
.FDA in an NDA.
While the majority ofthe elements defining an adequate and well-controlled study
can be satisfied through a published paper (elements#1-6), there are two elements
that cannot be met by a study published in the medical literature: element #7
(availability of a study report with full protocol and primary data) and element #8
(a determination of
whether the data analysis was appropriate). Thus, for
purposes ofthis review, only elements #1-6 will be used to qualify a study as
being adequate and well-controlled.
2.4 Search Medical Literature Databases and ldentif.v Relevant
Studies
Food and Drug Administration 10
March 19,
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The Medica1 Application of Marijuana: A Review of Published Clinica1 Studies
We identified randomized, double-blind, placebo-controlled clinical studies
conducted with marijuana to assess marijuana's efficacy in any therapeutic
indication. Two primary medical literature databases were searched for all studies
posted to the databases prior to February 2013
3
:
.
PubMed: PubMed is a database of
published medical and scientific studies
that is maintained by the U.S. National Library of
Medicine (NLM) at the
National Institute of Health (NIH) as a part ofthe Entrez system of
information retrieval. PubMed comprises more than 24 million citations
for biomedical literature from MEDLINE, life science journals, and online
books (http://www.ncbi.nlm.nih.gov/pubmed).
.
ClinicalTrials.gov: ClinicalTrials.gov is a database ofpublicly and
privately supported clinical studies that is maintained by the NLM.
Information about the clinical studies is provided by the sponsor or
Principal Investigator of the study. Information about the studies is
submitted to the website ("registered") when the studies begin, and is
updated throughout the study. In some cases, results ofthe study or
resulting publication citations are submitted to the website after the study
ends (https :/I clinicaltrials. gov Ict2/ about -site/background).
ClinicalTrials.gov was searched for all studies administering marijuana. The
results ofthis search were used to confirm that no completed studies with
published data were missed in the literature search. During the literature search,
references found in relevant studies and systematic reviews were evaluated for
additional relevant citations. All languages were included in the search. The
PubMed search yielded a total of 566 abstracts.
4
Of
these abstracts, a full-text
review was conducted with 85 papers to assess eligibility. From this evaluation,
only 11 of
85 studies met the 6 CFR elements for inclusion as adequate and well-
controlled studies.
Figure 1 (below) provides an overview of the process used to identify studies
from the PubMed search. The eleven studies reviewed were published between
1974 and 2013. Ten ofthese studies were conducted in the United States and one
study was conducted in Canada. These eleven studies examined the effects of
smoked and vaporized marijuana for the indications of
chronic neuropathic pain,
spasticity related to multiple sclerosis (MS), appetite stimulation in patients with
human immunodeficiency virus (HIV), glaucoma, and asthma. All included
studies used adult patients as subjects. All studies conducted in the United States
3
While not a systematic review, we have followed the recent published literature on marijuana use for
possible therapeutic purposes and, as of
January 2015, we found only one new study that would meet our
criteria (Naftali et al., 2013). This study examined the effects of smoked marijuana on Crohn's disease.
4
The following search strategy was used, "(cannabis OR marijuana) AND (therapeutic use OR therapy)
AND (RCT OR randomized controlled trial OR "systematic review" OR clinical trial OR clinical trials)
NOT ("marijuana abuse" [Mesh] OR addictive behavior OR substance related disorders)".
Food and Drug Administration 11
March 19,
2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
were conducted under an investigational new drug (IND) as Phase 2
investigations.
Figure 1: Identification
of
Studies from PubMed Search
I
566 Abstracts identified in PubMed search
I
___.
481 Excluded because either clearly
irrelevant ., excluded article type b, or not
RCT"
85 Full-text articles assessed for eligibility
I I
76 Excluded
63 Administered individual cannabinoids
d or
marijuana plant derived products
27 Administered delta
9
-THC
20 Administered marijuana plant extracts
4 Administered Cannabidiol
f--.
4 Administered hemp seed oil
I Administered Rimonabant .
6 Were mechanistic studies
7 Had a primary focus on safety
l
9 r Articles from the PubMed search meet inclusion ~riteria I
"Articles were deemed irrelevant if they examined safety or adverse event related outcomes,
including psychoactive effects or other adverse events. ~xcluded article types included
comments, reviews, meta-analyses, and news articles.
0
Randomized Controlled Trials.
dCannabinoids administered included synthetic cannabinoids. "R.imonabant is a cannabinoid
receptor antagonist. rAn additional 2 studies meeting the inclusion criteria were fomi.d through
the reference search:
Two qualifying studies, which assessed marijuana for glaucoma, were previously
reviewed in the 1999 Institute of
Medicine (IOM) report entitled "Marijuana and
Medicine: Assessing the Science Base."
5
We did our own analysis ofthese two
studies and concurred with the conclusions in the IOM report. Thus, a detailed
discussion of
the two glaucoma studies is not included in the present review. The
present review only discusses 9 of
the identified 11 studies. For a summary ofthe
study design for alll1 qualifying studies, see Tables 1-5 (located in
the
Appendix).
5
In January 1997, the White House Office ofNational Drug Control Policy (ONDCP) requested that the IOM conduct
a review of
the scientific evidence to assess the potential health benefits and risks of
marijuana and its constituent
cannabinoids. Information for this study was gathered through scientific workshops, site visits to cannabis buyers'
clubs and HIV I Acquired Immunodeficiency Syndrome (AIDS) clinics, analysis of
the relevant scientific literature, and
exter:Jsive cor:Jmltatior:J 1with biomedical alld social scie11tists The z:epoct was fir:Jali:zed and published ill 1999
Food and Drug Administration 12 March 19,
2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Based on the selection criteria for relevant studies described in Section 2.3
("Define 'Adequate and Well-Controlled Clinical Studies"'), a nwnber of
clinical
studies that investigated marijuana, as defined in this review, were excluded from
this review. Studies that examined the effects of marijuana in healthy subjects
were excluded because they did not test a patient population with a medical
condition (Flom et al., 1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al.,
1974; Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001; Wallace
et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by Tashkin et al. was
excluded because it had a single-blind, rather than double-blind, study design.
Two other studies were excluded because the primary outcome measure assessed
safety rather than a therapeutic outcome (Greenberg et al., 1994; Abrams et al.,
2003).
2.5 Review and Analyze Qualifying Clinical Studies
Qualified clinical studies that evaluated marijuana for therapeutic purposes were
examined in tenns of adequacy of
study design including method of
drug
administration, study size, and subject inclusion and exclusion criteria.
Additionally, the measures and methods of
analysis used in the studies to assess
the treatment effect were examined.
3. Results and Discussion
The 11 qualifying studies in this review assessed a variety of
therapeutic
indications. In order to better facilitate analysis and discussion of
the studies, the
following sections group the studies by therapeutic area. Within each section,
each individual study is sUm.marized in tenns of its design, outcome data, and
important limitations. This infonnation is also provided in the Appendix in
tabular form for each study.
3.1 Neuropathic Pain
Five randomized, double-blind, placebo-controlled Phase 2 clinical studies have
been conducted to examine the eff~cts of
inhaled marijuana smoke on
.neuropathic pain associated with HIV -sensory neuropathy (Abrams et al., 2007;
Ellis et al., 2009) and chronic neuropathic pain from multiple causes (Wilsey et
al., 2008; Ware et al., 201 0; Wilsey et al., 2013). Table 1 of
the Appendix
summarizes these studies.
3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy
Two studies examined the effect of marijuana to reduce the pain induced by HIV-
sensory neuropathy.
Abrams et al. (2007) conducted the first study entitled "Cannabis in painful HIV-
associated sensory neuropathy. a randomized placebo-contro11ed trial." The
Food and Drug Administration 13 . . March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
subjects were 50 adult patients with uncontrolled HIV -associated sensory
neuropathy, who had at least 6 experiences with smoking marijuana. The subjects
were split into two parallel groups of 25 subjects each. More than 68% of
subjects were current marijuana users, but all individuals were required to
discontinue using marijuana prior to the study. Most subjects were taking
medication for pain during the study, with the most common medications being
opioids and gabapentin. Upon entry into the study, subjects had an average daily
pain score of at least 30 on a 0-100 visual analog scale (VAS).
Subjects were randomized to receive either smoked marijuana (3.56% THC
6
) or
smoked placebo cigarettes three times per day for 5 days, using a standardized
cued smoking procedure: (1) 5-second inhale, (2) 10-second holding smoke in
the lungs, (3) 40-second exhale and breathing normally between puffs. The
authors did not specify how many puffs the subjects smoked at each smoking
session, but they stated that one cigarette was smoked per smoking session.
Primary outcome measures included daily VAS ratings of
chronic pain and the
percentage of subjects who reported a result of more than 30% reduction in pain
intensity. The ability of smoked marijuana to induce acute analgesia was assessed
using both thermal heat model and capsaicin sensitization model, while anti-
hyperalgesia was assessed with brush and von Frey hair stimuli. The immediate
analgesic effects of smoked marijuana was assessed using a 0-1 00 point VAS at
40-minute intervals three times before and three times after the first and last
smoking sessions, which was done to correspond to the time of
peak plasma
cannabinoid levels. Notably, not all subjects completed the induced pain portion
of the study (n=
11 in marijuana group, 9 in placebo group) because oftheir
inability to tolerate the stimuli. Throughout the study, subjects also completed the
Profile of
Mood States (POMS) questionnaire, as well as subjective VAS
measures of
anxiety, sedation, disorientation, paranoia, confusion, dizziness, and
nausea.
As a result, the median daily pain was reduced 34% by smoked marijuana
compared to 17% by placebo (p=0.03). Ofthose subjects who smoked marijuana,
52% reported a>30% reduction in pain compared to 24% in the placebo group
(p=0.04). Although marijuana reduced experimentally induced hyperalgesia (p ~
0.05) during the first smoking sessions, marijuana did not alter responses to
acutely painful stimuli.
There were no serious adverse events (AEs) and no episodes of hypertension,
hypotension, or tachycardia requiring medical intervention. No subjects withdrew
from the study for drug-rdated reasons. Subjects in the marijuana group reported
higher ratings on the subjective measures of anxiety, sedation, disorientation,
confusion, and dizziness compared to the placebo group. There was one case of
6
The drug dose is reported as percentage ofTHC present in the marijuana rather than ~illigrams
ofTHC
present in each cigarette because ofthe difficulty in determining the amount ofTHC delivered by inhalation
(>ee di>cn>sioll ill the >ectioll e!ltitled "3 7 2 M:arijualla Dose Stalldardi:zatioll")
Food and Drug Administration 14 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
severe dizziness in a marijuana~treated subject. By the end of
the study, subjects
treated with marijuana and placebo reported a reduction in total mood disturbance
as measured by POMS.
The authors conclude that smoked marijuana effectively reduced chronic
neuropathic pain from HIV -associated sensory neuropathy with tolerable side
effects. However, limitations of
this study include: maintenance of subjects on
other analgesic medication while being tested with marijuana and a lack of
information about the number of
puffs during each inhalation of smoke. These
limitations make it difficult to conclude that marijuana has analgesic properties on
its own and that the actual AEs experienced during the study in response to
marijuana are tolerable. However, the study produced positive results suggesting
that marijuana should be studied further as an adjunct treatment for uncontrolled
HIV~associated sensory neuropathy.
Ellis et al. (2009) conducted a more recent study entitled "Smoked medicinal
cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial." The
subjects were 28 HIV~positive. adult male patients with intractable neuropathic
pain that was refractory to the effects of
at least two drugs taken for analgesic
purposes. Upon entry into the study, subjects had a mean score of> 5 on the Pain
Intensity subscale ofthe Descriptor Differential Scale (DDS). Subjects were
allowed to continue taking their current routine of
pain medications, which
included opioids, non~narcotic analgesics, antidepressants, and anticonvulsants.
Previous experience with marijuana was not required for participation in the
study, but 27 of28 subjects (96%) reported previous experience with marijuana.
However, ofthese 27 experienced subjects, 63% (n=l8) reported no marijuana
use within the past year.
The study procedures compared the effects of the target dose ofmarijuana and
placebo during two treatment periods lasting 5 days, with 2-week washout
periods. The marijuana strengths available were 1%, 2%, 4%, 6%, or 8% THC
concentration by weight. Subjects smoked marijuana or placebo cigarettes four
times per day, approximately 90-120 minutes apart, using a standardized cued
smoking procedure: (1) 5-second smoke inhalation, (2) 10-second hold of smoke
in lungs, (3) 40-second exhale and normal breathing between puffs. The
investigators did not provide a description of the nun:J.ber of
puffs taken at any
smoking session. All subjects practiced the smoking procedures using placebo
marijuana prior to test sessions.
On the first day of
each test period, dose titration occurred throughout the four
smoking sessions scheduled for that day, with a starting strength of 4% TIIC
concentration. Subjects were allowed to titrate to a personalized "target dose,"
which was defined as the dose that provided the best pain relief without
intolerable adverse effects. This dose titration was accomplished by allowing
subjects to either increase the dose incrementally (to 6% or 8% THC) to improve
analgesia, or to decrease the dose incrementally (to 1% or 2% THC) ifAEs were
intolerable. For the next 4 days of
each test period, the subjects smoked their
Food and Drug Administrati9n 15 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
target dose during each of
the four daily smoking sessions. To maintain the blind,
placebo marijuana was represented as containing 1 %-8% THC, even though it did
not contain any cannabinoids.
The primary outcome measure was the change in pain magnitude on the DDS at
the end of each test period compared to baseline, with a clinically significant level
of analgesia considered to be a reduction in pain of
at least 3 0%. Additional
measures included the POMS, the Sickness Impact Profile (SIP), the Brief
Symptom Inventory (BSI), and the UKU Side Effect Rating Scale and a
subjective highness/sedation VAS.
During the marijuana treatment week, 19 subjects titrated to the 2%-4% THC
dose while the 6%-8% dose was preferred by 8 subjects and 1 subject chose the
1% dose. In contrast, during the placebo treatment week, all 28 subjects titrated
to the highest possible dose of
"8% THC" that contained no actual crumabinoids,
suggesting that placebo treatment provided little analgesic relief.
The degree of
pain reduction was significantly greater after administration of
marijuana compared to placebo (median change of3.3 points on DDS,p=0.016).
The median change from baseline in VAS pain scores was -17 for marijuana
treatment compared to -4 for placebo treatment (p<O.OOl). A larger proportion of
subjects who were treated with marijuana (0.46) reported a>30% reduction in
pain, compared to placebo (0.18). Additionally, the authors report improvements
in total mood disturbance, physical disability, and quality of
life as measured on
POMS, SIP, and BSI scales after both placebo and marijuana tr~tment (data not
provided in paper).
In terms of safety, there were no alterations in HIV disease parameters in response
to marijuana or placebo. The authors report that marijuana led to a greater degree
ofUKU responses as well as AEs such as difficulty in concentration, fatigue,
sleepiness or sedation, increased duration ofsleep, reduced salivation and thirst
compared to placebo (data not provided in paper). Two subjects withdrew from
the study because of
marijuana-related AEs: one subject developed an intractable
smoking-related cough during marijuana administration and the sole marijuana-
.
naive subject in the study experienced an incident of
acute cannabis-induced
psychosis.
7
The authors conclude that smoked marijuana effectively reduced chronic
neuropathic pain from HIV-associated sensory neuropathy. The limitations of
this study include: a lack of information about the number ofpuffs during each
inhalation of
smoke; a lack of
information about the specific timing ofthe
subjective assessments and collection of
AEs relative to initiation of
the smoking
7
At the time ofthe study, the following criteria from the Diagnostic and Statistical Manual of
Mental Disorders (DSM-
IV-TR. 2000) were used to diagnose substance-induced psychotic disorders: prominent halluCinations or delusions;
hallucinations and/or delusions that develop during, or within one month ot; intoxication or withdrawal; the disturbance
is not better accounted for by a psychotic disorder that is not substance induced. The disturbance does not occur
excln~>ivc:ly d
11
rillg the course of a delirium
Food and Drug Administration 16 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
sessions; and the inclusion of
only one marijuana-naive subject. These limitations
make it difficult to conclude that the actual AEs experienced during the study in
response to marijuana are tolerable. It is especially concerning that the only
marijuana-naive subject left the study because of
serious psychiatric responses to
marijuana exposure at analges'ic doses. However, the study produced positive
results suggesting that marijuana should be studied further as an adjunct treatment
for uncontrolled HIV -associated sensory neuropathy.
3.1.2 Central and Peripheral Neuropathic Pain
Three studies examined the effect of
marijuana on chronic neuropathic pain.
Wilsey et al. (2008) examined chronic neuropathic pain from multiple causes in
the study entitled "A Randomized, Placebo-Controlled, Crossover Trial of
Cannabis Cigarettes in Neuropathic Pain." The subjects were 32 patients with a
variety ofneuropathic pain conditions, including 22 with complex regional pain
syndrome, 6 with spinal cord injury, 4 with multiple sclerosis, 3 with diabetic
neuropathy, 2 with ilioinguinal neuralgia, and 1with lumbosacral plexopathy. All
subjects reported a pain intensity of
at least 30 on a 0-100 VAS and were allowed
to continue taking their regular medications during the study period, which
included opioids, antidepressants, anticonvulsants, and non-steroidal anti-
inflammatory drugs (NSAIDs). All subjects were required to have experience
with marijuana but could not use any cannabinoids for 30 days before study
sessions.
The study consisted of
three test sessions with an interval of
3-21 days between
sessions. Treatment conditions were high-strength marijuana (7% delta-9-THC),
low-strength marijuana (3.5% delta-9-THC), and placebo cigarettes, administered
through a standardized cued-puff
procedure= (1) "light the cigarette" (30 seconds),
(2) "get ready" (5 seconds), (3) "inhale" (5 seconds), (4) "hold smoke in lungs"
(10 seconds), (5) "exhale," and (6) wait before repeating the puff
cycle (40
seconds). Participants took 2 puffs after baseline measurements, 3 puffs an hour
later, and 4 puffs an hour after that, for a cumulative dose of
9 puffs per test
session.
Hourly assessment periods were scheduled before and after each set of
puffs and
for 2.additional hours during the recovery period. Plasma cannabinoids were
measured at baseline, 5 minutes after the first puff and again at 3 hours after the
last puff
cycle.
The primary outcome measure was spontaneous pain relief, as measured by a 0-
100 point VAS for current pain. Pain unpleasantness was measured on a 0-100
point VAS, and degree of
pain relief was measured on a 7-point Patient Global
-Impression of
Change (PGIC) scale. Secondary measures included the
Neuropathic Pain Scale (NPS), a 0-100 point VAS for al1odynia, and changes in
thennal pain threshold. Subjective measures were also evaluated with unipolar 0-
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The Medical Application of Marijuana: A Review of Published Clinica1 Studies
I 00 point VAS for any drug effect, good drug effect, bad drug effect, high, drunk,
impaired, stoned, like the drug effect, sedated, confused, nauseated, desire more
of
the drug, anxious, down, hungry, and bipolar 0-100 point VAS for sad/happy,
anxious/relaxed, jittery/calm, bad/good, paranoid/self-assured, fearful/unafraid.
Neurocognitive assessments measured attention and concentration, learning and
memory, and fine motor speed.
Marijuana produced a reduction in pain compared to placebo, as measured by the
pain VAS, the PGIC and on pain descriptors in the NPS, including sharp (P <
.001), burning (P < .001), aching (P < .001), sensitive (P=.03), superficial (P <
.01) and deep pain (P < .001). Notably, there were no additional benefits from the
7% THC strength ofmarijuana compared to the 3.5% THC strength, seemingly
because of
cumulative drug effects over time. There were no changes in allodynia
or thermal pain responsivity following administration of
either dose of
marijuana.
Marijuana at both strengths produced increases on measures of any drug effect,
good drug effect, high, stoned, impairment, sedation, confusion, and hunger. The
7% THC marijuana increased anxiety scores and bad drug effect (later in session)
compared to placebo. Neither strength of marijuana affected the measures of
mood. On neurocognitive measures, both the 3.5% THC and 7% THC marijuana
produced impairment in learning and memory, while only the 7% THC marijuana
impaired attention and psychomotor speed, compared to placebo. There were no
adverse cardiovascular side effects and no subjects dropped out because of
an
adverse event related to marijuana.
The authors conclude that marijuana may be effective at ameliorating neuropathic
pain at doses that induce mild cognitive effects, but that smoking is not an
optimum route of administration. The limitations of this study include: inclusion
of
subjects with many forms of
neuropathic pain and maintenance of subjects on
other analgesic medication while being tested with marijuana. These limitations
make it difficult to conclude that marijuana has analgesic properties on its own
and that the actual AEs experienced during the study in response to marijuana are
tolerable. The authors compared pain score results by the type of
pain condition,
with no significant differences found; however, the sample size of this study was
small thus a type II error may have been present. Thus, it is difficult to determine
if
any particular subset of neuropathic pain conditions would benefit specifically
from marijuana administration. However, the study produced positive results
suggesting that marijuana should.be studied further as an adjunct treatment for
uncontrolled neuropathic pain.
The second study, conducted by Ware et al. (2010) in Canada is entitled
"Smoked cannabis for chronic neuropathic pain: a randomized controlled trial."
The subjects were 21 adult patients with neuropathic pain caused by trauma or
surgery compounded with allodynia or hyperalgesia, and a pain intensity score
greater than 4 on a 10 point VAS. All subject~ maintained their current analgesic
medication and they were allowed to use acetaminophen for breakthrough pain.
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Eighteen subjects had previous experience with marijuana but none of them had
used marijuana within a year before the study.
The study design used a four-period crossover design, testing marijuana (2.5%,
6.0% and 9.4% THC) and placebo marijuana. The 2.5% and 6.0% doses of
marijuana were included to increase successful blinding. Each period was 14
days in duration, beginning with 5 days on the study drug followed by a 9-day
washout period. Doses were delivered as 25 mg of marijuana that was smoked in
a single inhalation using a titanium pipe. The first dose of each period was self-
administered using a standardized puff procedure: (1) inhale for 5 seconds, (2)
hold the smoke in their lungs for 10 seconds, and (3) exhale. Subsequent doses
were self-administered in the same manner for a total of three times daily at home
on an outpatient basis for the first five days of each period.
The primary measure was an 11-point pain intensity scale, averaged over the 5
day treatment period, which was administered once daily for present, worst, least
and average pain intensity during the previous 24 hours. Secondary measures
included an acute pain 0-100 point VAS, pain quality assessed with the McGill
Pain Questionnaire, sleep assessed with the Leeds Sleep Evaluation
Questionnaire, mood assessed with the POMS, quality of life assessed using the
EQ-5D health outcome instrument. Subjective measures included 0-100 point
VAS scales for high, relaxed, stressed and happy.
Over the first three hours after smoking marijuana, ratings of pain, high,
relaxation, stress, happiness and heart rate were recorded. During the five days of
each study period, partiCipants were contacted daily to administer questionnaires
on pain intensity, sleep, medication and AEs. Subjects returned on the fifth day to
complete questionnaires on pain quality, mood, quality of life and assessments of
potency. At the end of the study, participants completed final adverse event .
reports and potency assessments.
The average daily pain intensity was significantly lower on 9.4% THC marijuana
(5.4) than on placebo marijuana (6.1) (p=0.023). The 9.4% THC strength also
produced more drowsiness, better sleep, with less anxiety and depression,
compared to placebo (all p < 0.05). However, there were no significant
differences on POMS scores or on VAS scores for high, happy, relaxed or
stressed between THC doses.
The most frequent drug-related adverse events reported in the group receiving
9.4% THC marijuana were headache, dry eyes, burning sensation, dizziness,
numbness, and cough. Reports of high and euphoria occurred on only three
occasions, once in each dose of THC. There were no significant changes in vital
signs, heart-rate variability, or renal function. One subject withdrew from the
study due to increased pain during administration of
6% THC marijuana.
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The authors conclude that smoked marijuana reduces neuropathic pain, improves
mood and aids in sleep, but that smoking marijuana is not a preferable route of
administration. The limitations of
this study include: the lack of information on
timing of
assessments during the outpatient portion of
the study and maintenance
of subjects on other analgesic medication while being tested with marijuana.
These limitations make it difficult to conclude that marijuana has analgesic
properties on its own and that the actual AEs experienced during the study in
response to marijuana are tolerable. However, the study produced positive results
suggesting that marijuana should be studied further as an adjunct treatment for
uncontrolled neuropathic pain. .
Wilsey et al. (2013) conducted the most recent sttidy entitled "Low-Dose
Vaporized Cannabis Significantly Improves Neuropathic Pain." This study is the
only one in this review that utilized vaporization as a method ofmarijuana
administration. The subjects were 36 patients with a neuropathic pain disorder
(CRPS, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or
nerve injury) who were maintained on their current medications (opioids,
anticonvulsants, antidepressants, and NSAIDs). Although subjects were required
to have a history of
marijuana use, they refrained from use of
cannabinoids for 30
days before stu~y sessions.
Subjects participated in three sessions in which they received 1.29% or 3.53%
THC marijuana or placebo marijuana. The marijuana was vaporized using the
Volcano vaporizer and a standardized cued-puff procedure: (1) "hold the
vaporizer bag with one hand and put the vaporizer mouthpiece in their mouth" (30
seconds), (2) "get ready" (5 seconds), (3) "inhale" (5 seconds), (4) "hold vapor in
lungs" (1 0 seconds), (5) "exhale and wait" before repeating puff cycle (40
seconds). Subjects inhaled 4 puffs at 60 minutes. At 180 minutes, the vaporizer
was refilled with marijuana vapor and subjects were allowed to inhale 4 to 8 puffs
using the cued procedure. Thus, cumulative dosing allowed for a range of 8 to 12
puffs in total for each session, depending on the subjects desired response and
tolerance. The washout time between each session ranged from 3-14 days.
The primary outcome variable was spontaneous pain relief, as assessed using a 0-
100 point VAS for current pain. Secondary measures included the Patient Global
Impression of
Change (PGIC), the NPS, and a 0-100 point VAS for allodynia.
Acute pain threshold was measured with a thermal pain model. Subjective
measures included 0-100 point unipolar VAS for any drug effect, good drug
effect, bad drug effect, high, drunk, impaired, stoned, drug liking, sedated,
confused, nauseated, desire more drug, anxious, down and hungry. Bipolar 0-100
point VAS included sad/happy, anxious/relaxed, jittery/calm, bad/good,
paranoid/self-assured, and fearfuVunafraid. Neurocognitive assessments assessed
attention and concentration, learning and memory, and fine motor speed.
A 30% reduction in pain was ach,ieved in 61% of
subjects who received the
3.53% THC marijuana, in 57% of
subjects who received the 1.29% THC
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The Medical Application of Marijuana: A Review of
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marijuana and in 26% of subjects who received the placebo marijuana (p=0.002
for placebo vs. 3.53% THC, p=0.007 for placebo vs 1.29% THC; p>0.05 1.29%
THC vs. 3.53% THC). Both strengths ofmarijuana significantly decreased pain
intensity, unpleasantness, sharpness, and deepness on NPS, as well as pain ratings
on the PGIC, compared to placebo. These effects on pain were maximal with
cumulative dosing over the course of
the study session, with maximal effects at ..
180 minutes. There were no effects ofmarijuana compared to placebo on
measures ofallodynia or thermal pain. Subjects correctly identified the study
treatment 63% ofthe time for placebo, 61% of
the time for 1.29% THC, and 89%
of
the time for 3.53% THC.
On subjective measures, marijuana produced dose-dependent increases compared
to placebo on ratings for: any drug effect, good drug effect, drug liking, high,
stoned, sedated, confused, and hungry. Both strengths of
marijuana produced
similar increases in drunk or impaired compared to placebo. In contrast, desire
for drug was rated as higher for the 1.29% THC marijuana compared to the 3.53%
THC marijuana. There were no changes compared to placebo for bad effect,
nauseous, anxiety, feeling down or any of
the bipolar mood assessments. There
was dose-dependent impairment on learning and memory from marijuana
compared to placebo, but similar effects between the two strengths of
marijuana
on attention.
The authors conclude that vaporization of
relatively low doses ofmarijuana can
.produce improvements in analgesia in neuropathic pain patients, especially when
patients are allowed to titrate their exposure. However, this individualization of
doses may account for the general lack of
difference between the two strengths of
marijuana. No data were presented regarding the total amount ofTHC consumed
by each subject, so it is difficult to determine a proper dose-response evaluation.
Additional limitations ofthis study are the inclusion of
subjects with many forms
of
neuropathic pain and maintenance of
subjects on other analgesic medication
while being tested with marijuana. These limitations make it difficult to conclude
that marijuana has analgesic properties on its own~ It
is also difficult to determine
ifany particular subset of
neuropathic pain conditions would benefit specifically
from marijuana administration. However, the study produced positive results .
suggesting that marijuana should be studied further as an adjunct treatment for
uncontrolled neuropathic pain.
3.2 Appetite Stimulation in HIV
Two randomized, double-blind, placebo-controlled Phase 2 studies examined the
effects of
smoked marijuana on appetite in HIV-positive subjects (Haney et al.,
2005; Haney et al., 2007). Table 2 ofthe Appendix summarizes both studies.
The first study, conducted by Haney et al. (2005) is entitled "Dronabinol and
marijuana in HIV+ manjuana smokers: acute effects on caloric intake and mood."
The subjects were 30 HIV-positive patients who were maintained on two
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antjretroviral medications and either had clinically significant decreases in lean
muscle mass
8
(low-BIA group, n= I 5) or normal lean muscle mass (normal-BIA
group, n=l5). All subjects had a history of smoking marijuana at least twice
weekly for 4 weeks prior to entry into the study. On average, individuals had
smoked 3 marijuana cigarettes per day, 5-6 times per week for I 0-12 years.
Subjects participated in 8 sessions that tested the acute effects ofO, 10, 20, and 30
mg dronabinol oral capsules and marijuana cigarettes with 0%, 1.8%, 2.8%, and
3.9% THC concentration by weight, using a double-dummy design (with only one
active drug per session). The doses of
dronabinol .are higher than those doses
typically prescribed for appetite stimulation in order to help preserve the blinding.
There was a one-day washout period between test sessions.
Marijuana was administered using a standardized cued procedure: (1) "light the
cigarette" (30 seconds), (2) "prepare" (5 seconds), (3) "inhale" (5 seconds), (4)
"hold smoke in lungs" (10 seconds), and (5) "exhale." Each subject smoked three
puffs in this manner, with a 40-second interval between each puff.
Caloric intake was used as a surrogate measure for weight gain. Subjects received
a box containing a variety of
food and beverage items and were told to record
consumption ofthese items following that day's administration of the test drug.
Subjective measures included 0-100 point VAS for feel drug effect, good effect,
bad effect, take drug again, drug liking, hungry, full, nauseated, thirsty, desire to
eat. Neurocognitive measures and vital signs were monitored.
The low BIA group consumed significantly more calories in the 1.8% and 3.9%
THC marijuana conditions (p<O.Ol) and the 10, 20, and 30 mg dronabinol
conditions (p<O.Ol) compared with the placebo condition. In contrast, in the
normal BIA group, neither marijuana nor dronabinol significantly affected caloric
intake. This lack of
effect may be accountable, however, by the fact that this
group consumed approximately 200 calories more than the low BIA group under
baseline conditions.
Ratings ofhigh and good drug effect were increased by all drug treatments in both
the low-BIA and normal-BIA groups, except in response to the 10 mg dose of
dronabinol. The 3.9% THC marijuana increased ratings of good drug effect, drug
liking and desire to smoke again compared with placebo. Ratings of
sedation
were increased in both groups by 10 and 30 mg dronabinol, and in the normal
BIA group by the 2.8% THC marijuana. Ratings of
stimulation were increased in
the normal BIA group by 2.8% and 3.9% THC marijuana and by 20 mg
dronabinol. Increases in ratings of
forgetfulness, withdrawn, dreaming, clumsy,
heavy limbs, heart pounding, jittery, and decreases in ratings of energetic, social,
and talkative were reported in the normal BIA group with 30 mg dronabinol.
8
Lean muscle mass was assessed using bioelectrical impedance analysis (BIA). The low-BIA group was
classified with having <90% RIA, and the nonnal-BIA group was classified with having >90% RIA
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There were no significant changes in vital signs or performance on neutocognitive
measures in response to marijuana. Notably, the time course of subjective effects
peaked quickly and declined thereafter for smoked marijuana, while oral
dronabinol responses took longer to peak and persisted longer. Additionally,
marijuana but not dronabinol produced dry mouth and thirst.
In general, AEs reported in this study were low in both drug conditions for both
subject groups. In the low BIA group, nausea was reported by one subject in both
the 10 and 20 mg dronabinol conditions, while an uncomfortable level of
intoxication was produced by the 30 mg dose in two subjects. There were no AEs
reported in this group following marijuana at any dose. In the normal BIA group,
the 30 mg dose of
dronabinol produced an uncomfortable level of intoxication in
three subjects and headache in one subject, while the 3.9% marijuana produced
diarrhea in one subject.
The authors conclude that smoked marijuana can acutely increase caloric intake in
low BIA subjects without significant cognitive impairment. However, it is
possible that the low degree of cognitive impairment reported in this study may
reflect the development oftolerance to cannabinoids in this patient population,
since all individuals had current histories of
chronic marijuana use. Additional
limitations in this study include not utilizing actual weight gain as a primary
measure. However, the study produced positive results suggesting that marijuana
should be studied further as a treatment for appetite stimulation in HIV patients.
A second study conducted by Haney et al. (2007) is entitled "Dronabinol and
marijuana in HIV-positive marijuana smokers: Caloric intake, mood, and sleep."
The design of this study was nearly identical to the one conducted by this
laboratory in 2005 (see above), but there was no stratification of
subjects by BIA.
The subjects were 10 HIV-positive patients who were maintained on two
antiretroviral medications and had a history of
smoking marijuana at least twice
weekly for 4 weeks prior to entry into the study. On average, individuals had
smoked 3 marijuana cigarettes per day, 5 times per week for 19 years.
Subjects participated in 8 sessions that tested the acute effects of 0, 5 and 10 mg
dronabinol oral capsules and marijuana cigarettes with 0, 2.0% and 3.9% THC
concentration by weight, using a double-dummy design (with 4 sessions involving
only one active drug and 4 interspersed placebo sessions). Both drug and placebo
sessions lasted for 4 days each, with active drug administration occurring 4 times
per day (every 4 hours). Testing occurred in two 16-day inpatient stays. In the
intervening outpatient period, subjects were allowed to smoke marijuana prior to
re-entry to the study unit for .the second inpatient stay.
Marijuana was administered using a standardized cued procedure: (I) "light the
cigarette" (30 seconds), (2) "prepare" (5 seconds), (3) "inhale" (5 seconds), (4)
"hold smoke in lungs" (10 seconds), and (5) "exhale." Each subject smoked three
puffs in this manner, with a 40-second interval between each puff..
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Caloric intake was used as a surrogate measure for weight gain, but subjects were
also weighed throughout the study (a measure which was not collected in the
2005 study by this group). Subjects received a box containing a variety of
food
and beverage items and were told to record consumption of
these items following
that day's administration of
the test drug. Subjective measures included 0-1 00
point VAS for drug effect, good effect, bad effect, take drug again, drug liking,
hungry, full, nauseated, thirsty, desire to eat. Neurocognitive measures and vital
signs were monitored. Sleep was assessed using both the Nightcap sleep
monitoring system and selected VAS measures related to sleep.
Both 5 and 10 mg dronabinol (p < 0.008) and 2.0% and 3.9% THC marijuana (p <
0.01) dose-dependently increased caloric intake compared with placebo. This
increase was generally accomplished through increases in incidents of eating,
rather than an increase in the calories consumed in each incident. Subjects also
gained similar amounts of weight after the highest dose of each cannabinoid
treatment: 1.2 kg (2.6 lbs) after 4 days of 10 mg dronabinol, and 1.1 kg (2.4 lbs)
after 4 days of 3.9% THC marijuana. The 3.9% THC marijuana dose also
increased the desire to eat and ratings of
hunger.
Ratings of
good drug effect, high, drug liking, and desire to smoke again were
significantly increased by 10 mg dronabinol and 2.0% and 3.9% THC marijuana
doses compared to placebo. Both marijuana doses increased ratings of stimulated,
friendly, and self-confident. The 10 mg dose of
dronabinol increased ratings of
concentration impairment, and the 2.0% THC marijuana dose increased ratings of
anxious. Dry mouth was induced by 10 mg dronabinol (10 mg) and 2.0% THC
marijuana. There were no changes in neurocognitive performance or objective
sleep measures from administration of
either cannabinoid. However, 3.9% THC
marijuana increased subjective ratings of
sleep.
The authors conclude that both dronabinol and smoked marijuana increase caloric
intake and produce weight gain in IDV -positive patients. However, it is possible
that the low degree of
cognitive impairment reported in this study may reflect the
development of
tolerance to cannabinoids in this subject population, since all
individuals had current histories of chronic marijuana use. This study produced
positive results suggesting that marijuana should be studied further as a treatment
for appetite stimulation in HIV patients.
3.3 Spasticity in .Multiple Sclerosis
Only one randomized, double-blind, placebo-controlled Phase 2 study examined
the effects of
smoked marijuana on spasticity in MS. .
This study was conducted by Corey-Bloom et al. (2012) and is entitled "Smoked
cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled
trial." The subjects were 30 patients with MS-associated spasticity and had
moderate increase in tone (score 2: 3 points on the modified Ashworth scale).
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Participants were allowed to continue other MS medications, with the exception
ofbenzodiazepines. Ofthe 30 subjects, 80% had a history of
marijuana use and
33% had used marijuana within the previous year. .
Subjects participated in two 3-day test sessions, with an 11-day washout period.
During each test session they smoked a 4.0% THC marijuana cigarette once per
day or a placebo cigarette once per day. Smoking occurred through a
standardized cued-puff procedure: (1) inhalation for 5 seconds, (2) breath-hold
and exhalation for 10 seconds, (3) pause between puffs for 45 seconds. Subjects
completed an average of four puffs per cigarette.
The primary outcome measure was change in spasticity on the modified Ashworth
scale. Additionally, subjects were assessed using a VAS for pain, a timed walk,
and cognitive tests (Paced Auditory Serial Addition Test) and AEs.
Treatment with 4.0% THC marijuana reduced subject scores on the modified
Ashworth scale by an average of2.74 points more than placebo (p < 0.0001) and
reduced VAS prun scores compared to placebo (p=0.008). Scores on the
cognitive measure decreased by 8.7 points more than placebo (p=0.003).
However, marijuana did not affect scores for the timed walk compared to placebo.
Marijuana increased the rating of feeling high compared to placebo.
Seven subjects did not complete the study due to adverse events (two subjects felt
uncomfortably "high," two had dizziness, and one had fatigue). Of
those seven
subjects who withdrew, five had little or no previous experience with marijuana.
When the data were re-analyzed to include these drop-out subjects, with the
presumption they did not have a positive response to treatment, the effect of
marijuana was still significant on spasticity.
The authors conclude that smoked marijuana had usefulness in reducing pain and
spasticity associated with MS. It is concerning that marijuana-naYve subjects
dropped out of
the study because they were unable to tolerate the psychiatric AEs
induced by marijuana. The authors suggest that future studies should examine
whether different doses can result in similar beneficial effects with less cognitive
impact. However, the current study produced positive results suggesting that
marijuana should be studied further as an adjunct treatment for spasticity in MS
patients.
3.4 Asthma
Tashkin et al. (1974) examined bronchodilation in 10 subjects with bronchial asthma in
the study entitled "Acute Effects of Smoked Marijuana and Oral 1:!..
9
-
Tetrahydrocannabinol on Specific Airway Conductance in Asthmatic Subjects." The
study was a double-blind, placebo-controlled, crossover design. All subjects were
clinically stable at the time of
the study; four subjects were symptom free, and six
subjects had chronic symptoms ofmild to moderate severity. Subjects were tested with
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The Medical Application ofMm.ijuana; A Review ofPublished Clinical Studies
0.25ml of isoproterenol HCl prior to the study to ensure they responded to bronchodilator
medications. Subjects were not allowed to take bronchodilator medication within 8 hours
prior to the study. Previous experience with marijuana was not required for participation
in the study, but 7 of
the 10 subjects reported previous use of
marijuana at a rate ofless
than one marijuana Cigarette per month. No subjects reported marijuana use within 7
days ofthe study.
The study consisted of
four test sessions with an interval of at least 48 hours between
sessions. On two test sessions subjects smoked 7 mglkg of
body weight of either
marijuana, with 2% THC concentration by weight, or placebo marijuana. During the
other two test sessions, subjects ingested capsules with either 15mg of
synthetic THC or
placebo. Marijuana was administered using a uniform smoking technique: subjects
inhaled deeply for 2-4 seconds, held smoke in lungs for 15 seconds, and resumed normal
breathing for approximately 5 seconds. The author did not provide a description of
the
number of
puffs taken at any smoking session. The authors state that the smoking
procedure was repeated until the cigarette was consumed, which took approximately 1 0
minutes.
The outcome measure used was specific airway conductance (SGaw), as calculated using
measurements ofthoracic gas volume (TGV) and airway resistance (Raw) using a
variable-pressure body plethysmograph. Additionally, an assessment of
degree of
intoxication was administered only to those subjects reporting previous marijuana use.
This assessment consisted of
subjects rating "how 'high' they felt" on a scale of 0-7, 7
representing "the 'highest' they had ever felt after smoking marijuana".
Marijuana produced a significant increase of
33-48% in average SGaw compared to both
baseline and placebo (P < 0.05). This significant increase in SGaw lasted for at least 2
hours after administration. The average TGV significantly decreased by 4-13%
compared to baseline and placebo (P < 0.05). The author stated that all subjects reported
feelings of intoxication after marijuana administration.
The authors conclude that marijuana produced bronchodilation in clinically stable
astlunatic subjects with minimal to moderate bronchospasms. Study limitations include:
inclusion of
subjects with varying severity of
asthmatic symptoms, use of
SGaw to
measure lupg responses to marijuana administration, and administration of
smoke to
asthmatic subjects. Smoke delivers a number ofharmful substances and is not a,n optimal
delivery symptom, especially for asthmatic patients. Forced expiratory volume (FEVI)
via spirometry is the gold standard to assess changes in lung function, pre and post
astluna treatment, by pharmacotherapy. SGaw has been shown to be a valid tool in
bronchoconstriction lung assessment; however, since the FEVl method was not utilized,
it is unclear whether these results would correlate ifthe FEVI method had been
employed.
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3.5 Glaucoma
Two randomized, double-blind, placebo-controlled Phase 2 clinical studies
examined smoked marijuana in glaucoma (Crawford and Merritt, 1979;
Merritt et al., 1980). In both studies, intraocular pressure (lOP) was significantly
reduced 30 minutes after smoking marijuana. Maximal effects occurred 60-90
minutes after smoking, with lOP returning to baseline within 3-4 hours. These
two studies were included in the 1999 IOM report on the medical uses of
marijuana. Because our independent analysis of
these studies concurred with the
conclusions from the 1999 IOM report, these studies will not be discussed in
further detail in this review. No recent studies have been conducted examining
the effect of
inhaled marijuana on lOP in glaucoma patients. This lack of recent
studies may be attributed to the conclusions made in the 1999 IOM report that
while cannabinoids can reduce lOP, the therapeutic effects require high doses that
produce short-lasting responses, with a high degree of
AEs. This high degree of
AEs means that the potential harmful effects of
chronic marijuana smoking may
outweigh its modest benefits in the treatment of
glaucoma.
3.6 Conclusions
Ofthe eleven randomized, double-blind, placebo-controlled Phase 2 clinical
studies thatmet the criteria for review (see sections 2.2 and 2.3), ten studies
administered marijuana through smoking, while one study utilized marijuana
vaporization. In these eleven studies, there were five different therapeutic
indications: five examined chronic neuropathic pain, two examined appetite
stimulation in HIV patients, two examined glaucoma, one examined spasticity in
MS, and one examined asthma.
There are limited conclusions that can be drawn from the data in these published studies
evaluating marijuana for the treatment of
different therapeutic indications. The analysis
relied on published studies, thus information available about protocols, procedures, and
results were limited to documents published and widely available in the public domain.
The published studies on medical marijuana are effectively proof-of-concept studies.
Proof-of-concept studies provide preliminary evidence on a proposed hypothesis
regarding a drug's effect. For drugs under development, the effect often relates to a
short-term clinical outcome being investigated. Proof-of-concept studies serve as the link
between preclinical studies and dose ranging clinical studies. Therefore, proof-of-
concept studies are not sufficient to demonstrate efficacy ofa drug because they provide
only preliminary information about the effects of
a drug. Although these studies do not
provide evidence that marijuana is effective in treating a specific, recognized disorder,
these studies do support future larger well-controlled studies to assess the safety and
efficacy of
marijuana for a specific medical indication. Overall, the conclusions below
are preliminary, based on very limited evidence.
Food and Drug Administration 27 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
3.6.1 Conclusions for Chronic Neuropathic Pain
In subjects with chronic neuropathic pain who are refractory to other pain
treatments, five proof-of-concept studies produced positive results regarding the
use of smoked marijuana for analgesia. However, the subjects in these studies
continued to use their current analgesic drug regime, and thus no conclusions can
be made regarding the potential efficacy ofmarijuana for neuropathic pain in
patients not taking other analgesic drugs. Subjects also had numerous forms of
neuropathic pain, making it difficult to identify whether a specific set of
symptoms might be more responsive to the effects ofmarijuana. It is especially
concerning that some rnarijuana-nai've subjects had intolerable psychiatric
responses to marijuana exposure at analgesic doses.
3.6.2 Conclusions for Appetite Stimulation in HIV
In subjects who were HIV -positive, two proof-of-concept studies produced
positive results with the use of both dronabinol and smoked marijuana to increase
caloric intake and produce weight gain in HIV -positive patients. However, the
amount ofTHC in the marijuana tested in these studies is four times greater than
the dose of dronabinol typically tested for appetite stimulation (1 0 mg vs. 2.5 mg;
Haney et al., 2005). Thus, it is possible that the low degree of
AEs reported in
this study may reflect the development of
tolerance to cannabinoids in this patient
population, since all individuals had current histories of chronic marijuana use.
Thus, individuals with little prior exposure to marijuana may not respond
similarly and may not be able to tolerate sufficient marijuana to produce appetite
stimulation.
3.6.3 Conclusions for Spasticity in MS
In subjects with MS, a proof of
concept study produced positive results using
smoked marijuana as a treatment for pain and symptoms associated with
treatment-resistant spasticity. The subjects in this study continued to take their
current medication regiment, and thus no conclusions ean be made regarding the
potential efficacy of marijuana when taken on its own. It is also concerning that
marijuana-nai've subjects dropped out of the study because they were unable to
tolerate the psychiatric AEs induced by marijuana. The authors suggest that
future studies should examine whether different doses can result in similar
beneficial effects with less cognitive impact.
3.6.4 Conclusions for Asthma
In subjects with Clinically stable asthma, a proof of
concept study produced positive
results of smoked marijuana producing bronchodilation. However, in thi.s study
marijuana was administered at rest and not while experiencing bronchospasms.
Additionally, the administration of
marijuana through smoking introduces harmful and
irritating substances to the subject, which is undesirable especially in asthmatic patients.
Food and Drug Administration 28 March 19,
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The Medical Application of Marijuana: A Review of
Published Clinical Studies
Thus the results suggest marijuana may have bronchodilator effects, but it may also have
undesirable adverse effects in subjects with asthma.
3.6.5 Conclusions for Glaucoma
As noted in Sections 3.5, the two studies that evaluated smoked marijuana for
glaucoma were conducted decades ago, and they have been thoroughly evaluated
in the 1999 IOM report. The 1999 IOM report concludes that while the studies
with marijuana showed positive results for reduction in lOP, the effect is short-
lasting, requires a high dose, and is associated with many AEs. Thus, the
potential harmful effects may outweigh any modest benefit ofmarijuana for this
condition. We agree with the conclusions drawn in the 1999 IOM report.
3. 7 Design Challenges for Future Studies
The positive results reported by the studies discussed in this review support the
conduct of
more rigorous studies in the future. This section discusses
methodological challenges that have occurred in clinical studies with smoked
marijuana. These design issues should be addressed when larger-scale clinical
studies are conducted to ensure that valid scientific data are generated in studies
evaluating marijuana's safety and efficacy for a particular therapeutic use.
3.7.1 Sample Size
The ability for results from a clinical study to be generalized to a broader population is
reliant on having a sufficiently large study sample size. However, as noted above, all of
the 11 studies reviewed in this document were early Phase 2 .proof of
concept studies for
efficacy and safety. Thus, the sample sizes used in these studies were inherently small,
ranging from 10 subjects per treatment group (Tashkin et al., 1974; Haney et al., 2007) to
25 subjects per treatment group (Abrams et al., 2007). These sample sizes are
statistically inadequate to support a showing of
safety or efficacy. FDA's
recommendations about sample sizes for clinical trials can be found in the guidance for
industry E9 Statistical Principles for Clinical Trials (1 998).
9
For example, "the number
of
subjects in a clinical trial should always be large enough to provide a reliable answer
to the questions addressed. This number is usually determined by the primary objective
ofthe trial. The method by w}llch the sample size is calculated should be given in the
protocol, together with the estimates of
any quantities used in the calculations (such as
variances, mean values, response rates, event rates, difference to be detected)" (p. 21).
Other clinical FDA guidances for industry
10
may also contain recommendations
regarding the appropriate number of
subjects that should be investigated for a specific
medical indication.
9
E9 Statistical Principles for Clinical Trials can be found at:
www. [da.govldownloads!Drugs/GuidanceComplianceRegulatorylnformation/Guidances/ucm07 3137.pd[
10
Other guidances for industry can be found at:
www. fda. w!Dru~s/GuidqnceCompliqnceRe~ulatory lrzformation/Guidancesl ucm06498l.htm
Food and Drug Administration 29 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
3.7.2 Marijuana Dose Standardization
Dose standardization is critical for any clinical study in order to ensure that each subject
receives a consistent exposure to the test drug. The 2004 guidance for industry entitled
Botanical Drug Products
11
provides specific information on the development ofbotanical
drug products. Specifically, this guidance includes information about the need for well-
characterized and consistent chemistry for the botanical plant product and for consistent
and reliable dosing. Specifically for marijuana studies, dose standardization is important
because if
marijuana leads to plasma levels of cannabinoids that are significantly
different between subjects, this variation may lead to differences in therapeutic
responsivity or in the prevalence ofpsychiatric AEs.
In most marijuana studies discussed in this review, investigators use a
standardized cued smoking procedure. In this procedure, a subject is instn.Jcted to
inhale marijuana smoke for 5 seconds, hold the smoke in the lungs for 10 seconds,
exhale and breathe normally for 40 seconds. This process is repeated to obtain
the desired dose ofthe drug. However, this procedure may not lead to equivalent
exposure to marijuana and its constituent cannabinoids, based on several factors:
.
Intentional or unintentional differences in the depth of
inhalation may
change the amount of
smoke in the subject's lungs.
.
Smoking results in loss from side stream smoke, such that the entire dose
is not delivered to the subject.
.
There may be differences in THC concentration along the length of
a
marijuana cigarette. According to Tashkin et al. (1991), the area ofthe
cigarette closest to the mouth tends to accumulate a higher concentration
oflliC, but this section of
the cigarette is not smoked during a study.
For example, Wilsey et al. (2008) used this standardized smoking procedure . . The
reported mean (range) of
marijuana cigarettes consumed was 550 mg (200-
830mg) for the low strength marijuana (3.5% THC) and 490 mg (270-870mg) for
the high strength marijuana (7% THC). This wide range of
amounts of
marijuana
cigarette smoked by the individual subjects, even with standardized smoking
procedure and controlled number ofpuffs, supports the iss,ues with delivering
consistent doses with smoke marijuana.
In other marijuana studies that do not use a cued smoking procedure, subjects are
simply told to smoke the marijuana cigarette over a specific amount of
time
(usually 10 minutes) without further instruction (Crawford and Merritt, 1979;
Merritt et al., 1980; Ellis et al., 2009). The use of
a nonstandardized procedure .
may lead to non-equivalent exposures to marijuana and its constituent
11
Botanical Drug Products can be found at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnfonnation/Guidances/ucm070491.
df
Food and Drug Administration 30
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The Medical Application of Marijuana: A Review of Published Clinical Studies
cannabinoids between subjects because of
additional factors that are not listed
above, such as:
.
Differences in absorption and drug response if
subjects (especially
marijuana-naive ones) are not instructed to hold marijuana srrioke in their
lungs for a certain period oftime.
.
Prolonged periods between puffs may increase loss to side stream smoke.
.
Subjects may attempt to smoke the marijuana cigarette in the way they
would smoke a tobacco cigarette, which relies primarily on short, shallow
puffs.
In both standardized and non-standardized smoking procedures, subjects may
seek to control the dose ofTHC through self-titration (Crawford and Merritt,
1979; Merritt et al., 1980; Tashkin et al., 1974; Abrams et al., 2007; Ellis et al.,
2009). Self-titration involves an individual moderating the amount of
marijuana
smoke inhaled over time in order to obtain a preferred level of
psychoactive or
clinical response. The ability of
an individual to self-titrate by smoking is one
reason given by advocates of "medical marijuana" in support of
smoking of
marijuana rather than through its ingestion via edibles. However, for research
purposes, self-titration interferes with the ability to maintain consistent dosing
levels between subjects, and thus, valid comparisons between study groups.
All of
these factors can make the exact dose of
cannabinoids received by a subject
in a marijuana study difficult to determine with accuracy. Testing whether
plasma levels ofTHC or other cannabinoids are similar between subjects
following the smoking procedure would establish whether the procedure is
producing appropriate results. Additionally, studies could be conducted to
determine if
vaporization can be used to deliver consistent doses of
cannabinoids
from marijuana plant material. Specifically, vaporization devices that involve the
collection ofvapors in an enclosed bag or chamber may help with delivery of
consistent doses of
marijuana. Thus, more information could be collected on
whether vaporization is comparable to or different than smoking in terms of
producing similar plasma levels ofTHC in subjects using identical marijuana
plant material. .
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use
The studies that were reviewed administered the drug for short durations lasting
no longer than 5 days (Abrams et al., 2007; Ellis et al., 2009; Ware et al., 2010).
Thus all studies examined the short-term effect of
marijuana administration for
therapeutic purposes. However, many of
the medical conditions that have been
studied are persistent or expected to last the rest of
a patient's life. Therefore,
data on chronic exposure to smoked marijuana in clinical studies is needed. In
this way, more information will be available regarding whether tolerance,
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The Medical Application of Marijuana: A Review of
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physical dependence, or specific adverSe events develop over the course of time
with continuing use of
therapeutic marijuana.
3.7.4 Smoking as a Route of Administration
As has been pointed out by the IOM and other groups, smoking is not an optimum
route of
administration for marijuana-derived therapeutic drug products, primarily
because introducing the smoke from a burnt botanical substance into the lungs of
individuals with a disease state is not recommended when their bodies may be
physically compromised. The 1999 IOM report on medicinal uses of
marijuana
noted that alternative delivery methods offering the same ability of
dose titration
as smoking marijuana will be beneficial and may limit some of
the possible long-
term health consequences of smoking marijuana. The primary alternative to
smoked marijuana is vaporization, which can reduce exposure to combusted plant
material containing cannabinoids. The only study to use vaporization as the
delivery me,thod was Wilsey et al. (2013). The results from Wilsey et al. (2013)
showed a similar effect of
decreased pain as seen in the other studies using
smoking as the delivery method (Ware et al., 2010; Wilsey et al., 2008). This
similar effect of
decrease pain supports vaporization as a possibly viable route to
administer marijuana in research, while potentially limiting the risks associated
with smoking.
3.7.5 Difficulty in Blinding of
Drug Conditions
An adequate and well-controlled clinical study involves double-blinding, where
both the subjects and the investigators are unable to tell the difference between
the test treatments (typically consisting of
at least a test drug and placebo) when
they are administered. All of
the studies reviewed in this document administered
study treatments under double-blind conditions and
.thus were considered to have
an appropriate study design.
However, even under the most rigorous experimental conditions, blinding can be
difficult in studies with smoked marijuana because the rapid onset of
psychoactive effects readily distinguishes active from placebo marijuana. The
presence of
psychoactive effects also occurs with other drugs. However, most
other drugs have a similar psychoactive effect with substances with similar
mechanisms of
actjons. These substances can be used as positive controls to help
maintain blinding to the active drug being tested. Marijuana on the other hand,
has a unique set of
psychoactive effects which makes the use of
appropriate
positive controls difficult (Barrett et al., 1995). However, two studies did use
Dronabinol as a positive control drug to help maintain blinding (Haney et al.,
2005; Haney et al., 2007).
When blinding is done using only placebo marijuana, the ability to distinguish
active from placebo marijuana may lead to expectation bias and an alteration in
perceived responsivity to the therapeutic outcome measures. With marijuana-
experienced subjects, for example, there may be an early recognition of
the more
Food and Drug Administration 32 March 19,
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The Medical Application of Marijuana: A Review of Published Clinical Studies
subtle cannabinoid effects that can serve as a harbinger of
stronger effects, which
is less likely to occur with marijuana-naive subjects. To reduce this possibility,
investigators have tested doses ofmarijuana other than the one they were
interested in experimentally to maintain the blind (Ware et al., 2010).
Blin~ing can also be compromised by differences in the appearance of
marijuana
plant material based on THC concentration. Marijuana with higher
concentrations of
THC tends to be heavier and seemingly darker, with more "tar-
like" substance. Subjects who have experience with marijuana have reported
being able to identify marijuana from placebo cigarettes by sight alone when the
plant material in a cigarette was visible (Tashkin et al., 1974; Ware et al., 201 0).
Thus, to maintain a double-blind design, many studies obscure the appearance of
plant material by closing both ends ofthe marijuana cigarette and placing it in in
an opaque plastic tube.
While none of
these methods to secure blinding may be completely effective, it is
important to reduce bias as much as possible to produce consistent results
between subjects under the same experimental conditions.
3.7.6 Prior Marijuana Experience
Marijuana use histories in test subjects may influence outcomes, related to both
therapeutic responsivity and psychiatric AEs. Marijuana-naive subjects may also
experience a marijuana drug product as so aversive that they would not want to
use the drug product. Thus, subjects' prior experience with marijuana may affect
the conduct and results of studies.
Most ofthe studies reviewed in this document required that subjects have a
history ofmarijuana use (see tables in Appendix that describe specific
requirements for each study). However, in studies published in the scientific
literature, the full inclusion criteria with regard to specific amount of experience
with marijuana may not be provided. For those studies that do provide inclusion
criteria, acceptable experience with marijuana can range from once in a lifetime to
use multiple times a day.
The varying histories of
use might affect everything from scores on adverse event
measures, safety measures, or efficacy measures. Additionally, varying amounts
of
experience can impact cognitive effect measures assessed during acute
administration studies. For instance, Schreiner and Dunn (2012) contend _
cognitive deficits in heavy marijuana users continue for approximately 28 days
after cessation of
smoking. Studies requiring less than a month of
abstinence
prior to the study may still see residual effects ofheavy use at baseline and after
placebo marijuana administration, thus showing no significant effects on
cognitive measures. However, these same measurements in occasional or naive
marijuana users may demonstrate a significant effect after acute marijuana
administration. Therefore, the amount of
experience and the duration of
abstinence of
marijuana use are important to keep in mind when analyzing results
Food and Drug Administration 33 March 19,
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The Medical Application of Marijuana: A Review of
Published Clinical Studies
for cognitive and other adverse event measures. Lastly, a study population with
previous experience with marijuana may underreport the incidence and severity of
adverse events. Because most studies used subjects with prior marijuana
experience, we are limited in our ability to generalize the results, especially for
safety measures, to marijuana-nai've populations.
Of
the 11 studies reviewed in this document, 5 included both marijuana-nai've and
marijuana-experienced subjects (Corey-Bloom et al., 2012; Ellis et al., 2009;
Ware et al., 201 0; Merritt et al., 1980; Tashkin et al., 1974). Since the number of
marijuana-naive subjects in these studies was low, it was not possible to conduct a
separate analysis compared to experienced users. However, systematically
evaluating the effect of
marijuana experience on study outcomes is important,
since many patients who might use a marijuana product for a therapeutic use will
be marijuana-nai've.
Research shows that marijuana-experienced subjects have a higher ability to
tolerate stronger doses of oral dronabinol than marijuana-naive subjects (Haney et
al., 2005). Possibly, this increased tolerance is also the case when subjects smoke
or vaporize marijuana. Thus, studies could be conducted that investigate the role
ofmarijuana experience in determining tolerability of and responses to a variety
of THC concentrations in marijuana.
3.7.7 Inclusion and Exclusion Criteria
For safety reasons, all clinical studies have inclusion and exclusion criteria that
restrict the participation of individuals with certain medical conditions. For
studies that test marijuana, these criteria may be based on risks associated with
exposure to smoked material and the effects of
THC. Thus, most studies
investigating marijuana require that subjects qualify for the study based on
restrictive symptom criteria such that individuals do not have other symptoms that
may be known to interact poorly with cannabinoids.
Similarly, clinical studies with marijuana typically exclude individuals with
cardiac or pulmonary problems, as well as individuals with psychiatric disorders.
These exclusion criteria are based on the well-known effects of
marijuana smoke
to produce increases in heart rate and blood pressure, lung irritation, and the
exacerbation of
psychiatric disturbances in vulnerable individuals. Although
these criteria are medically reasonable for research protocols, it is likely that
future marijuana products will be used in patients who have cardiac, pulmonary,
or psychiatric conditions. Thus, individuals with these conditions should be
evaluated, whenever possible.
Additionally, all studies reviewed in this document allowed the subjects to
continue taking their current regimen of
medications. Thus all results evaluated
marijuana as an adjunct treatment for each therapeutic indication.
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The Medical Application of Marijuana: A Review of
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3.7.8 Number of Female Subjects
A common problem in clinical research is the limited number of
females who
participate in the studies.. This problem is present in the 11 studies reviewed in
this document, in which one study did not include any female subjects (Ellis et al.,
2009) and three studies had a low percentage of
female subjects (Abrams et al.,
2007; Haney et al., 2005; Haney et al., 2007). However, each ofthese four
studies investigated an HIV-positive patient population, where there may have
been a larger mal~ population pool from which to recruit compared to females.
Since there is some evidence that the density of
cannabinoid receptor type 1
(CB1) receptors in the brain may vary between males and females (Crane et al.,
2012), there may be differing therapeutic or subjective responsivity to marijuana.
Studies using a study population that is equal parts male and female may show
whether and how the effects of
marijuana differ between male and female
subjects.
35
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The Medical Application of Marijuana: A Review of Published Clinical Studies
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The Medical Application of Marijuana: A Review of Published Clinical Studies
Appendix (Tables)
Table 1: Randomized controlled, double-blind trias exammmg smokd
e mariJuana m treatment o
f neuropat tc pam
Author & Subjects (n) Drugs Study Primary Primary Outcome Adverse events/AEs
Date completed/randomized Admin. Methods Type Outcome Measure Results
Indication Subject characteristics Duration Measure
Abrams et al. Marijuana Group: 25/27 NIDA marijuana, Parallel VAS daily -52% of the marijuana -Rating for adverse events of
(2007) 22 males smoked Group pain score group showed >30% anxiety, sedation, disorientation,
5 females 0%, 3.65% THC decrease in pain score confusion, and dizziness were
HJV-Sensory 5-day compared to 24% of significantly higher in the
Neuropathy; Placebo Group: 25/28 Smoking Procedure: treatment placebo group. marijuana group compared to
Neuropathic 26 males -signal light cued period -Marijuana group had placebo group.
Pain 2 females smoking of marijuana significantly greater -Marijuana and placebo groups
cigarette with each reduction in daily pain showed a reduction in total mood
Inclusion Criteria: puff consisting of: score than placebo disturbance on POMS.
-documented HIV 1) 5s inhale smoke, group.
-documented HIV -SN 2) lOs hold smoke in AEs:
-pain score ~30mm VAS lungs -NNT=3.6 -1 grade 3 dizziness in marijuana
-prior marijuana use of
six 3) 40s exhale and group
or more times in lifetime breath normally -
-2 grade 3 anxiety, l in each group.
4) repeat procedure for
Previous Marijuana desired number of
Experience: puffs
-marijuana group: 21 # of puffs not
current users specified, only
-placebo group: 19 current specified that subjects
users smoked the entire
marijuana/placebo
Exclusion Criteria: cigarette
-substance abuse
(including tobacco) On 1
51
and last day of
-family history of intervention period
neuropathy due to causes BID.
not HIV related For all other days TID
-use of isoniazid, dapsone,
or metronidazole within 8
weeks of enrollment
Ellis et al. 28/34 NIDA marijuana, Crossover Pain -Pain reduction was -Mood disturbance, quality of life,
(2009) 28 males smoked magnitude significantly greater and psychical disability improved
0%, I%, 2%, 4%, 6%, Dose-
on DDS after marijuana for both marijuana and placebo.
HIVSensory Inclusion Criteria: 8%THC titration (on compared to placebo. -Moderate to severe adverse events
Food and Drug Administration 39 March 19,2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Author&
Date
Indication
Subjects (n)
completed/randomized
Subject characteristics
Drugs
Admin. Methods
Study
Type
Duratio11
Primary
Outcome
Measure
Primary Outcome
Measure Results
Adverse events/AEs
Neuropathy;
Neuropathic
Pain
-documented HIV
-documented neuropathic
pain refractory to ~2
analgesics
-pain score ~5 on pain
intensity subscale of DDS
Previous Marijuana
Smoking Procedures:
1
51
day)
2, 5-day
treatment
phase. with
2-week
washout
period
-NNT=3.5
were more common with
marijuana than placebo.
-HIV disease parameters did not
differ for marijuana or placebo.
-Adverse events included:
concentration difficulties, fatigue,
sleepiness or sedation, increased
duration of sleep, reduced
salivation, and thirst. These
adverse events were more frequent
in marijuana compared to placebo.
Withdrawals for drug related
~
-1 cannabis-nai've subject had
acute cannabis-induced psychosis
-I subjects developed an
intractable smoking-related cough
during marijuana administration
-Verbally cued
smoking of marijuana
cigarette with each
puff consisting of:
1) 5s inhale smoke,
2) lOs hold smoke in
lungs
3) 40s exhale and
breath nonnally
4) repeat procedure for
desired number of
puffs
-unkno,wn number of
puffs
QID
Experience:
-27 subjects had previous
experience
-63% of subjects had no
exposure for>
1 year
before study
-
Exclusion Criteria:
-current DSM-IV
substance abuse disorder
~lifetime history of
dependence on marijuana
-previous psychosis with or
intolerance to cannabinoids
-concurrent use of
approved cannabinoid
medications
-positive UDS for
cannabinoids during wash-
in week
-serious medical conditions
that affect safety
-alcohol or drug
dependence within 12
months of study
Wilsey eta!.
(2008)
Neuropathic
pain; Various
Causes
32138
20 males
18 females
Inclusion Criteria:
NIDA marijuana,
smoked
0%, 3.55%, 7% THC
Smoking Procedure:
Verbally cued
Crossover
3, 6-hour
sessions,
with 3-day
between
VAS
spontaneo
us pain _
intensity
-A significant decrease
in pain intensity for
both strengths of
marijuana compared to
placebo
-7% THC marijuana significantly
decreased functioning on
neurocognitive measures compared
to placebo.
-Subjective effects were greater for
7% THC marijuana than 3.55% -CRPS type I, spinal cord
Food and Drug Administration 40 March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Study Primary Primary Outcome
Drugs
Subjects (n) Adverse events/AEs
Date
Author &
Outcome Measure Results
Admin. Methods Type
completed/randomized
Duration Measure
injury, peripheral
Subject characteristics
Indication
smoking of marijuana sessions THC marijuana with significantly
neuropathy, or nerve cigarette with each more ratings of good drug effect,
damage puff consisting of: bad drug effect, feeling high,
-previous marijuana use 1) 5s inhale smoke, feeling stoned, impaired, sedation,
2) lOs hold smoke in confusion, and hunger compared to
Previous Marijuana lungs placebo.
Experience: 3) 40s exhale and
-median (range) time from
breath normally
previous exposure: L 7
4) repeat procedure for
years (31 days to 30 years)
desired number of
-median (range) exposure
puffs
duration: 2 years (1 day to
22 years).
Cumulative dosing
procedure:
Exclusion Criteria:
-escalate the number
-no marijuana or
of puffs from 2 to 4
cannabinoid medication
puffs over 3 smoking
use for 30 days prior to
sessions with I hour
study; confirmed by UDS
between sessions
-severe depression
-history of schizophrenia or
TID
bipolar depression
-uncontrolled hypertension,
cardiovascular disease, and
pulmonary disease
-active substance abuse
Ware eta!. NIDA placebo; Crossover -Average daily pain Pain
21/23 -Anxiety and depression were
(2010) Prairie Plant System intensity
11 males intensity was significantly improved with 9.4%
12 females Inc. (Canada) 4, 5-day on 11-item significantly lower THC compared to placebo.
marijuana, smoked out-
NRS after 9.4% THC Post-traumatic -No significant difference between
0%, 2.5%, 6%,9.4% patient*
Inclusion Criteria: compared to placebo. or placebo and 9.4% THC for
treatment
-neuropathic pain for :::>: 3 THC
postsurgical subjective effects.
months caused by trauma phase, with
pain
neuropathic
(25 mg of
or surgery 9-day AEs:
-allodynia and hyperalgesia marijuana/placebo washout -248 mild AEs were reported
-pain score >4cm VAS plant material was periods -6 moderate AEs were reported: 2
-no marijuana use for 1 placed in opaque fall, I increased pain, l numbness,
year prior to study gelatin capsules) 1 drowsiness, I pneumonia
-stable analgesic regimen -Most frequently reported drug-
Food and Drug Administration 41 March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Adverse events/AEs
Date
Author& Primary Outcome
Primary
Subjects (n) Drugs Study
Outcome Measure Results
completed/randomized Type
Admin. Methods
Indication Measure
-nonnal liver and renal
Subject characteristics Duration
related AEs for 9.4% THC:
function
Smoking Procedures:
headache, dry eyes, burning
open and tip content
-I) Break one capsule
sensation, dizziness, numbness,
Previous Mariju!l!)a and cough.
Experience:
into the bowl of
a
titanium pipe
-18 subjects had used
Withdrawals for drug related
marijuana before
2) light marijuana
reason:
3) 5s inhale smoke
material
-l subject had increased pain after
Exclusion Criteria: 6%-THC administration
-pain due to cancer or
4) lOs hold smoke in
-l subject tested positive for
nociceptive causes
lungs
cannabinoids in urine test during
-significant cardiac or
5) Exhale
placebo treatment
pulmonary disease
1 puff burned all 25
mg of plant material
-current substance abuse or
dependence (including
TID
marijuana)
-history of
psychotic
Intermediate doses .
disorders
were used to help
-current suicidal ideations
maintain blinding
Wilsey et al. 36139 -Scores for feeling stoned, feeling
(2013)
NIDA marijuana, Crossover VAS -Number of subjects
28 males high, like the drug effect, feeling
11 females
vaporized that showed a 30%
spontaneo
sedated, and feeling confused were 0%, 1.29%, 3.53% 3, 6-hour us pain reduction in pain
Neuropathic significantly greater for 3.53% THC sessions, intensity intensity was
Pain; Various Inclusion Criteria: THC marijuana compared to with at significantly greater for
Causes -CRPS type I, thalamic Smoking Procedures: both strengths of 1.29% THC marijuana, and for
pain, spinal cord injury,
leas/3 days
both strengths of
marijuana
peripheral neuropathy,
-
Verbally cued between marijuana compared to
inhalation of
vaporized compared to placebo.
radiculopathy, or nerve
sessions placebo.
-Scores for feeling drunk and
injury
material in the balloon -Both strengths of
feeling impaired are significantly
-previous marijuana use
with each puff marijuana showed a
greater in both strengths of
I) 5s inhale vapors,
consisting of: similar significant
marijuana compared to placebo.
Previous M1,gijuana
decrease in pain
2) lOs hold vapors in compared to placebo. -Scores for desired more of the
Experience: drug were significantly greater for
-median (range) time from
lungs
1.29% THC marijuana compared
last exposure prior to
3) 40s exhale and -NNT=3.2 for 1.29%
to placebo, with no significant
screening: 9.6 years (1 day
breath normally THC marijuana vs.
difference seen for 3.53% THC
to 45 years)
4) repeat procedure for placebo.
desired number of marijuana.
-16 current marijuana users
-NNT=2.9 for 3.53%
-3.53% THC marijuana had
and 23 past users
puffs THC marijuana vs.
significantly worse performance placebo.
Food and Drug Administration 42 March 19,2015
Author &
Date
Indication
Subjects (n)
completed/randomized
Subject characteristics
-# smoked daily: 6
current users, 5 past users
-# used approx. once
every 2 weeks: 8 current
users, 6 past users
-#used once every 4
weeks or less: 2 current
users, 12 past users
Exclusion Criteria:
-no marijuana or
cannabinoid medication
use for 30 days prior to
study; confirmed by UDS
-severe depression
-suicidal ideations
-diagnoses of
serious
mental illness
-uncontrolled hypertension,
cardiovascular disease, or
chronic pulmonary disease
-active substance abuse
Drugs
Admin. Methods
Study
Type
Duration
Primary
Outcome
Measure
Primary Outcome
Measure Results
Adverse events/AEs
BID
Cumulative & Flexible
Dosing:
-1
51
drug admin.
consisted of
4 puffs
from balloon.
-Followed 2 hours
later by 2nd drug
admin.
-2nd drug admin.
consisted of 4 to 8
puffs from balloon;
number of
puffs taken
was left up to the
subject so they could
self-titrate to their
target does, which
balanced desired
response and tolerance
levels.
than 1.29% THC marijuana for
learning and memory.
-Both strengths of
marijuana
significantly reduced scores on
attention compared-to placebo.
The Medical Application of Marijuana: A Review of Published Clinical Studies
..
*Out-patient: subjects were g~ven enough doses of mariJUana/placebo to last the 5-day treatment phase, and then were sent home for the remamder of
the treatment phase.
AE=Adverse Event; BID=drugadministered two times per day; CRPS=complex regional pain syndrome; DDS=Descriptor Differential Scale; NIDA=National Institute of
Drug
Abuse; NNT=Number Needed to Treat; NRS=Numeric Rating Scale; QID=drug administered four times per day; THC=delta-9-tetrahydrocannbinol; TID=drug administered three
times per day; UDS=urine drug screen; VAS= Visual Analog Scale.
Food and Drug Administration 43 March 19,2015
The Medical Application of Marijuana.: A Review of
Published Clinical Studies
T
a
ble 2 R
an
d . d
, e-
t appef1te stlmuIa
f1on m
. HIV/AIDS
om1ze , controIIed d oubl bl"
md t
na
. Is exammmg smok d e man]uana m trea ment or
Author & Subjects (n) Adverse events/AEs
Date
Primary Results
Drugs Study Type
completed/randomized Admin. Methods Duration Outcome (summary)
Indication Subject characteristics Measure
Haney et Low-BIA: 15/17 NIDA marijuana, -In Low-BIA all -Ratings of
high and good drug effect Crossover No primary
al. (2005) 12 males smoked were significantly increased for all outcome dronabinol doses and
3 females strengths of marijuana and all doses of
0%, 1.8%, 2.8%, 8, 7-hour measure is 1.8% and 3.9% THC
H/V+ with 3.9%THC .
Normal-BIA: 15/18 dronabinol except l Omg dronabinol.
session, with at specified marijuana significantly
either 15 males increased caloric intake -3.9% THC significantly increased ratings least 1 day
normal Dronabinol, oral of
dry mouth and thirsty compared to between Related compared with placebo.
muscle Inclusion Criteria: 0, 10, 20, 30mg sessions outcome placebo.
mass -21-50 years of
age -Low-BIA group showed no significant measure was
(Normal-
-prescribed at least 2 Double-dummy adverse event ratings, and in the normal-
caloric intake
BIA) or antiretroviral drugadmin. BlA group the only significant adverse
clinically medications Procedures: events in response to marijuana included:
significant -currently under the care -only 1 active dose diarrhea after 3.9% THC marijuana.
loss of .of
a physician for HlV -Dronabinol had more incidences of
per session
muscle management -one adverse events at all doses compared to
mass -medically and dronabinol/placebo marijuana.
(Low-BIA) psychiatrically stable capsule followed 1
-smoke marijuana~
hour later by
2x/week for past 4 weeks marijuana/placebo
smoking
Previous Marijuana
Experience: Smoking
-mean (SD) #of Procedures:
days/week of marijuana Verbally cued
use: Low-BIA= 6 (2); smoking of
-
Normal-BIA=5 (2) marijuana cigarette
-mean (SD) #marijuana with each puff
cigarettes/day: Low-
consisting of:
BIA=3 (2); Normal-
1) 5s inhale
BIA=3 (1)
smoke,
-mean (SO) years of 2) lOs hold smoke
marijuana use: Low-
in lungs
BIA=
12.2 (8.3); Normal-
3) 40s exhale and
BIA=10.8 (2.6)
breath normally
4) repeat for 3
Exclusion Criteria: puffs per smoking
-diagnosis ofnutritional session
malabsorption, major
depression, dementia, QD
Food and Drug Administration
44 March 19,2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Primary
Study Type Results Adverse events/AEs
Date
Drugs
Subjects (n)
Author&
Duration Outcome (summary)
Admin. Methods
completed/randomized
Measure
chronic diarrhea,
weakness, fever,
significant pulmonary
disease
-an opportunistic
infection within past 3
months
-obesity
-use of steroids within
past 3 weeks
-drug dependence
(excluding marijuana or
nicotine)
Haney et
Subject characteristics
Indication
Crossover No primary -Both strengths of
NIDA marijuana, -Both strengths of marijuana significantly
al. (2007)
10
outcome marijuana significantly smoked increased ratings of: good drug effect,
1 female
9 males
0%,2%, 3.9% 2, 16-day measure is increased caloric intake high, mellow, stimulate, friendly, and
treatment specified compared to placebo. ...
THC self-confident. Only 2% THC marijuana
Inclusion Criteria:
HJV+
phases, with 5-
-3.9% THC marijuana significantly increased ratings of anxious.
-21-50 years of
age 10 days Related significantly increased Dronabinol, oral -Both strengths of marijuana significantly
-taking~ 2 antiretroviral outcome
0, 5, lOmg between body weight compared increased subjective measures for
medications measures were to placebo. phases satisfied sleep and estimated time of
-under the care of a Caloric Intake sleep.
physician for HIV
Double-dummy
drug admin. Each 16-day &Body
management
treatment Weight
-medically and
Procedures:
-only 1 active dose phase
consisted of2,
psychiatrically stable per session
4-day active -one
-smoke marijuana~
drug period dronabinol/placebo
2x/week for the past 4 .
with 4-day capsule followed 1 weeks
hour later by placebo period
between active marijuana/placebo
Previous Marijuana
drug periods. smoking
Experience:
-mean (SD) #of
days/week of marijuana
Smoking
use: 4.6 (0.6).
Procedures:
-mean (SD) #marijuana
Light cued
'
cigarettes/day: 3.2 (0.8) smoking of
-mean (SD) years of
marijuana cigarette
marijuana use: 18.6 (3.3)
with each puff
Food and Drug Administration 45 March 19,2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Author &
Date
Indication
Subjects (n)
completed/randomized
Subject characteristics
Drugs
Admin. Methods
consisting of:
I) 5s inhale
smoke,
2) I Os hold smoke
in lungs
3) 40s exhale and
breath normally
4) repeat for 3
puffs per smoking
session
QID
Study Type
Duration
Primary
Outcome
Measure
Results
(summary)
Adverse events/AEs
Exclusion Criteria:
-diagnosis of nutritional
malabsorption, major
depression, dementia,
chronic diarrhea,
weakness, fever,
significant pulmonary
disease
-an opportunistic
infection within past 3
months
-obesity
-use of steroids within
past 3 weeks
-drug dependence
(excluding marijuana or
nicotine)
..
. .
AE-Adverse Event; BIA-Bwelectnc Impedance Analys1s; NIDA=Natwnal Institute of Drug Abuse; QD=drug admm1stered one time per day; QID=drug admm1stered four times
per day; THC=delta-9-tetrahydrocannbinol
Food and Drug Administration
46 March19, 2015
The Medical Application of Marijuana: A Review ofPublished Clinical Studies
Table 3: Randomized, controlled, double-blind trails examinin_gsmoked marijuana in treatment of spasticity in Multiple Sclerosis
Author & Subjects (n) Drugs Study Type Primary Primary Outcome Meas'ure Adverse events/AEs
Date completed/randomized Admin. Methods Duration Outcome Results
Indication Subiect characteristics Measure
Corey-
30/37 NIDA marijuana, Crossover Spasticity -Smoking marijuana . -Marijuana reduced scores on
Bloom eta!. 11 males smoked on the significantly .reduced spasticity cognitive measure compared to
(2012) 19 females 0%,4%THC 2, 3-day Modified scores compared to placebo placebo.
treatment Ashworth -Marijuana significantly increased
Multiple Inclusion Criteria: Smoking Procedure: periods, with Scale perceptions of"highness"
Sclerosis; -documented MS smoking of lJ day compared to placebo
Spasticity -spasticity marijuana cigarette washout
-moderate increase in with each puff period Withdrawals for drug-related
tone (score?: 3 on consisting of:
~
modified Ashworth scale 1) 5s inhale smoke, -2 subjects felt uncomfortably
2) lOs hold smoke in high
Previous Marijuana lungs -2 dizziness
Experience: 3) 45s exhale and
-1 fatigue
-24 subjects had previous breath normally
exposure to marijuana 4) repeat for an
-1 0 subjects used average of 4 puffs
marijuana within the year per smoking session
Exclusion Criteria: QD
-no marijuana smoking
for ~1 month prior to
screening
-psychiatric disorder
(other than depression)
-history of substance use
-substantial neurological
disease other than MS
-severe or unstable
medical illnesses
-known pulmonary
disorders
-using high dose narcotic
medication for pain
-using benzodiazepines
to control sp~ticity
..
AE-Adverse Event; MS-
Multiple Sclerosts; NlDA-Nahonal Institute of Drug Abuse; QD=drug admtmstered one time per day; THC=delta-9-tetrahydrocannbmol;
Food and Drug Administration .47 March 19, 2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of intraocular pressure in Glaucoma
Author& Subjects (n) Drugs Study Type Primary Results Adverse events/AEs
Date completed/randomized Admin. Methods Duration Outcome (summary)
Indication Subject characteristics Measure
-
Crawford& HT group: 8 NIDA marijuana, Crossover No primary -Marijuana decreased lOP by -Placebo marijuana increased
Merritt (1979) 4 males smoked outcome 37-44% from baseline. heart rate for 10 minutes in both
4 females 0%,2.8%THC 4, 1-day measure is -The maximal decrease in lOP groups.
Hypertensive
sessions, no specified was significantly greater in HT -The maximal increase in heart
and NT group: 8 Smoking time between ( -14mmHg) than NT (-
rate was significantly greater in
Normotensive 4 males Procedure: sessions Related 9mmHg) after marijuana. NT than HT after marijuana.
Glaucoma 4 females -instructed to outcome -The maximal decrease in blood
inhale 20 times measure pressure was significantly greater
Inclusion Criteria: deeply and retain was lOP in HT than NT after marijuana.
-documented glaucoma smoke in lungs
-smoke
Previous Marijuana marijuana/placebo
Experience: cigarette in 5
-all were marijuana naive minutes
Exclusion Criteria: QD
-coronary artery disease
Merritt et al. 18 NIDA marijuana, Crossover No primary -Marijuana significantly -Marijuana significantly
(1980) 12 males smoked outcome decreased lOP compared to increased heart rate compared to
6 females 0%,2%THC 2, 1-day measure is placebo. placebo
Glaucoma (31 glaucoma eyes,
sessions specified -Blood pressure significantly .
analyzed results for each Smoking decreased after marijuana
eye) Procedure: Related -All subjects experienced hunger,
-None described outcome thirst, euphoria, drowsy, and
Inclusion Criteria: -smoked 1 measure feeling cold
-documented glaucoma marijuana/placebo was lOP -Observed adverse events were
cigarette over 10-
greater in marijuana-naive
Previous Marijuana 20 minutes subjects than in subjects with
Experience:
prior marijuana experience.
-9 subjects had used
QD
marijuana at least once
AEs:
-5 subjects postural hypotension
Exclusion Criteria:
-8 subjects anxiety with
-cardiac, neurological, and
tachycardia and palpitations
psychiatric dysfunction
..
AE-Adverse Event; HT~Hypertenslve; IOP=Intraocular pressure; NIDA=Nauonal Institute of Drug Abuse; NT=Normotens1ve; QD=drug adm1mstered one t1me per day;
THC=dclta-9-tetrahydrocannbinol
Food and Drug Adrtl.inistra~ion 48 March 19,2015
The Medical Application of Marijuana: A Review of Published Clinical Studies
br d "I e
. t
rea
t
ment o as rna
Table 5: Randomized, contro
11
e
d
, dou
ble-
m tra1 s exammm2 smok d manjuana m f th
Author &
Date
Indication
10
al.(l974)
Tashkin et
Bronchial
Asthma
Subjects (n)
completed/randomized
ubject characteristics
S
Drugs
Admin. Methods
Study
Design
Duration
Primary
Outcome
Measure
Results
(summary)
Adverse events/AEs
5 males
asthma
bronchodilator
medication
Experience:
cigarette/month
females
Inclusion Criteria:
-diagnosis of bronchial
-asthma relieved by
-clinically stable
revious Marijuana
-7 subjects had previous
xposure to marijuana
-amount of
exposure < I
~clusion Criteria:
no marijuana use 57
days of study
psychiatric illness
5
P
e
E
-
-
NIMH (NIDA)
marijuana, smoked
0%,2%THC
Dronabinol, oral
0, 15mg
Dosing is 7mglkg of
body weight of plant
material
Smoking Procedure:
smoking of
marijuana cigarette
with each puff
consisting of:
I) 2-4s deep inhale
smoke,
2) l5s hold smoke in
lungs
3) Ss exhale and
breath normally
4) repeat till entire
cigarette is smoked
QD
Crossover
4, 1-day
sessions..
with at least
48 hours
between
sessions
No primary
outcome
measure is
specified
Related
outcome
measure
was sGaw
-Marijuana significantly
increased sGaw (33-48%)
compared to placebo and
baseline
-Marijuana initially significantly
increased pulse rate compared to
placebo, and then at 90 minutes
pulse rate was significantly
decreased compared to baseline.
-All subjects felt intoxicated after
marijuana.
..
AE-Adverse Event, NIDA~Nattonal Institute of
Drug Abuse, QD-
drug admmtstered one ttme per day, sGao,v=Spectfic Atrway Conductance, THC-delta-9-tetrahydrocannbmol
Food and Drug Administration 49 March 19,2015
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