UTopiAH’s life expectancy and death rate are below the Marijuana states, which as of 2017, filled the top quintile state rankings. See Part 16. These parts contain the 2015 Drug Enforcement Agency’s response to a 2011 petition from the Governors of Washington and Rhode Island to legalize Marijuana, a DEA Schedule One Drug. . The letter is viewable at https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana.

[Continued from Part 39]

Part 40 Marijuana Application 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) neuropathic pain, MS, asthma, HIV, glaucoma, designs, smoking, Blinding.

[Part 39 pages 1-13]

3. Results and Discussion……………..……. 13

3.1 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 of Drug 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

4. References ………36 [Part 41]

Appendix (Tables)…………………………….. 39 [Excluded]

[FDA March page 2 ]

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 summarized in terms of its design, outcome data, and important limitations. This information 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 effects 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., 2010; 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-controlled trial.” The

[FDA page 13 March]

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).

[footnote 6 The drug dose is reported as percentage of THC present in the marijuana rather than milligrams of THC

present in each cigarette because of the difficulty in determining the amount of THC delivered by inhalation

(see discussion in the section entitled “3 7 2 Marijuana Dose Standardization”)

Subjects were randomized to receive either smoked marijuana (3.56% THC ) 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 of their 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). Of those 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 < = [less than equal] 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-related 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

[FDA   Page 14 March]

were 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 o f 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 of the Descriptor Differential Scale (DDS). Subjects were allowed to continue taking their current routine o f 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 of 28 subjects (96%) reported previous experience with marijuana. However, of these 27 experienced subjects, 63% (n=l8) reported no marijuana use within the past year.

The study procedures compared the effects of the target dose of marijuana 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 number 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% THC 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) if AEs were intolerable. For the next 4 days of each test period, the subjects smoked their

[FDA   page 15 March]

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 30%. 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 of 3.3 points on DDS,p=0.016). The median change from baseline in V AS pain scores was -17 for marijuana treatment compared to -4 for placebo treatment (p<0.001). 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 treatment (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 of UKU responses as well as AEs such as difficulty in concentration, fatigue, sleepiness or sedation, increased duration of sleep, 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

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 of puffs during each inhalation of smoke; a lack of information about the specific timing of the subjective assessments and collection of AEs relative to initiation of the smoking

7
At the time of the 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 or intoxication or withdrawal; the disturbance is not better accounted for by a psychotic disorder that is not substance induced. The disturbance does not occur exclusively during the course of a delirium.

[FDA page 16 March]

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 analgesic 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 of neuropathic 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 1 with lumbosacral plexopathy. All subjects reported a pain intensity of at least 30 on a 0-100 V AS 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 p o i n t V A S , a n d d e g r e e o f p a i n r e l i e f w a s m e a s u r e d o n a 7- p o i n t P a t i e n t G l o b a l

-Impression of Change (PGIC)scale. Secondary measures included the Neuropathic Pain Scale (NPS), a 0-100 point VAS for allodynia, and changes in thermal pain threshold. Subjective measures were also evaluated with unipolar 0­

[FDA page 17 March]

I00 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 V AS 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 V AS, 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 of marijuana compared to the 3.5% THC strength, seemingly because of cumulative drug effects overtime. 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.

[FDA PAGE 18 MARCH ]

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 o f 6% THC marijuana.

[FDA PAGE 19 March]

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 study entitled “Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain.” This study is the only one in this review that utilized vaporization as a method of marijuana 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 study 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 arrange of 8 to 12 puffs in total for each session, depending on the subjects desired response and tolerance. The 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 o f Change (PGIC), the NPS, and a 0-100 point V AS for allodynia. Acute pain threshold was measured with a thermal pain model. Subjective measures included 0-100 point unipolar V AS 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 fearful, unafraid. Neurocognitive assessments assessed attention and concentration, learning and memory, and fine motor speed.

A 30% reduction in pain was achieved in 61% of subjects who received the 3.53% THC marijuana, in 57% of subjects who received the 1.29% THC

[FDA PAGE 20 MARCH]

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 of marijuana 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 of marijuana compared to placebo on measures of allodynia or thermal pain. Subjects correctly identified the study

treatment 63% of the 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 o f marijuana

on attention.

The authors conclude that vaporization o f relatively low doses of marijuana 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 of THC consumed by each subject, so it is difficult to determine a proper dose-response evaluation. Additional limitations of this 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 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.

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 of the Appendix summarizes both studies.

The first study, conducted by Haney et al. (2005) is entitled “Dronabinol and marijuana in HIV+ marijuana smokers: acute effects on caloric intake and mood.” The subjects were 30 HIV-positive patients who were maintained on two

[FDA PAGE 21 MARCH]

antiretroviral medications and either had clinically significant decreases in lean

muscle mass (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 I0-12 years.

Subjects participated in 8 sessions that tested the acute effects of 0, 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 of these 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<0.01) and the 10, 20, and 30 mg dronabinol conditions (p<0.01) 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 of high 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% RI

[FDA page 22 March]

There were no significant changes in vital signs or performance on neurocognitive 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 o f tolerance 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 an 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.

[FDA page 23 March]

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 0-100 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 o f 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).

[FDA page 24 March]

Participants were allowed to continue other MS medications, with the exception of benzodiazepines. Of the 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 of 2.74 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-naive 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 9 The study entitled “Acute Effects of Smoked Marijuana and Oral Delta 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 of mild to moderate severity. Subjects were tested with

[FDA   page 25           March]

0.25 ml 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 of less than one marijuana Cigarette per month. No subjects reported marijuana use within 7 days of the study.

The study consisted of four test sessions with an interval oat least 48 hours between sessions. On two test sessions subjects smoked 7 mg/kg 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 15 mg 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 10 minutes.

The outcome measure used was specific airway conductance (SGaw), as calculated using measurements of thoracic 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 o f 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 o f intoxication after marijuana administration.

The authors conclude that marijuana produced broncho dilation in clinically stable asthmatic subjects with minimal to moderate broncho spasms. Study limitations include: inclusion of subjects with varying severity of asthmatic symptoms, use of SGaw to measure lung responses to marijuana administration, and administration o f smoke to asthmatic subjects. Smoke delivers a number of harmful substances and is not an 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 asthma treatment, by pharmacotherapy. SGaw has been shown to be a valid tool in broncho constriction lung assessment; however, since the FEVl method was not utilized, it is unclear whether these results would correlate If the FEVI method had been employed.

[FDA page 26 March]

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 IOP 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

Of the eleven randomized, double-blind, placebo-controlled Phase 2 clinical studies that met 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 evaluatingmarijuanaforthetreatmentofdifferenttherapeuticindications. 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 of a 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.

[FDA page 27 March]

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 of marijuana 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 of marijuana. It is especially concerning that some marijuana-naive 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 o f both dronabinol and smoked marijuana to increase caloric intake and produce weight gain in HIV-positive patients. However, the amount of THC in the marijuana tested in these studies is four times greater than the dose of dronabinol typically tested for appetite stimulation (10 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 can be made regarding the potential efficacy of marijuana when taken on its own. It is also concerning that marijuana-naive 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 this 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.

[FDA page 28             March]

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 of marijuana 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 (1998).9 For example, “the number of subjects in a clinical trial should always be large enough to provide reliable answer to the questions addressed. This number is usually determined by the primary objective of the trial. The method by which 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 [FOOD AND DRUG ADMINISTRATION] guidances for industry
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/ucm073137.pd[

10  Other guidances for industry can be found at:
www. fda.gov/Drugs/GuidanceComplianceRegulatory lnformation/Guidancesl ucm06498l.htm

[Food and Drug Administration page 29 March 19, 2015]

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

provides specific information on the development of botanical 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 of psychiatric AEs.

In most marijuana studies discussed in this review, investigators use a standardized cued smoking procedure. In this procedure, a subject is instructed 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 of the drug. However, this procedure may not lead to equivalent exposure to marijuana and its constituent cannabinoids, based on several factors:

Botanical Drug Products

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 ofa marijuana cigarette. According to Tashkin et al. (1991), the area of the cigarette closest to the mouth tends to accumulate a higher concentration of THC, 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 (200­ 830 mg) for the low strength marijuana (3.5% THC) and 490 mg (270-870 mg) 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 of puffs, supports the issues 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 ofa 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.pdf

[FDA   Page 30            March]

cannabinoids between subjects because o f 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 smoke in their lungs for a certain period of time.

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 of THC 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 o f cannabinoids received by a subject in a marijuana study difficult to determine with accuracy. Testing whether plasma levels of THC 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 of vapors 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 of THC 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 ofa 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,

[FDA                page 31              March]

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 o f 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 method 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 actions. 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

[FDA   page 32              March]

subtle cannabinoid effects that can serve as a harbinger of stronger effects, which is less likely to occur with marijuana-naïve subjects. To reduce this possibility, investigators have tested doses of marijuana other than the one they were interested in experimentally to maintain the blind (Ware et al., 2010).

Blinding 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., 2010). Thus, to maintain a double-blind design, many studies obscure the appearance of plant material by closing both ends of the marijuana cigarette and placing it in in (sic) 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 o f studies.

Most of the studies reviewed in this document required that subjects have a history of marijuana 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 o f use might affect everything from scores on adverse event measures, safety measures, or efficacy measures. Additionally, varying amounts o f 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 of heavy 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

[FDA                page 33              March]

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-naive populations.

Of the 11 studies reviewed in this document, 5 included both marijuana-naive and marijuana-experienced subjects (Corey-Bloom et al., 2012; Ellis et al., 2009; Ware et al .,2010; 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-naive.

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 of marijuana 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 restricttheparticipationofindividualswithcertainmedicalconditions. 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.

[FDA    page 34              March    ]

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 of these four studies investigated an HIV-positive patient population, where there may have been a larger male 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.

[FDA               page 35            March]

Addiction Research Center Inventory (ARCI)

adenosine triphosphate (ATP)

adrenocorticotropic hormone (ACTH),

biologics license application (BLA)

cannabinoid receptor type 1 (CB1)

cannabichromene (CBC)

cannabidiol (CBD)

cannabinol (CBN)

Conditioned place preference (CPP)

Controlled Substances Act (CSA)

Controlled Substance Staff, Center for Drug Evaluation and Research, FDA

delta 9-THC

Diagnostic and Statistical Manual (DSM-5)

Drug Abuse Warning Network (DAWN) SAMHSA

Emergency Department [ED]

FDA Center for Drug Evaluation and Research

Food and Drug Administration (FDA)

U.S. Department of Health and Human Services (HHS)

International Classification of Diseases (ICD-10

[Investigational new drug] IND

IQ Intelligence Quotient

Monitoring the Future (MTF) survey

National Institutes of Health’s National Institute on Drug Abuse (NIH/NIDA)

[National Survey on Drug Use and Health] (NSDUH)

[new drug application] NDA

NMDA antagonists; N-Methyl-D-aspartate -anesthetics that antagonize, or inhibit the action

Substance Abuse and Mental Health Services Administration (SAMHSA)

System to Retrieve Information from, Drug Evidence (STRIDE) DEA’s

tetrahydrocannabinol (THC)

Treatment Episode Data Set (TEDS) 2011

[Continued next Part 41]

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