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. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Drug Alcohol Depend. 2018 Apr 17;187:254–260. doi: 10.1016/j.drugalcdep.2018.02.022

The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration

Nicolas J Schlienz 1, Dustin C Lee 1, Maxine L Stitzer 1, Ryan Vandrey 1
PMCID: PMC5959782  NIHMSID: NIHMS961368  PMID: 29689485

Abstract

Background

There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users.

Methods

Non-treatment seeking daily cannabis users (N=13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180–240 mg/day; 60–80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions.

Results

Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions.

Conclusions

Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders.

Keywords: Dronabinol, THC, Cannabis, Marijuana, Withdrawal, Pharmacotherapy

1. Introduction

Cannabis (marijuana, hashish) is the most widely used internationally regulated drug, with estimates that 2.7–4.9% of the world population aged 15–64 use cannabis at least once annually (UNODC, 2014). Most cannabis users are able to use the drug in a controlled manner and are able to reduce or quit use with no formal treatment (Hughes et al., 2016). However, a subset of individuals develop a pattern of cannabis use that contributes to significant psychosocial distress and they have great difficulty initiating and sustaining abstinence during attempts to quit (Budney et al., 2007; Copeland et al., 2001; Davis et al., 2014; Stephens et al., 2002). Evidence-based behavioral treatments for substance use disorders (e.g., motivational interviewing (MI), cognitive behavioral therapy (CBT), contingency management (CM)) are effective in the treatment of cannabis use disorders, but the majority of individuals receiving these interventions fail to achieve sustained abstinence (Benyamina et al., 2008; Budney et al., 2015; Davis et al., 2014; Nordstrom and Levin, 2007). Thus, there is a clear need for advancing the treatment of cannabis use disorder (CUD).

One approach is to identify medications likely to assist in the initiation and/or maintenance of abstinence. Dronabinol (oral delta-9-tetrahydrocannabinol (THC); Marinol®) has been extensively studied as a potential cannabis pharmacotherapy in both laboratory and clinical settings (Budney et al., 2007; Haney et al., 2004, 2008; Hart et al., 2002; Levin et al., 2011, 2016; Vandrey et al., 2013). Dronabinol is an attractive candidate medication for treating CUD based on the success of comparable agonist or partial agonist medications in the treatment of opioid use disorders (e.g., methadone or buprenorphine; Stotts et al., 2009) and tobacco use disorders (nicotine or varenicline; Raupach and van Schayck, 2011).

In laboratory studies with non-treatment seeking daily cannabis users, dronabinol (30–120 mg/day) reliably and dose-dependently suppressed cannabis withdrawal symptoms (Budney et al., 2007; Haney et al., 2004, 2008; Vandrey et al., 2013). Dronabinol maintenance (40–120 mg/day) reduced subjective ratings of ‘good drug effect’ and attenuated increased heart rate following acute administration of smoked cannabis (Hart et al., 2002; Vandrey et al., 2013). Two prior studies evaluated whether dronabinol maintenance alters cannabis self-administration. One study found no effect of dronabinol maintenance (40–80 mg/day; 10 or 20 mg qid) on rates of cannabis (1.8% THC) self-administration (Hart et al., 2002). In a second study, dronabinol (60 mg/day; 20 mg tid) combined with adrenergic agonist lofexidine (2.4 mg/day), but not dronabinol alone, reduced cannabis self-administration in a laboratory model of relapse (Haney et al., 2008).

Case reports and randomized controlled trials have described the use of dronabinol in clinical settings. Levin and Kleber (2008) detailed two case reports in which treatment-resistant cannabis users achieved sustained cannabis abstinence with the assistance of open-label dronabinol. In one case, dronabinol (40 mg/day) was administered to help initiate abstinence and discontinued following a dose taper. In the second case, dronabinol (initially 40–50 mg/day and tapered to 15–20 mg/day during maintenance) was continued indefinitely due to several instances of cannabis relapse and excessive alcohol consumption upon dronabinol discontinuation. In both cases, concomitant psychiatric medications were administered. To date, two controlled clinical trials of dronabinol-assisted treatment have been completed. In one randomized controlled trial, dronabinol (up to 40 mg/day) reduced subjective ratings of withdrawal and improved treatment retention compared with participants receiving placebo; however, no differences in cannabis use outcomes were observed between study conditions (Levin et al., 2011). In the second study, a combination of dronabinol (20 mg tid) and lofexidine (0.6 mg tid) was compared with placebo. Participants in both medication conditions (active and placebo) decreased cannabis use and approximately 30% achieved at least three weeks of consecutive abstinence, but there was no difference in cannabis use outcomes by medication assignment (Levin et al., 2016).

Despite work evaluating dronabinol as a potential therapeutic in the treatment of CUD relative to other medications, the question remains whether the dronabinol doses previously evaluated have been appropriate for achieving clinical effects given the magnitude of cannabinoid tolerance that can result from daily cannabis use. Prior studies have indicated that daily or near-daily cannabis users can tolerate acute THC doses up to 90 mg (Lile et al., 2013) and daily doses of up to 210 mg (Benowitz and Jones, 1981). Long-term maintenance on high doses of dronabinol is not an attractive clinical approach in the absence of a demonstrated patient or public health gain in switching from inhaled cannabis to oral THC, however, short-term use of dronabinol with concurrent behavioral therapy may be well-tolerated and could help treatment-seeking cannabis users achieve an initial period of abstinence and transition to complete abstinence with a dose taper. Thus, the present study was conducted to evaluate whether, and to what degree, high-dose dronabinol maintenance could reduce cannabis self-administration among daily users. We hypothesized that dose-dependent effects of dronabinol would be observed on rates of cannabis self-administration under progressive ratio and forced-choice experimental conditions. This study also extends previous research by providing additional data regarding the safety and tolerability of acute and repeated dronabinol dose effects in heavy cannabis users.

2. Material and methods

2.1 Participants and Recruitment

Cannabis users were recruited through newspaper advertisements and flyers posted on campus and community bulletin boards. Volunteers were eligible for the study if they: 1) were at least 18 years of age; 2) self-reported a minimum of 25 days of cannabis use per month in the previous year and provided a urine specimen with > 50 ng/mL THCCOOH; 3) were not currently taking psychoactive medication; 4) did not meet DSM-IV-TR criteria for an Axis I psychiatric disorder other than nicotine or cannabis dependence; 5) had a negative urine toxicology test for illicit drugs other than cannabis at study admission; 6) were not pregnant, breast feeding, or planning to become pregnant within the next 3 months; 7) were not seeking treatment for cannabis-related problems or using cannabis for a medical disorder; 8) had a normal electrocardiogram (ECG) at intake and no major cardiac events (e.g., heart attack) in the six months prior to study admission.

Written informed consent was obtained prior to clinical evaluation and study participation. The study was approved by the John Hopkins Medicine IRB and conducted in accordance with the ethical standards of the Declaration of Helsinki. Study eligibility was ascertained with a telephone interview followed by a comprehensive in-person clinical evaluation. A physical evaluation, including ECG, was conducted by study medical staff. Routine blood chemistry tests were completed, and participants with clinically significant impairment of kidney/liver function were excluded. The Timeline Follow-Back method (TLFB; Sobell and Sobell, 1992) was used to obtain the amount and frequency of substance use during the prior 3 months. Urine testing for recent drug use and pregnancy was conducted using qualitative rapid tests. The DSM Checklist (Hudziak et al., 1993) modified to include DSM-IV-TR criteria was used to diagnose current Axis I psychiatric disorders. The Marijuana Quit Questionnaire (MQQ; Boyd et al., 2005) was used to obtain a detailed cannabis use history.

Sixteen participants were enrolled in the study, and 13 completed the protocol and were included in the final analysis. Of study non-completers, two were discharged because they indicated a preference for 0.0% THC cannabis (placebo) over 5.7% THC cannabis in the initial exposure period (described in 2.2.1 below), and one participant voluntarily withdrew from the study for personal reasons. Study completers had an average (SD) age of 25 (5) years; 10 were male and 3 were female; 11 were African American, 1 was Caucasian, and 1 was multi-racial. Participants were daily cannabis users, had an average (SD) age of first cannabis use at 15 (2) years of age, had been using cannabis frequently for 9 (6) years, and smoked cannabis 4 (2) times per day at the time of study entry. Ten of the 13 participants met DSM-IV-TR criteria for cannabis dependence. The use of alcohol and other illicit drugs was infrequent (average alcohol consumption was < 1 drink per week). Tobacco use was self-reported by eight participants and was allowed ad-libitum during the study.

2.2 Study Procedures

The study used a within-subjects crossover design to compare the effects of low-dose (120 mg/day; 40 mg tid) and high-dose (180–240 mg/day; 60–80 mg tid) dronabinol maintenance relative to placebo on cannabis (placebo and 5.7% THC) self-administration behavior during progressive ratio and forced-choice (cannabis versus money) conditions. The study was conducted on the residential research unit of the Johns Hopkins University Behavioral Pharmacology Research Unit (BPRU) and lasted 39–40 days. The first two study days provided initial exposure and discrimination training to the two cannabis doses (placebo and 5.7% THC). This was followed by a 1–2-day dronabinol dose run-up evaluation to determine individual participant tolerability of acute dronabinol doses up to a target dose of 80 mg. Following the dronabinol dose run-up evaluation, participants completed three counterbalanced dronabinol maintenance phases (placebo, low-dose, high-dose), each lasting 12 consecutive days. Dronabinol dose order was counterbalanced across participants using a balanced Latin Square procedure.

2.2.1 Cannabis Exposure and Discrimination Testing

Participants were told that there were two types of cannabis cigarettes used in the study, labeled “Drug A” and “Drug B.” Participants completed a drug sampling procedure on the first two days of the study. On Day 1, participants self-administered five cannabis cigarettes of “Drug A” and on Day 2 they self-administered five cannabis cigarettes of “Drug B” (1 cigarette each at 11:00, 14:00, 17:00, 20:00, and 23:00). Cannabis self-administration occurred in an ad-libitum manner and subjective drug effect rating assessments were conducted after each exposure. The order of exposure (whether “Drug A” was placebo or 5.7% THC cannabis) was counterbalanced across participants. On the morning of Day 3, participants were asked to rate the quality of each “type” of cannabis (e.g., provide an approximate street value) and indicate whether they preferred Drug A or Drug B. Two participants indicated a preference for placebo cannabis over active cannabis and were discharged from the study on Day 3 prior to dronabinol dosing.

2.2.2 Dronabinol Dose Run-Up Evaluation

Beginning on Day 3, participants received escalating doses of dronabinol at 09:00, 14:00, and 19:00. The dose run-up began with acute administration of 40 mg based on good tolerability of this dose used in a prior study in our laboratory (Vandrey et al., 2013), and increased in 20 mg increments to a maximum of 80 mg, unless a dose was not tolerated by the study participant. Dose intolerance was defined as a participant who reported any of the following: 1) were unwilling to take the drug again; 2) rated unpleasant side effects as “severe”; or 3) exhibited severe intoxication observed by research staff (e.g., vomiting, inability to complete study tasks or other signs of significant impairment/dysfunction). When dose intolerance occurred, the subsequent dose that was administered was 10 mg less than the previous dose. This procedure was carried out until participants were either administered and tolerated the maximum dose of 80 mg or a lower maximum tolerated dose was identified. The maximum tolerated acute dose was 60 mg for 4 participants and 80 mg for the remaining 9 participants. No cannabis was administered during the dronabinol dose run-up evaluation.

2.2.3 Dronabinol Maintenance Periods

Once the maximum dronabinol dose was determined, participants completed three sequential 12-day dronabinol maintenance periods (placebo, low-dose, high-dose) with dose order counterbalanced across participants. Participants were administered dronabinol at 09:00, 14:00, and 19:00 each day during each maintenance period. Participants were told that they may receive dronabinol or placebo at any time during the study, that the medication dose they received would change periodically throughout the study, and that any changes that occurred would be predetermined and would be unaffected by their self-administration or choice behavior. Because the behavioral effects of dronabinol tend to abate after approximately four to six hours and withdrawal effects begin to onset within 24 hours of abstinence, washout periods were not used between each 12-day maintenance period.

During each 12-day dronabinol maintenance period, participants could access and self-administer cannabis during four experimental conditions: 1) progressive ratio access to smoked 5.7% THC cannabis (3 days); 2) progressive ratio access to smoked placebo cannabis (3 days); 3) forced-choice between self-administering smoked 5.7% THC cannabis or receiving money (3 days); and 4) forced-choice between self-administering smoked placebo cannabis or receiving money (3 days). Cannabis type (Drug A, Drug B) and access condition (progressive ratio, forced-choice) were randomly assigned for each day as well as the order in which they occurred (Table 1 illustrates a sample schedule). On the morning of each study day, participants were informed of the type of cannabis available for that day and the condition under which it could be accessed (e.g., “Today you will be able to choose between receiving Drug A or $2”).

Table 1.

Example Cannabis Access Schedule

Study Day
1 2 3 4 5 6 7 8 9 10 11 12
Cannabis Type PL A A PL A PL PL A A PL PL A
Self-Admin Type Ch PR Ch PR Ch PR Ch PR Ch Ch PR PR
Choice Value $2.00 $0.25 $2.00 $1.00 $1.00 $0.25
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Note: Self-Admin=Self-Administration; PL=Placebo Cannabis; A =Active Cannabis; Ch=Cannabis vs. Money Choice; PR=Progressive Ratio

2.2.4 Cannabis Self-Administration

2.2.4.1 Progressive Ratio Procedure

On half of the study days, participants could complete behavioral (progressive ratio) response requirements to “earn” cannabis cigarettes between the hours of 10:00 and 22:00. The cannabis access period did not begin until 10:00 so that there was adequate time for the volunteers to experience the effects of the 09:00 dronabinol dose prior to making the decision whether to seek access to cannabis. The progressive ratio task consisted of increasing behavioral response requirements (computer mouse clicks) that participants could complete to earn one cannabis cigarette for immediate ad-libitum consumption. The initial response requirement was low (1500 clicks per cannabis cigarette), increased on a graduated schedule (i.e., 2100, 2800, 3600, 4500, 5500, 6600, 7800, 9100, 10500, 12000, 13600, 15300, 17100, 19000, 21000, 23100, 25300, 27600, 30000), and ended with a very high response requirement (32500 clicks per cannabis cigarette).

2.2.4.2 Cannabis Versus Money Choice Procedure

On half of the study days participants were randomized to make five discrete choices (at 10:00, 13:00, 16:00, 19:00, and 22:00) between smoking a single cannabis cigarette (either placebo cannabis or 5.7% THC cannabis) versus receiving a predetermined amount of money ($0.25, $1.00, or $2.00 USD). In pilot testing for this study, use of a $5 choice resulted in exclusive responding to the monetary alternative, independent of dronabinol maintenance conditions, for most participants. Lower magnitude alternatives ($0.25, $1.00, or $2.00 USD) were determined to maximize the sensitivity of observing preference switching behavior due to dronabinol maintenance and is consistent with the prior study of dronabinol maintenance on cannabis self-administration conducted by Hart and colleagues (2002).

During each 12-day dronabinol maintenance period, participants completed cannabis versus money choice days for each of the three monetary values two times, once when placebo cannabis was available and once when 5.7% THC cannabis was available. Cannabis type and the magnitude of the monetary alternative was constant across all five choices on a given day. At the designated time for each choice, a study staff member presented the participant with the amount of money designated for the choice sessions on that day and placed a cannabis cigarette, a lighter, and an ashtray on a table in front of the participant. Participants were given the option to receive and bank the money or spend the full amount to purchase the cannabis cigarette. If the participant elected to purchase cannabis, the cannabis cigarette was smoked immediately after; participants were not permitted to save it to smoke later in the day. If participants chose to keep the money, they “deposited” it into a lock-box that contained their study earnings.

A limitation of providing cash rewards to participants during inpatient studies is that they often cannot use the money until after the study is completed. This delay in redemption is likely to result in the monetary reinforcers being devalued by the participants (Bickel & Johnson, 2003). To reduce the likelihood or at least the degree to which the monetary incentives were devalued in this study, participants were able to use their earnings to purchase items (e.g., snacks, order food delivery, cell phone minutes, etc.) during their stay. Any remaining earnings balance was provided to participants in cash upon discharge from the study.

2.3 Study Drugs

Dronabinol (Marinol®) was obtained, prepared, and dispensed by the Johns Hopkins Investigational Drug Pharmacy. To ensure proper blinding, all dronabinol doses were enclosed in large (size 000) opaque capsules filled to equal weight with lactose.

Cannabis cigarettes were obtained from the Drug Supply Program of the National Institute on Drug Abuse (NIDA). Placebo cannabis cigarettes contained approximately one gram of cannabis from which cannabinoids had been removed via ethanol extraction. “Active” cannabis cigarettes contained approximately one gram of 5.7% THC cannabis. Cannabis smoking occurred in a room outside of the residential research unit that was constructed with an active exhaust system designed for research with smoked substances.

2.4 Study Assessments

The primary outcome measure was the number of cannabis cigarettes self-administered during each progressive ratio and cannabis versus money choice condition. In addition, participants completed subjective measures of drug effects, cannabis withdrawal and craving, health, and sleep each day. At 09:00, participants completed the Marijuana Withdrawal Checklist (MWC; Budney et al., 1999) to measure cannabis withdrawal symptoms during the prior 24 hours. A sleep diary was used to obtain self-reported latency to sleep onset, total sleep, number of nocturnal awakenings, time awake after sleep onset, and 100 mm visual analog scale (VAS) ratings of sleep quality, mood on awakening, and alertness on awakening. A self-reported adverse event form was completed in which participants used a 4-point Likert scale (none, mild, moderate, severe) to rate their prior 24-hour experience with respect to a list of medication side effects included on the package insert for dronabinol. Vital signs were obtained (via automated monitor) at 09:00, 14:00, and 19:00 each day.

2.5 Data Analysis

Study outcome measures were analyzed using separate repeated measures regressions with an AR(1) covariance structure. The primary outcome measure was the amount of cannabis self-administered, which was assessed separately during progressive ratio and forced-choice access conditions. Planned comparisons (Student-Newman-Kuels (SNK) multiple comparison tests) were conducted to evaluate differences between dronabinol dose conditions (low-dose vs. placebo, high-dose vs. placebo, low-dose vs. high-dose). For cannabis self-administration outcomes, planned comparisons were only conducted to evaluate self-administration of 5.7% THC cannabis because the impact of placebo cannabis self-administration is not relevant to the clinical application of dronabinol in the treatment of CUD. Also, evaluation of adverse events associated with each dronabinol dose was limited to assessments conducted on study days when participants self-administered placebo cannabis due to the confounding effects of smoking 5.7% THC cannabis cigarettes on other study days. Analyses were completed using SAS statistical software (Version 9.1), and an α value of .05 was used for all tests.

3. Results

3.1 Cannabis Self-Administration

3.1.1 Progressive Ratio Procedure

Significant main effects of cannabis-type (F(1,12)=391.5, p<.001) and dronabinol maintenance dose (F(2,24)=9.1, p=0.001) were observed for self-administration on days in which cannabis access was available under a progressive ratio reinforcement schedule. As expected, participants self-administered significantly fewer placebo cannabis cigarettes compared with 5.7% THC cannabis cigarettes on progressive ratio study days. Maintenance on both low-dose (120 mg) and high-dose (180–240 mg) dronabinol significantly reduced self-administration of 5.7% THC cannabis compared with placebo dronabinol maintenance under progressive ratio access. There was no difference between low-dose and high-dose dronabinol maintenance on the number of 5.7% THC cannabis cigarettes self-administered (p=.63). Figure 1 (panel A) illustrates the number of 5.7% THC cannabis cigarettes self-administered at each dronabinol maintenance dose. Cannabis self-administration under progressive ratio conditions did not differ based on the order in which participants received the 3 dronabinol maintenance doses.

Figure 1.

Figure 1

Figure 1

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Figure 1A. Results of progressive ratio (panel A) self-administration of active (i.e. 5.7% THC) cannabis cigarettes.

Figure 1B. Results of forced-choice (panel B) self-administration of active (i.e. 5.7% THC) cannabis cigarettes.

Note: Asterisks (*) represent a significant difference in self-administration during active (120 or 180–240 mg) dronabinol maintenance compared to placebo. *p≤ 0.05. Error bars represent the standard error of the mean

3.1.2 Cannabis vs. Money Choice Procedure

Significant main effects of cannabis-type were observed for self-administration at all three monetary choice values ($0.25, $1.00, or $2.00 USD; (Fs(1,12)=52.2–117.3; all ps<.001). As was observed for the progressive ratio condition, participants self-administered a greater number of 5.7% THC cannabis cigarettes compared with placebo. Figure 1 (panel B) displays the average number of times participants chose to self-administer 5.7% THC cannabis cigarettes as a function of the alternative monetary choice value and dronabinol maintenance dose condition. In the $0.25 USD choice condition, high-dose, but not low-dose dronabinol maintenance reduced self-administration of 5.7% THC cannabis compared with placebo dronabinol maintenance (p=.05). In the cannabis versus $1.00 USD choice condition, both low-dose and high-dose dronabinol maintenance significantly reduced self-administration of 5.7% THC cannabis compared with placebo dronabinol maintenance (p=.01 and p=.03, respectively). In the $2.00 USD choice condition, low-dose (p=.03), but not high-dose (p=.23) dronabinol maintenance significantly reduced 5.7% THC cannabis self-administration compared with placebo. There were no differences between low-dose and high-dose dronabinol maintenance on 5.7% THC cannabis self-administration at any monetary value in the forced-choice test (all ps>.25).

3.2 Cannabis Withdrawal

Significant dronabinol dose effects were observed for most cannabis withdrawal symptoms and the composite WDS (provided in Table 2). Compared with placebo, low-dose dronabinol maintenance significantly reduced self-report ratings of depressed mood, decreased appetite, irritability, sleep difficulty, increased aggression, stomach pains, strange/wild dreams, general physical discomfort, and the composite WDS on study days in which placebo cannabis was available for self-administration. Similarly, high-dose dronabinol maintenance significantly reduced ratings of depressed mood, decreased appetite, irritability, sleep difficulty, sweating, restlessness, increased aggression, general physical discomfort, and the WDS on placebo cannabis days. There were no differences in withdrawal between the low-dose and high-dose dronabinol maintenance conditions.

Table 2.

Cannabis withdrawal scores, drug effects, adverse events, and blood pressure ratings on placebo cannabis days by dronabinol maintenance dose condition.

Placebo
Mean (SEM)		 Low-Dose
Mean (SEM)		 High-Dose
Mean (SEM)
MWC Items
 Depressed Mood 0.17 (0.12) 0.04 (0.04)* 0.04 (0.04)*
 Decreased Appetite 0.33 (0.19) 0.09 (0.08)* 0.08 (0.06)*
 Irritability 0.22 (0.14) 0.09 (0.09)* 0.09 (0.07)*
 Sleep Difficulty 0.72 (0.30) 0.41 (0.24)* 0.36 (0.17)*
 Sweating 0.18 (0.11) 0.09 (0.06) 0.01 (0.01)*
 Restlessness 0.15 (0.13) 0.09 (0.09) 0.03 (0.03)*
 Increased Aggression 0.12 (0.09) 0.02 (0.02)* 0.00 (0.00)*
 Stomach Pains 0.14 (0.12) 0.03 (0.03)* 0.05 (0.04)
 Strange/Wild Dreams 0.14 (0.10) 0.03 (0.03)* 0.05 (0.03)
 General Physical Discomfort 0.17 (0.12) 0.01 (0.01)* 0.06 (0.06)*
MWC Composite WDS 2.44 (0.90) 0.95 (0.40)* 0.91 (0.38)*
DEQ Items
 Drug Effect 4.26 (0.48) 9.77 (0.73)* 8.98 (0.70)*
 Good Drug Effect 5.06 (0.55) 9.60 (0.72) 9.84 (0.74)*
 Heart Racing/Pounding 0.99 (0.16) 1.48 (0.24) 2.34 (0.34)*
 Craving 64.56 (1.44) 50.49 (1.50)* 48.80 (1.43)*
 Irritable 2.29 (0.34) 2.10 (0.27) 0.80 (0.13)*
 Hungry 11.40 (0.77) 14.45 (0.82) 9.46 (0.66)
Adverse Events
 Dry Mouth 0.24 (0.15) 0.28 (0.16) 0.42 (0.20)*
Blood Pressure
 Systolic 126.43 (0.51) 121.00 (0.46)* 118.62 (0.46)*
 Diastolic 72.11 (0.35) 67.69 (0.36) 66.55 (0.36)
 Heart Rate (Beats Per Minute) 71.67 (0.43) 73.81 (0.42) 74.69 (0.50)*
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Note:

*

significantly different from placebo (all ps<.05)

3.3 Dronabinol Drug Effects/Adverse Events

Compared with placebo, maintenance on low-dose dronabinol increased self-reported ratings of ‘feel a drug effect,’ ‘feel a good drug effect,’ and decreased ratings for ‘craving’ on days in which placebo cannabis was available for self-administration. Compared with placebo, high-dose dronabinol maintenance significantly increased ratings of ‘feel a drug effect,’ ‘feel a good drug effect,’ ‘dry mouth’ and ‘feel your heart racing/pounding,’ and significantly lowered ratings of ‘feel irritable,’ and ‘craving’ on placebo cannabis self-administration days. No significant differences between placebo and either dronabinol dose condition were observed on ratings of ‘unpleasant drug effect,’ ‘feel sick,’ ‘feel anxious or nervous,’ ‘feel relaxed,’ ‘feel paranoid,’ ‘feel sleepy or tired,’ ‘feel alert,’ and ‘feel restless.’ Few significant differences emerged between the two active dronabinol dose conditions on subjective drug effect measures. Compared with the low dose, high-dose dronabinol had significantly lower ratings of ‘feel irritable’ and ‘feel hungry or have the munchies.’

3.4 Cardiovascular Effects

Significant dronabinol dose effects were observed on placebo cannabis self-administration days. Low-dose dronabinol maintenance significantly reduced both systolic and diastolic blood pressure (BP) compared with placebo but did not affect heart rate. Maintenance on the high-dose dronabinol significantly reduced systolic and diastolic blood pressure and increased heart rate. Though statistically significant, mean differences between placebo and the high-dose maintenance condition were 6 mmHg systolic BP, 5 mmHg diastolic BP, and 3 beats per minute for heart rate, none of which are clinically significant. No significant differences in blood pressure or heart rate were observed between the low-dose and high-dose dronabinol conditions.

4. Discussion

The present study extends previous work evaluating the therapeutic potential of oral dronabinol for the treatment of cannabis use disorder (CUD). This study examined daily dronabinol doses (120–240 mg/day) that were substantially higher than those previously tested (40–80 mg/day) and measured the impact of sustained (12-day) dronabinol versus placebo dosing on cannabis self-administration, withdrawal, and craving, in addition to cardiovascular and self-reported drug effects associated with the dronabinol maintenance doses. Under both progressive ratio access and forced-choice (drug versus money) conditions, active dronabinol maintenance significantly reduced self-administration of smoked cannabis containing 5.7% THC.

The reduction of cannabis self-administration at both maintenance doses is the highlight of the present study given that multiple prior studies failed to observe dronabinol-related reductions in cannabis self-administration (Hart et al., 2002; Levin et al., 2011, 2016). The exception was a study by Haney and colleagues that showed the combination of dronabinol (60 mg/day) and lofexidine (2.4 mg/day), but not dronabinol alone, decreased cannabis consumption in a laboratory model of relapse (Haney et al., 2008). One possible explanation for the difference in findings is that the dronabinol doses used in published laboratory studies and randomized controlled trials (range=40–80 mg/day) may have been insufficient to reduce cannabis self-administration among heavy daily cannabis users who likely had developed tolerance to THC effects (Haney et al., 2008; Hart et al., 2002; Levin et al., 2011, 2016). Also, participants in the Hart et al. study (2002) could choose between self-administering one cannabis cigarette or receive a $2.00 voucher provided at the end of the study. In contrast, participants in the present study were given cash in hand and could use that money to order food/snacks, pay for cell phone service, and other commodities. Our procedure may have provided a more sensitive assessment given that behavioral economics research has demonstrated that a delay in the redemption/receipt of money reduces its value (see Johnson and Bickel, 2003; Johnson et al., 2010).

Consistent with prior work (Budney et al., 2007; Haney et al., 2004; Vandrey et al., 2013), dronabinol suppressed cannabis withdrawal, reduced craving, and produced few adverse events. Of the adverse effects ratings that reached statistical significance (dry mouth, sweating, reduced blood pressure, increased heart rate), qualitative evaluations indicated that these effects were of mild severity and no participants were discharged from the study as a result of these events. Should its therapeutic utility be established, these observations support the safety of chronic dosing with dronabinol in daily cannabis users.

In the current study, there were minimal differences between the low (120 mg/day) and high (180–240 mg/day) dronabinol doses on cannabis self-administration and withdrawal; both significantly reduced the number of cannabis cigarettes consumed under the progressive ratio and forced-choice tasks and suppressed withdrawal and craving to a similar extent. Though qualitatively similar, significant differences between active dronabinol doses of drug effect ratings were limited to two items. Compared to the low dose, ratings of ‘feel irritable’ and ‘feel hungry or have the munchies’ were lower for the high dose. Cardiovascular effects (blood pressure, heart rate) and adverse events did not significantly differ between the two active dronabinol dose conditions. Though dose requirements likely vary across individuals, our findings suggest that the low dose (120 mg/day) may be sufficient to achieve theoretically desirable therapeutic benefits. For cases where initial treatment response to a low dose is poor, data also suggest that titration to a higher dronabinol dose may confer a favorable risk-benefit ratio. However, the study failed to provide unequivocal support for dronabinol’s therapeutic value. Dronabinol reduced but did not extinguish cannabis self-administration in contrast to opioid research where self-administration is suppressed with a sufficiently high dose of opioid agonist medication (Donny et al., 2005).

Failure to observe complete elimination of cannabis self-administration may be attributed to the pharmacology of dronabinol (partial agonist), or to other unique study characteristics. Specifically, both dronabinol doses used in this study are well above that recommended for FDA approved indications in the general population. Thus, both doses in this study may have reached the ceiling of its efficacy in reducing cannabis self-administration, withdrawal, and craving, but also did not achieve a dose-orderly increase in the strength of subjective drug effects that would completely suppress self-administration behavior as occurs with full-agonist opioids. This may also explain why cannabis self-administration decreased as a function of the value of the monetary reward in the forced-choice procedure, but that reduction in self-administration was not always orderly across dronabinol dose conditions.

It is important to note that participants were not treatment-seeking or otherwise motivated to abstain from using cannabis aside from the behavioral or monetary costs incurred as part of the protocol. Prior work indicates that cannabis users who are not seeking treatment are unlikely to decline the opportunity to self-administer cannabis without appropriately scaled behavioral or monetary contingencies (Haney, 2008; Kelly et al., 1997). Further, the impact of behavioral contingencies (progressive ratio) may have been undermined because the study was conducted in a residential research environment that provided limited access to non-drug use activities. Together, these features may explain the high rate of cannabis self-administration on progressive ratio task days and the decreased sensitivity of this task to dronabinol administration compared with the cannabis versus monetary choice procedure. Cannabis self-administration has also been shown to vary as a function of task difficulty (Ward et al., 1997). These intricacies highlight the challenges in developing medication screening models that possess predictive validity to clinical trials outcomes and should be considered in future work.

In summary, these data indicate that high-dose dronabinol is well-tolerated in daily cannabis users and may have therapeutic utility for assisting in abstinence initiation and/or relapse prevention for individuals with CUD. Although clinical trials of dronabinol therapy at lower doses have been negative (Levin and Kleber, 2008; Levin et al., 2011, 2016), our data suggest that further clinical trial research using a higher dronabinol dose is warranted.

Highlights.

  • Oral dronabinol (120–240 mg/day) reduced cannabis self-administration.

  • Dronabinol suppressed withdrawal, craving, and subjective drug effect ratings.

  • Adverse/cardiovascular effects were clinically insignificant.

  • The higher dose range was safe and generally well-tolerated.

  • High-dose dronabinol treatment should be subject to further clinical evaluation.

Acknowledgments

Role of Funding Source

This research was supported by grants R01 DA025044 and T32 DA07209 from the National Institute on Drug Abuse (NIDA). The study design; collection, analysis, and interpretation of data; writing of the report; and decision to submit the report for publication were all completed at the sole discretion of the authors with no role of any funding agencies. This study was registered on clinicaltrials.gov, identifier NCT00893074.

The authors thank Jeannie Fry, Elizabeth Girling, Linda Felch, the research staff of the Johns Hopkins Behavioral Pharmacology Research Unit (BPRU), and staff at the NIDA Drug Supply Program and RTI International for their outstanding support and contributions to the implementation and completion of the study.

Footnotes

Contributors

RV and MLS contributed to the design and execution of the study. NJS, DCL, and RV analyzed and interpreted the data, and all authors contributed to the preparation of the written manuscript. All authors were responsible for and approved the final manuscript.

Conflict of Interest

Dr. Vandrey has received consulting fees or honoraria from Zynerba Pharmaceuticals, Insys Therapeutics, and several small businesses that cultivate, process, and/or dispense cannabis under state medical cannabis access programs.

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