Abstract
Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.
Keywords: antagonist, cannabis, marijuana, rimonabant, withdrawal
The endogenous cannabinoid (endocannabinoid) system, comprising cannabinoid receptors on neurons and other cell types and endogenous ligands for these receptors, modulates a variety of important physiological functions,1,2 including food and drug intake, body weight, fat metabolism, body temperature, blood pressure, and cognition.3–7 Animal and human studies indicated therapeutic potential for antagonists at the cannabinoid CB1 receptor.8–10 Several such antagonists were in advanced clinical development for the treatment of obesity, metabolic syndrome, and nicotine and alcohol dependence.11–15 One antagonist, rimonabant, was marketed in several dozen countries around the world for the treatment of obesity.
One potential limitation to widespread clinical use of CB1 antagonists might be elicitation of cannabis withdrawal. Cannabis is the most widely used illicit psychoactive substance, with up to 190 million users worldwide.16 An estimated 10% of cannabis smokers are dependent. Ingestion of a receptor antagonist by substance-tolerant individuals can elicit a substance-specific withdrawal syndrome, as occurs with opioids after naloxone, a mu-opioid receptor antagonist, or benzodiazepines after flumazenil, a benzodiazepine receptor antagonist. Antagonist-elicited withdrawal is typically qualitatively similar to abstinence-elicited (ie, spontaneous) withdrawal but has a more rapid onset and greater intensity of symptoms.
In cannabinoid-tolerant rodents and dogs, administration of rimonabant elicited a cannabis withdrawal syndrome, with quicker onset and greater intensity than after spontaneous cannabis withdrawal.17 Rimonabant-elicited cannabis withdrawal has recently been demonstrated in rhesus monkeys made dependent with chronic subcutaneous Δ9-tetrahydrocannabinol (THC) (1 mg/kg per 12 hours).18 However, antagonist-elicited cannabis withdrawal has not been reported in humans.
We present here data from the first human study of antagonist-elicited cannabis withdrawal, after administration of the selective CB1 antagonist rimonabant to cannabis-tolerant individuals.
MATERIALS AND METHODS
Subjects
Adult (18–45 years old), non—treatment-seeking cannabis smokers recruited from the community by advertising and word-of-mouth met the following inclusion criteria: cannabis use for at least 1 year, with daily use for the 3 months before unit admission; a urine specimen positive for cannabinoids in the 30 days before study enrollment; sitting blood pressure (BP) of 140/90 mm Hg or less and heart rate of 100 beats per minute or less; and estimated IQ of 85 or higher (Wechsler Abbreviated Scale of Intelligence). Applicants were excluded for any of the following: past or present clinically significant medical condition that might interfere with safe study participation; current physical dependence on any substance other than cannabis, nicotine, or caffeine; 6 or more standard alcohol drinks per day 4 or more times per week in the month before study entry; history of a clinically significant adverse event associated with cannabis intoxication or withdrawal; history of epileptic seizures or head trauma with loss of consciousness greater than 3 minutes; history of psychosis or any current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorder (other than cannabis, caffeine, or nicotine dependence or simple phobia); Attention Deficit/ Hyperactivity Disorder Screening Rating Scale score of 24 or higher on either the A or B subscale. Women could not be pregnant or breast-feeding. Women with childbearing potential had to use an intrauterine device or hormonal contraceptive and have a negative serum pregnancy test.
Applicants underwent a comprehensive medical and psychological evaluation, including medical history and physical examination, psychiatric and drug use history, clinical laboratory tests, 12-lead electrocardiogaphy (ECG) with 3-minute rhythm strip, tuberculosis skin test, structured psychiatric diagnostic interview, and psychological testing. Qualified applicants gave written informed consent when not acutely intoxicated or in withdrawal and were compensated for their time and inconvenience. The institutional review boards of the National Institute on Drug Abuse (NIDA) Intramural Research Program, the University of Maryland School of Medicine, and the Maryland Department of Health and Mental Hygiene approved the study.
Study Design
This study was designed to determine the lowest dose of CB1 receptor antagonist that would reliably elicit withdrawal in cannabis-dependent individuals. Subjects were admitted in the evening to either of 2 closed clinical research units within approximately 24 hours of last cannabis use. Starting the next afternoon, after collection of all baseline measures, they received escalating daily doses of oral synthetic THC (dronabinol) for 8 days to maintain and standardize cannabis tolerance and dependence. On the morning of the ninth day, immediately after the last oral dronabinol dose, they were randomly assigned to receive a double-blind single oral dose of rimonabant or placebo. Subjects were discharged from the research unit on the 10th day, 24 hours after rimonabant or placebo dosing. Psychological and physiological measures of cannabis intoxication and withdrawal, safety measures such as vital signs, ECG, and adverse effects checklists, and biologic specimens for assay of cannabinoids were obtained periodically throughout the 10 days on the research unit.
Subjects were randomized in blocks of six. Within each block, 5 subjects received rimonabant and 1 received placebo. The first medication block was completed with a 20-mg oral rimonabant dose. Rimonabant dosing started at 20 mg because this was the marketed dose of rimonabant for treatment of obesity. The protocol was terminated prematurely during the second (40-mg) medication block. Three subjects had received 40-mg rimonabant and 1 received placebo when the rimonabant manufacturer stopped worldwide clinical trials, ending clinical development efforts.19
Research Setting
Subjects were housed on either the Behavioral Pharmacology Research Unit at the Johns Hopkins Bayview Medical Center, Baltimore, Md, or at the Maryland Psychiatric Research Center, Catonsville, Md. Behavioral Pharmacology Research Unit and Maryland Psychiatric Research Center are closed units with 24-hour staffing, ensuring that subjects had no access to drugs except those provided in the study.
Medication
Subjects received open-label oral synthetic THC (dronabinol) on days 2 to 9, in the form of 20-mg capsules of Marino® (Unimed, Marietta, Ga), to maintain and standardize cannabis dependence and tolerance across subjects, while minimizing short-term adverse effects. Dronabinol was given in increasing total daily dosage, but always in 20-mg individual doses, with increasing frequency every 4 to 6 hours around the clock. Dronabinol doses were given twice on day 2 (40-mg total), 5 times on days 3 to 6 (100-mg total), 6 times on days 7 to 8 (120-mg total), and twice (40-mg total) on day 9, before rimonabant on day 9. A dronabinol dose was held if the subject had an abnormal ECG, BP greater than 140/90 mm Hg, or heart rate more than 100 beats per minute.
Rimonabant and matching placebo were provided by Sanofi-Aventis (Malvern, Pa). Rimonabant or placebo was given at 9:30 a.m. on day 9, immediately after the second (and last) dronabinol dose of the day. To reduce subjects’ expectancy of withdrawal, single-blind rimonabant placebo was given on days 3 (8 a.m.), 5 (10 a.m.), and 7 (10 a.m.) immediately after a dronabinol dose.
Pharmacodynamic Assessments
Common signs and symptoms of cannabis intoxication and withdrawal, drawn from the published literature,20–24 were assessed periodically, starting the evening of admission (day 1), with 2 batteries of self-report items. The batteries combined items typical of intoxication and withdrawal to minimize cueing of subjects. The short battery (subjective effects scale, taking approximately 3.5 minutes to complete) was administered twice daily (10 a.m., 8 p.m.), plus every 30 minutes for 3 hours after administration of placebo rimonabant on days 3, 5, and 7; every 30 minutes for 7 hours after administration of rimonabant or placebo on day 9; and 8 a.m. on day 10. This short battery consisted of eleven 100-mm visual analog scales (VASs) and thirteen 5-point Likert scale items (none, slight, mild, moderate, severe). The VAS assessed good drug effect, high, stoned, stimulated, sedated, anxious, depressed, irritable, restless, craving for marijuana, and angry/aggressive. Visual analog scales were anchored on the left with “not at all” and on the right with “most ever.” The score for each VAS was the number of mm the subject marked to the right of the left anchor point. The Likert scales assessed the following: difficulty concentrating, altered sense of time, slowed or slurred speech, body feels sluggish or heavy, feel hungry, feel thirsty, shakiness/tremulousness, nausea, headache, palpitations, upset stomach, dizzy, and dry mouth or throat.
The longer battery, administered twice daily at approximately 10 a.m. and 8 p.m. and taking approximately 20 minutes, consisted of the SCL-90R25 and a cannabis checklist of twentyfour 5-point Likert scale items. The Likert scales assessed: shaky/ tremulous, decreased appetite, diarrhea/loose stools, nauseous, sweating, hiccups, decreased sexual arousal, stuffy nose, strange or vivid dreams, hot flashes, chills, increased appetite, fatigue/ tiredness, yawning, increased sexual arousal, muscle aches or pains, heaviness in limbs, noises seem louder than usual, talkative, stomach pain, mellow, clumsy, muscle spasms, and blurred vision. As part of the longer battery, the St. Mary’s Hospital Sleep Questionnaire26 was given every morning and the 12-item Marijuana Craving Questionnaire27 every evening.
Safety Assessments
Vital signs were checked thrice daily (generally 8 a.m., 4 p.m., 11 p.m.) and every 2 hours for 8 hours after the first dose of dronabinol on day 2; every 30 minutes for 3 hours, then every hour for the next 5 hours after the placebo rimonabant dose on days 3, 5, and 7 (to preserve the single blind); and every 30 minutes for 3 hours, then every hour for the next 8 hours after rimonabant or placebo on day 9. A 12-lead ECG with 3-minute rhythm strip was done on day 2 (8 a.m.), then twice daily (7:00–8:30 a.m., 7 p.m.) on days 3, 5, 7, and 9. ontinuous peripheral monitoring of heart rate, heart rhythm (2-lead ECG), blood pressure, and pulse oximetry was done for 3 hours (or until vital signs returned to within 20% of baseline values) after a placebo rimonabant or rimonabant dose on days 3, 5, 7, and 9.
Before unit discharge on day 10, vital signs, mental status, and motor coordination were evaluated to establish that it was safe for subjects to return home.
Pharmacokinetic Assessments
Peripheral blood was collected periodically through an indwelling venous catheter for the assay of THC and metabolites and rimonabant. Specimens were collected in heparinized tubes, stored on ice no more than 2 hours before centrifugation, and separated plasma stored frozen at —20°C (rimonabant specimens) or refrigerated at 4°C (cannabinoid specimens) until analysis. Specimens were assayed for THC, its psychoactive metabolite, 11-hydroxy-THC (11-OH-THC), and inactive metabolite 11-nor-9-carboxy-THC (THCCOOH) by 2-dimensional gas chromatography–mass spectrometry with cryofocusing, with a limit of quantification of 0.25 ng/mL for THC and THCCOOH and 0.5 ng/mL for 11-OH-THC. Specimens were collected the evening of admission and thrice daily (8:00 or 10:00 a.m., 8:00 or 8:30 p.m., and 10:00 or 10:30 p.m.) on days 2 to 9, plus at 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5, 7.5, 10.5, 12.5, and 22.5 hours after the last dronabinol administration on day 9.
Peripheral venous blood for assay of rimonabant was collected 1.5 hours before and 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5, 7.5, 10.5, 12.5, and 22.5 hours after rimonabant administration on day 9. Rimonabant was quantified in specimens by a validated liquid chromatography–tandem mass spectrometry method with a 1.0-ng/mL limit of quantification. Intra-assay bias was −7.4% to 6.0%, and intra-assay imprecision (%CV) was 1.8% to 5.7%. The interassay bias ranged from — 1.8% to 1.5%, with interassay imprecision of 2.5% to 10.1% (Sanofi-Aventis). The internal standard was [2H]10—rimonabant and linearity extended from 1 to 200 ng/mL. Rimonabant was extracted from plasma on 96-well Varian SPEC PLUS C19AR solid-phase extraction plates (Agilent Technologies, Santa Clara, Calif) before injection onto a Phenomenex IB-SIL 5 C8 BD (50 × 4.6 mm; 5 µm) column. The mobile phase was (A) 2 mM ammonium acetate/ 0.2% formic acid and (B) 2 mM ammonium acetate/0.2% formic acid acetonitrile/water (98/2, vol/vol) at 0.5 mL/min. The initial gradient was 60% A/40% B for 3 minutes, increasing to 100% B by 5 minutes and returning to 60% A at 5.1 minutes. A Finnigan TSQ 7000 triple quadrupole mass spectrometer (Thermo/Finnigan Ltd, Waltham, Mass) monitored precursor ions m/z 463 and m/z 473 for rimonabant and [2H]10—rimonabant, respectively, and the product ion m/z 363 for both analytes.
Statistical Analysis
The original study design called for 20-, 40-, 60-, and 80-mg doses of rimonabant in each successive block of 6 subjects until robust, reliable cannabis withdrawal was observed in all subjects treated with a given dose. Blinded safety reviews after each rimonabant dose level were conducted before proceeding to the next dose. Reliable withdrawal was defined as all 5 subjects receiving rimonabant (the sixth received placebo) in the block showing at least 150% (2.5-fold) increases (or 1.5-point increase when baseline value was 0) over prerimonabant baseline in at least 3 of 6 primary VAS items: “anxious,” “depressed,” “irritable,” “restless,” “angry-aggressive,” and “craving for marijuana” within 3 hours after rimonabant dosing. This criterion for withdrawal was based on published human experimental studies of spontaneous cannabis withdrawal.20,29 χ2 tests were used to compare the proportion of subjects receiving rimonabant or placebo who showed significant postrimonabant change on any of the 6 primary VAS items.
The study was prematurely terminated when rimonabant was withdrawn from clinical development by the manufacturer, Sanofi-Aventis, after marketing authorization in the European Union was suspended because of increased rates of depression and suicidality in outpatients. Termination occurred after only 10 subjects completed, of whom only 8 received rimonabant. Therefore, to supplement this prespecified analysis, we performed 4 additional sets of post hoc analyses using data from all 10 completing subjects (8 rimonabant, 2 placebo). First, a within-subjects comparison of the maximum change from baseline for the 6 primary VAS items on day 7 (single-blind rimonabant placebo) and day 9 (double-blind active rimonabant) was performed for the 8 subjects who received active rimonabant on day 9. This comparison was done in 2 ways: (1) as a non-parametric test for differences in average maximum changes, using Cochran-Mantel-Haenszel statistics, and (2) as a comparison of the frequency distribution of maximum changes, using the χ2 test. Second, a fixed-effects multiple regression model (SAS Proc Mixed, SAS Institute, Cary, NC) evaluated the association, for all 10 subjects, between peak rimonabant plasma concentration (placebo rimonabant = 0) and peak change from prerimonabant baseline in each of the 6 primary VAS items, heart rate, and systolic and diastolic blood pressure. The same procedure evaluated the association between rimonabant/THC or rimonabant/(THC + 11-OH-THC) plasma concentration ratios or area-under-the-rimonabant-concentration-by-time curve (0–8 hours) (AUC0–8) and these withdrawal measures. Third, repeated-measure analysis of covariance (SAS Proc Mixed) was used to evaluate the trend over time of each primary VAS item and cardiovascular measure, with baseline (prerimonabant or preplacebo) value as a covariate. A spatial power covariance structure with correlation decreasing with increasing time was used to account for the correlation between repeated measures collected over unequally spaced time intervals. Fourth, nonpara-metric Wilcoxon rank tests (SAS NPAR1WAY procedure) were used to compare the peak change from prerimonabant baseline, and the time to peak change, between rimonabant and placebo groups for each primary VAS item and cardiovascular measure.
A power analysis based on a between-subjects, placebo-controlled design, assuming use of a rimonabant dose identified by the prespecified criteria as eliciting cannabis withdrawal, yielded a power of at least 0.8 to detect cannabis withdrawal, assuming 18 subjects received rimonabant and 18 received placebo, with a withdrawal effect size of 0.7 (based on means and SDs of VAS changes during spontaneous withdrawal in human experimental studies29 and a 2-tailed α = 0.05). Thus, the post hoc analyses, which included only 10 subjects (8 rimonabant, 2 placebo), were underpowered to detect cannabis withdrawal.
Comparisons of pharmacokinetic parameters between the 2 rimonabant dose groups used independent t tests. Correlations between rimonabant dose and pharmacokinetic parameters were analyzed with Pearson r.
All statistical tests used 2-tailed α = 0.05. Pharmacodynamic analyses used SAS statistical software version 9.1 (SAS Institute, Cary, NC). Pharmacokinetic analyses used SPSS statistical software version 15.0 (SPSS, Inc, Chicago, Ill).
RESULTS
Subject Characteristics
A total of 596 individuals were screened for the study, of whom 14 subjects (all men) were considered eligible and offered enrollment. Most unsuccessful subjects did not keep their screening appointment (63%). Other reasons for applicant exclusion included women not using acceptable contraception (9%), abnormalities on medical screening (9%), IQ less than 85 (8%), and substance use outside protocol eligibility limits (5%). All 14 eligible subjects enrolled and 10 completed the study. Of the remaining 4 subjects, 1 subject withdrew for personal reasons before receiving rimonabant, 2 subjects were discharged because of adverse events before receiving rimonabant (1 subject because of psychological reactions to dronabinol, 1 subject because of premature ventricular contractions), and 1 subject had not yet been admitted when the study was terminated.
The 13 subjects who received study medication had the following sociodemographic characteristics: mean (SD) age, 24.6 (3.7) years; 10 African-American, 2 white, 1 other; 1 Hispanic; body mass index, 26.0 (5.0) kg/m2; years of education, 12.9 (1.7); and IQ, 100.3 (10.9). Subjects had smoked cannabis for 10.6 (3.8) years, starting at age 14.0 (2.4) years. All smoked cannabis at least 500 times, with 5 reporting more than 10,000 episodes. All but 1 subject smoked cannabis plus blunts and/or hashish (1 smoked only blunts). Seven subjects smoked cannabis the day of admission, 5 subjects smoked the day before, and 1 subject smoked 2 days before. Nine subjects were current cigarette smokers and 3 subjects were past smokers. All subjects were lifetime alcohol drinkers but 2 subjects had not drunk in the 2 weeks before study screening. Lifetime use of other illegal drugs was limited: 7 subjects ingested opiates other than heroin and 4 subjects used intranasal cocaine. No subject took other illegal drugs in the 2 weeks before study screening.
Pharmacokinetic Data
There were no significant differences between the 20- and 40-mg rimonabant dose groups in mean peak rimonabant plasma concentration (Cmax) (195.0 [83.4] vs 288.0 [100.6] ng/mL, respectively, t = 1.42, df = 6, P = 0.21), time to peak concentration (Tmax) (1.7 [1.0] vs 1.3 [0.3] hours, t = 0.57, df = 6, P = 0.59), area-under-the-time-by-plasma-concentration curve (AUC) (1087.0 [351.6] vs 1490.0 [538.6] h/ng per milliliter, t = 1.30, df = 6, P = 0.24), or half-life (17.4 [6.4] vs 8.8 [4.5] hours, t = 2.03, df = 6, P = 0.09). Because there were no significant dose differences in rimonabant pharmacokinetic variables, data were combined from all 8 subjects receiving rimonabant, yielding Cmax = 229.9 (95.8) ng/mL, Tmax = 1.6 (0.8) hours, AUC = 1238.1 (443.9) h/ng per milliliter, and half-life = 14.2 (7.0) hours. There were no significant correlations between rimonabant dose (mg/kg body weight) and any of these pharmacokinetic parameters: r = 0.38, P = 0.35 for Cmax, r = 0.17, P = 0.69 for Tmax, r = 0.60, P = 0.12 for AUC, and r = 0.19, P = 0.66 for half-life.
Cannabinoid plasma pharmacokinetics were previously described for the first 6 subjects in this study.30 All 10 subjects had variable concentrations because of erratic oral absorption and enterohepatic circulation (Table 1). At the time of rimonabant administration (9:30 a.m. on day 9), median THC and 11-OH-THC concentrations were 6.7 ng/mL (range, 4.6–14.2 ng/mL) and 9.5 ng/mL (range, 5.4–20.4 ng/mL), respectively. Median THC and 11-OH-THC concentrations generally peaked approximately 1.5 hours after rimonabant (or placebo) administration at 14.3 and 16.5 ng/mL, respectively. At 22.5 hours after the final dronabinol (and rimonabant) dose, median THC and 11-OH-THC plasma concentrations were 3.2 ng/mL (range, 1.2–5.2 ng/mL) and 2.2 ng/mL (range, 0–6.3 ng/mL), respectively.
TABLE 1.
Plasma Concentrations of THC, 11-OH –THC, and Rimonabant on the Day of Oral Rimonabant Administration in 10 Daily Cannabis Smokers
| Time Point |
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 9 |
Day 10 |
||||||||||||
| ID | Analyte, ng/mL |
9:30 a.m. |
10:30 a.m. |
11:00 a.m. |
11:30 a.m. |
Noon | 1:00 p.m. |
2:00 p.m. |
3:00 p.m. |
5:00 p.m. |
8:00 p.m. |
10:00 p.m. |
8:00 a.m. |
| 1 | THC | 7.8 | 5.3 | 5.2 | 5.0 | 4.2 | 4.5 | 4.2 | 3.8 | 4.2 | 9.1 | 4.8 | 2.6 |
| 11-OH-THC | 11.1 | 7.0 | 6.1 | 5.4 | 4.6 | 5.1 | 4.8 | 4.9 | 4.1 | 8.1 | 4.3 | 1.6 | |
| Rimonabant | <LOQ | 30.7 | 63.0 | 89.5 | 101.0 | 102.0 | 90.5 | 76.2 | 49.6 | 70.0 | 49.1 | 19.2 | |
| 2 | THC | 14.2 | 42.4 | 31.3 | 18.8 | 17.8 | 10.9 | 8.4 | 7.7 | 7.6 | 6.0 | 7.6 | 5.2 |
| 11-OH-THC | 20.4 | 37.8 | 36.7 | 29.2 | 23.8 | 17.8 | 14.9 | 14.6 | 13.0 | 10.6 | 9.7 | 6.3 | |
| Rimonabant | <LOQ | 157.0 | 264.0 | 181.0 | 143.0 | 140.0 | NR | 67.0 | 37.2 | 28.8 | 23.6 | 17.6 | |
| 3 | THC | 7.7 | 6.0 | 5.6 | 6.3 | 12.8 | 11.1 | 8.5 | 6.5 | 8.2 | 5.8 | 5.4 | 4.3 |
| 11-OH-THC | 7.3 | 5.8 | 5.7 | 5.8 | 11.6 | 9.9 | 7.5 | 7.0 | 6.6 | 4.4 | 4.2 | 2.2 | |
| Rimonabant | <LOQ | 126.0 | 98.8 | 71.8 | 50.1 | 46.9 | 33.6 | 33.2 | 17.6 | 12.8 | 10.7 | 8.0 | |
| 4 | THC | 10.8 | 12.8 | 12.3 | 12.1 | 9.7 | 7.6 | 5.2 | 5.5 | 4.7 | 4.9 | 4.2 | 3.3 |
| 11-OH-THC | 15.3 | 16.7 | 18.9 | 18.1 | 16.8 | 14.1 | 11.1 | 10.2 | 7.8 | 7.2 | 5.3 | 3.4 | |
| Rimonabant | <LOQ | <LOQ | <LOQ | <OQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | |
| 5 | THC | 6.5 | 28.4 | 20.3 | 16.1 | 11.8 | 9.8 | 8.6 | 6.4 | 6.7 | 5.8 | 4.9 | 5.0 |
| 11-OH-THC | 9.9 | 27.4 | 24.3 | 18.8 | 15.4 | 13.8 | 11.4 | 8.6 | 8.1 | 6.2 | 4.6 | 2.8 | |
| Rimonabant | <LOQ | 187.0 | 190.0 | 172.0 | 120.0 | 90.5 | 70.0 | 54.7 | 40.1 | 34.3 | 27.6 | 22.6 | |
| 6 | THC | 5.9 | 16.0 | 16.3 | 16.5 | 11.4 | 6.8 | 5.9 | 4.5 | 4.0 | 3.4 | 3.5 | 2.4 |
| 11-OH-THC | 9.0 | 17.7 | 15.6 | 13.7 | 11.1 | 10.0 | 7.8 | 6.0 | 4.6 | 2.8 | 2.6 | 1.8 | |
| Rimonabant | <LOQ | 293.0 | 248.0 | 168.0 | 131.0 | 95.3 | 93.4 | 61.4 | 54.2 | 39.6 | 44.8 | 35.6 | |
| 10 | THC | 4.6 | 6.0 | 7.1 | 7.0 | 5.8 | 7.0 | 5.2 | 5.0 | 5.2 | 4.0 | 4.0 | 3.1 |
| 11-OH-THC | 5.4 | 5.6 | 9.0 | 7.6 | 8.2 | 8.4 | 5.5 | 5.2 | 4.8 | 4.3 | 3.3 | 2.1 | |
| Rimonabant | <LOQ | 185.0 | 160.0 | 143.0 | 115.0 | 109.0 | 72.2 | 67.7 | 49.9 | 30.7 | 23.5 | 17.3 | |
| 11 | THC | 5.4 | 6.3 | 17.3 | 13.8 | 7.9 | 5.3 | 4.6 | 4.3 | 3.6 | 3.5 | 2.6 | 3.7 |
| 11-OH-THC | 10.7 | 13.2 | 23.3 | 26.2 | 15.5 | 10.7 | 8.0 | 7.0 | 5.8 | 5.2 | 4.5 | 3.0 | |
| Rimonabant | <LOQ | 316.0 | 386.0 | 378.0 | 305.0 | 233.0 | 144.0 | 111.0 | 79.1 | 49.0 | 45.0 | 26.9 | |
| 12 | THC | 6.0 | 4.8 | 5.0 | 7.8 | 8.2 | 6.4 | 5.7 | 6.5 | 4.2 | 1.6 | 1.5 | 1.3 |
| 11-OH-THC | 7.0 | 5.7 | 5.8 | 7.7 | 6.9 | 6.2 | 6.2 | 6.6 | 4.2 | 1.4 | 1.1 | 1.1 | |
| Rimonabant | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | <LOQ | |
| 13 | THC | 6.8 | 11.6 | 19.8 | 18.6 | 9.1 | 5.2 | 4.0 | 3.7 | 3.2 | 1.4 | 1.7 | 1.2 |
| 11-OH-THC | 8.2 | 13.4 | 17.5 | 13.3 | 9.0 | 7.5 | 5.8 | 4.9 | 3.9 | 1.5 | 1.4 | 0.0 | |
| Rimonabant | <LOQ | 198.0 | 293.0 | 187.0 | 156.0 | 137.0 | 78.3 | 57.2 | 36.6 | 28.0 | 30.3 | 29.3 | |
Rimonabant 20 mg (subjects 1, 2, 3, 5, and 6), 40 mg (subjects 10, 11, and 13), or placebo (subjects 4 and 12) was given double-blind at 9:30 a.m. on day 9 after 8 days of escalating doses of oral dronabinol (40–120 mg/d). Peripheral venous blood samples were collected at the indicated time points. See text for methodological details.
LOQ indicates limit of quantification.
Cannabis Withdrawal
The prespecified criterion for cannabis withdrawal was not met in the 20- or 40-mg rimonabant groups (two of three 40-mg subjects did not achieve withdrawal criterion) (Table 2). Three of 5 subjects in the 20-mg rimonabant group, 1 of 3 subjects in the 40-mg rimonabant group, and none of 2 subjects in the placebo group met the prespecified withdrawal criterion, that is, at least 150% increase in at least 3 of the 6 primary VAS items. Individual VAS items showed 150% increases as follows: restless, 6 subjects (four 20 mg and two 40 mg); irritable, 3 subjects (all 20 mg); depressed, 3 subjects (all 20 mg); angry, 3 subjects (two 20 mg and one 40 mg); craving, 3 subjects (two 20 mg and one 40 mg [and 1 of 2 placebo subjects]); and anxious, 2 subjects (one 20 mg and one 40 mg). There was no significant medication group difference in proportion of subjects with increased VAS score for any VAS item (data not shown). There was no significant change in SCL-90 depression subscale score on day 9, that is, before or after rimonabant or during placebo dosing (data not shown). Only 2 subjects had an increase in this subscale score: 1 received placebo and 1 received 20 mg of rimonabant.
TABLE 2.
Cannabis Withdrawal Response to Oral Rimonabant in 10 Daily Cannabis Smokers
| Time Point |
|||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 9 |
Day 10 |
||||||||||||||||||
| ID | VAS Measure | 8:00 a.m. |
9:30 a.m. |
10:00 a.m. |
10:30 a.m. |
11:00 a.m. |
11:30 a.m. |
Noon | 12:30 p.m. |
1:00 p.m. |
1:30 p.m. |
2:00 p.m. |
2:30 p.m. |
3:00 p.m. |
3:30 p.m. |
4:00 p.m. |
4:30 p.m. |
8:00 p.m. |
8:00 a.m. |
| 1 | Anxious | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | — | — | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Depressed | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | — | — | 0 | 58 | 39 | 12 | 27 | 0 | 1 | |
| Irritable | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | — | — | 0 | 0 | 25 | 0 | 11 | 0 | 0 | |
| Restless | 0 | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 0 | — | — | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Marijuana craving | 18 | 1 | 1 | 1 | 0 | 0 | 1 | 2 | 0 | — | — | 0 | 0 | 41 | 32 | 0 | 0 | 41 | |
| Angry-aggressive | 0 | 2 | 1 | 1 | 0 | 1 | 1 | 2 | 1 | — | — | 0 | 0 | 1 | 0 | 1 | 0 | 1 | |
| Total VAS score | 18 | 5 | 5 | 4 | 0 | 2 | 3 | 8 | 2 | — | — | 0 | 58 | 106 | 44 | 39 | 0 | 43 | |
| 2 | Anxious | 1 | 1 | 0 | 1 | 0 | 0 | 1 | — | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 1 | 0 |
| Depressed | 1 | 2 | 1 | 1 | 0 | 1 | 0 | — | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | |
| Irritable | 0 | 0 | 1 | 0 | 0 | 1 | 1 | — | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 2 | 0 | |
| Restless | 1 | 0 | 0 | 1 | 0 | 1 | 0 | — | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 1 | |
| Marijuana craving | 1 | 1 | 2 | 1 | 0 | 1 | 0 | — | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 1 | |
| Angry-aggressive | 1 | 2 | 1 | 1 | 1 | 2 | 0 | — | 1 | 1 | 0 | 0 | 3 | 0 | 1 | 1 | 1 | 1 | |
| Total VAS score | 5 | 6 | 5 | 5 | 1 | 6 | 2 | — | 2 | 2 | 3 | 1 | 5 | 4 | 4 | 4 | 6 | 4 | |
| 3 | Anxious | 5 | 6 | 6 | 7 | 7 | 8 | 9 | 8 | 9 | 7 | 3 | 7 | 9 | 5 | 7 | 5 | 8 | 7 |
| Depressed | 8 | 9 | 8 | 6 | 7 | 7 | 8 | 7 | 10 | 6 | 6 | 5 | 7 | 11 | 8 | 4 | 11 | 8 | |
| Irritable | 60 | 50 | 33 | 58 | 35 | 35 | 34 | 43 | 42 | 72 | 51 | 36 | 31 | 91 | 42 | 51 | 9 | 7 | |
| Restless | 10 | 13 | 9 | 9 | 9 | 9 | 44 | 11 | 16 | 45 | 10 | 48 | 44 | 47 | 29 | 62 | 42 | 51 | |
| Marijuana craving | 84 | 55 | 48 | 49 | 53 | 47 | 60 | 55 | 51 | 100 | 96 | 63 | 48 | 94 | 61 | 73 | 12 | 32 | |
| Angry-aggressive | 39 | 8 | 10 | 8 | 10 | 6 | 10 | 11 | 16 | 12 | 7 | 17 | 16 | 14 | 8 | 11 | 11 | 10 | |
| Total VAS score | 206 | 141 | 114 | 137 | 121 | 112 | 165 | 135 | 144 | 242 | 173 | 176 | 155 | 262 | 155 | 206 | 93 | 115 | |
| 4 | Anxious | 8 | 8 | 6 | 8 | 6 | 7 | 10 | 7 | 6 | — | 10 | 6 | 9 | 7 | 8 | 9 | 12 | 7 |
| Depressed | 9 | 8 | 4 | 6 | 6 | 7 | 4 | 7 | 5 | — | 13 | 8 | 7 | 7 | 5 | 10 | 12 | 7 | |
| Irritable | 9 | 8 | 12 | 6 | 18 | 7 | 14 | 7 | 13 | — | 9 | 7 | 9 | 8 | 17 | 11 | 11 | 7 | |
| Restless | 16 | 9 | 22 | 7 | 10 | 8 | 2 | 7 | 6 | — | 7 | 9 | 10 | 11 | 19 | 12 | 9 | 7 | |
| Marijuana craving | 30 | 26 | 36 | 29 | 28 | 29 | 37 | 23 | 30 | — | 32 | 29 | 33 | 31 | 30 | 28 | 48 | 30 | |
| Angry-aggressive | 4 | 10 | 15 | 5 | 11 | 9 | 9 | 6 | 8 | — | 15 | 13 | 10 | 19 | 18 | 7 | 15 | 9 | |
| Total VAS score | 76 | 69 | 95 | 61 | 79 | 67 | 76 | 57 | 68 | — | 86 | 72 | 78 | 83 | 97 | 77 | 107 | 67 | |
| 5 | Anxious | 0 | 0 | 1 | 1 | 2 | 2 | 2 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 |
| Depressed | 0 | 0 | 0 | 2 | 1 | 2 | 2 | 3 | 2 | 0 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| Irritable | 0 | 0 | 1 | 2 | 1 | 2 | 1 | 3 | 2 | 1 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| Restless | 0 | 0 | 1 | 2 | 1 | 3 | 2 | 4 | 1 | 1 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| Marijuana craving | 0 | 0 | 1 | 3 | 1 | 3 | 2 | 3 | 3 | 0 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| Angry-aggressive | 0 | 1 | 1 | 3 | 3 | 3 | 2 | 5 | 3 | 1 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| Total VAS score | 0 | 1 | 5 | 13 | 9 | 15 | 11 | 20 | 13 | 3 | 0 | 0 | 0 | 0 | — | 0 | 0 | 0 | |
| 6 | Anxious | 10 | 18 | 13 | 13 | 16 | 16 | 12 | 15 | 14 | 16 | 19 | 15 | 20 | 20 | 18 | 18 | 23 | 14 |
| Depressed | 1 | 2 | 3 | 2 | 1 | 2 | 11 | 10 | 8 | 2 | 8 | 6 | 13 | 4 | 7 | 6 | 4 | 5 | |
| Irritable | 7 | 12 | 11 | 10 | 11 | 13 | 7 | 10 | 9 | 10 | 13 | 12 | 16 | 18 | 14 | 15 | 17 | 12 | |
| Restless | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 1 | 4 | 4 | 6 | 5 | 13 | 10 | 10 | 20 | 8 | |
| Marijuana craving | 5 | 4 | 1 | 2 | 5 | 4 | 5 | 2 | 2 | 4 | 5 | 2 | 4 | 4 | 6 | 5 | 9 | 7 | |
| Angry-aggressive | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | |
| Total VAS score | 23 | 36 | 28 | 27 | 33 | 37 | 36 | 39 | 34 | 38 | 50 | 41 | 58 | 60 | 56 | 55 | 74 | 47 | |
| 10 | Anxious | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 |
| Depressed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Irritable | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Restless | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 8 | |
| Marijuana craving | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | |
| Angry-aggressive | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Total VAS score | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 17 | |
| 11 | Anxious | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Depressed | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | |
| Irritable | 0 | 16 | 16 | 3 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | |
| Restless | 1 | 0 | 0 | 3 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 3 | |
| Marijuana craving | 81 | 83 | 80 | 71 | 77 | 69 | 72 | 73 | 76 | 87 | 78 | 75 | 70 | 81 | 79 | 83 | 86 | 94 | |
| Angry-aggressive | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 1 | 4 | 1 | |
| Total VAS score | 83 | 102 | 97 | 78 | 81 | 70 | 72 | 74 | 77 | 88 | 82 | 80 | 70 | 83 | 80 | 85 | 92 | 99 | |
| 12 | Anxious | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 0 | 0 | 0 |
| Depressed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 0 | 0 | 0 | |
| Irritable | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 0 | 0 | 0 | |
| Restless | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 0 | 0 | 0 | |
| Marijuana craving | 14 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 100 | 38 | 0 | |
| Angry-aggressive | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 0 | 0 | 0 | |
| Total VAS score | 14 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | — | — | 100 | 38 | 0 | |
| 13 | Anxious | 999 | 0 | 1 | 0 | 1 | 1 | 1 | — | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Depressed | 999 | 0 | 0 | 1 | 0 | 1 | 0 | — | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
| Irritable | 999 | 0 | 0 | 0 | 0 | 1 | 0 | — | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
| Restless | 999 | 10 | 0 | 0 | 0 | 1 | 0 | — | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Marijuana craving | 999 | 53 | 63 | 50 | 51 | 44 | 48 | — | 45 | 68 | 64 | 54 | 51 | 90 | 68 | 66 | 83 | 74 | |
| Angry-aggressive | 999 | 0 | 0 | 0 | 0 | 0 | 1 | — | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
| Total VAS score | 999 | 63 | 64 | 51 | 52 | 48 | 50 | — | 45 | 70 | 64 | 54 | 51 | 90 | 68 | 67 | 84 | 75 | |
Rimonabant 20 mg (subjects 1,2,3,5, and 6), 40 mg (subjects 10,11, and 13), or placebo (subjects 4 and 12) was given double-blind at 9:30 a.m. on day 9, after 8 days of escalating doses of oral dronabinol (40–120 mg/d). Six core symptoms of cannabis withdrawal were assessed by 100-mm VAS at the indicated time points. See text for methodological details.
“—” indicates no data.
The 4 sets of post hoc analyses did not show any evidence of significant cannabis withdrawal. There was no significant difference in mean maximum change from baseline between the placebo rimonabant day (day 7) and the active rimonabant day (day 9) for any of the 6 primary VAS items and there were no significant differences in the frequency distributions of the maximum change scores (data not shown). There was no significant association between peak rimonabant plasma concentration, rimonabant AUC0–8h, nor rimonabant/THC or rimonabant/ (THC + 11-OH-THC) plasma concentration ratios for any of the 6 primary VAS items (data not shown) or for peak change from prerimonabant baseline in heart rate and systolic or diastolic blood pressure (data not shown). There was no significant effect of rimonabant on the postbaseline time course (continuous variable) or the peak postbaseline change (categorical variable) of any withdrawal measure (data not shown). Diastolic blood pressure achieved its peak increase significantly sooner after rimonabant (median, 5 hours) than after placebo (median, 22.5 hours) (z = 1.98, with 0.5 continuity correction, P = 0.05) (Table 3). There was no significant difference in time to peak change for any other withdrawal variable (data not shown).
TABLE 3.
Cardiovascular Response to Oral Rimonabant in 10 Daily Cannabis Smokers
| Time Point |
||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 9 |
Day 10 |
|||||||||||||||||
| ID | Vitals Measure |
8:00 a.m. |
9:30 a.m. |
10:00 a.m. |
10:30 a.m. |
11:00 a.m. |
11:30 a.m. |
Noon | 12:30 p.m. |
1:30 p.m. |
2:30 p.m. |
3:30 p.m. |
4:00 p.m. |
4:30 p.m. |
5:30 p.m. |
6:30 p.m. |
11:00 p.m. |
8:00 a.m. |
| 1 | Systolic BP |
109 | 110 | 115 | 126 | 107 | 109 | 111 | 124 | 130 | 139 | 141 | 121 | 130 | 124 | 136 | 122 | 118 |
| Diastolic BP |
65 | 62 | 63 | 52 | 52 | 53 | 64 | 59 | 83 | 86 | 64 | 70 | 85 | 63 | 82 | 76 | 67 | |
| Heart rate |
66 | 60 | 89 | 62 | 60 | 58 | 66 | 62 | 72 | 88 | 73 | 69 | 79 | 70 | 76 | 71 | 61 | |
| 2 | Systolic BP |
120 | 130 | 119 | 122 | 126 | 130 | 121 | 127 | 140 | 128 | 143 | 136 | 132 | 120 | 128 | 140 | 129 |
| Diastolic BP |
70 | 74 | 67 | 68 | 70 | 77 | 69 | 77 | 70 | 77 | 81 | 76 | 71 | 74 | 77 | 84 | 77 | |
| Heart rate |
74 | 72 | 65 | 65 | 62 | 64 | 60 | 60 | 60 | 61 | 61 | 63 | 71 | 64 | 67 | 69 | 89 | |
| 3 | Systolic BP |
119 | 999 | 118 | 126 | 137 | 140 | 152 | 141 | 138 | 147 | 999 | 136 | 148 | 130 | 134 | 135 | 124 |
| Diastolic BP |
64 | 999 | 56 | 59 | 62 | 60 | 61 | 62 | 55 | 69 | 999 | 59 | 64 | 57 | 73 | 69 | 64 | |
| Heart rate |
65 | 999 | 71 | 68 | 71 | 70 | 64 | 65 | 90 | 68 | 999 | 71 | 78 | 71 | 68 | 71 | 66 | |
| 4 | Systolic BP |
106 | 999 | 109 | 112 | 110 | 110 | 118 | 116 | 122 | 119 | 123 | 129 | 124 | 116 | 112 | 125 | 127 |
| Diastolic BP |
50 | 999 | 55 | 64 | 54 | 52 | 54 | 52 | 65 | 61 | 71 | 53 | 65 | 60 | 66 | 60 | 77 | |
| Heart rate |
73 | 999 | 66 | 68 | 70 | 63 | 70 | 62 | 88 | 79 | 65 | 68 | 70 | 67 | 67 | 68 | 70 | |
| 5 | Systolic BP |
109 | 999 | 98 | 91 | 100 | 102 | 102 | 105 | 113 | 112 | 118 | 116 | 117 | 116 | 118 | 111 | 106 |
| Diastolic BP |
67 | 999 | 58 | 51 | 51 | 51 | 55 | 58 | 68 | 72 | 61 | 61 | 62 | 76 | 76 | 68 | 71 | |
| Heart rate |
65 | 999 | 74 | 61 | 71 | 65 | 61 | 60 | 68 | 68 | 60 | 64 | 62 | 89 | 66 | 91 | 70 | |
| 6 | Systolic BP |
111 | 999 | 109 | 111 | 111 | 109 | 112 | 103 | 119 | 122 | 104 | 114 | 110 | 113 | 124 | 117 | 113 |
| Diastolic BP |
55 | 999 | 55 | 55 | 54 | 62 | 55 | 56 | 67 | 62 | 55 | 54 | 64 | 62 | 66 | 60 | 67 | |
| Heart rate |
70 | 999 | 65 | 71 | 70 | 65 | 66 | 63 | 74 | 62 | 66 | 69 | 59 | 73 | 65 | 68 | 67 | |
| 10 | Systolic BP |
132 | 131 | 133 | 142 | 148 | 145 | 132 | 130 | 139 | 149 | 140 | 150 | 131 | 140 | 144 | 147 | 132 |
| Diastolic BP |
78 | 66 | 73 | 73 | 73 | 74 | 73 | 63 | 80 | 71 | 70 | 71 | 74 | 75 | 79 | 72 | 69 | |
| Heart rate |
66 | 73 | 69 | 61 | 66 | 72 | 85 | 71 | 81 | 81 | 92 | 105 | 71 | 106 | 77 | 99 | 80 | |
| 11 | Systolic BP |
126 | 124 | 124 | 147 | 138 | 153 | 131 | 144 | 148 | 144 | 149 | 148 | 126 | 138 | 151 | 134 | 135 |
| Diastolic BP |
81 | 87 | 75 | 81 | 78 | 90 | 79 | 75 | 88 | 88 | 89 | 82 | 89 | 76 | 79 | 80 | 86 | |
| Heart rate |
89 | 75 | 78 | 85 | 98 | 84 | 89 | 83 | 88 | 93 | 80 | 113 | 91 | 92 | 93 | 93 | 83 | |
| 12 | Systolic BP |
123 | 123 | 140 | 140 | 127 | 120 | 123 | 135 | 128 | 143 | 129 | 142 | 137 | 144 | 151 | 130 | 140 |
| Diastolic BP |
66 | 53 | 61 | 61 | 50 | 51 | 60 | 61 | 57 | 63 | 58 | 58 | 62 | 70 | 67 | 63 | 76 | |
| Heart rate |
58 | 57 | 54 | 58 | 61 | 56 | 60 | 55 | 58 | 57 | 56 | 71 | 83 | 86 | 93 | 93 | 58 | |
| 13 | Systolic BP |
104 | 98 | 120 | 109 | 122 | 123 | 111 | 116 | 121 | 132 | 134 | 145 | 125 | 128 | 127 | 131 | 117 |
| Diastolic BP |
57 | 51 | 66 | 56 | 51 | 65 | 54 | 54 | 63 | 84 | 71 | 67 | 68 | 60 | 69 | 67 | 62 | |
| Heart rate |
62 | 64 | 65 | 54 | 63 | 78 | 68 | 67 | 68 | 57 | 59 | 64 | 64 | 70 | 59 | 73 | 55 | |
Rimonabant 20 mg (subjects 1, 2, 3, 5, and 6), 40 mg (subjects 10, 11, and 13), or placebo (subjects 4 and 12) was given double-blind at 9:30 a.m. on day 9 after 8 days of escalating doses of oral dronabinol (40–120 mg/d). Systolic and diastolic blood pressure (BP; mm Hg) and heart rate (beats per minute) were assessed at the indicated time points. See text for methodological details.
No subject reported symptoms suggestive of cannabis withdrawal during initiation and escalation of dronabinol dosing (days 1–6).
Safety and Tolerability
Both the single dose of rimonabant and the long-term oral dronabinol were well tolerated by subjects. The blinded safety review after completion of the 20-mg dose block showed no reason not to proceed to the next dose block (40 mg). Only 2 adverse events (both in the same subject) were considered possibly related to rimonabant. This subject reported transient (lasting 1 hour) mild intensification of preexisting intermittent sadness, beginning 5.5 hours after receiving 20 mg of rimonabant, and mild nausea lasting 30 minutes beginning 23 hours after dosing (also considered possibly related to dronabinol). Both adverse events resolved without treatment or sequelae. No ECG changes or abnormalities in vital signs, oxygen saturation, or continuous cardiac monitoring occurred after rimonabant administration.
Two subjects were discontinued from the study because of adverse events considered probably due to dronabinol (and before receiving rimonabant). One subject retrospectively reported 30 minutes of depressed mood, suicidal thoughts, and paranoia occurring on the night of day 3, that is, after receiving 6 doses of dronabinol. Dronabinol was discontinued the next day, and he was discharged in good condition. A second subject had 2 hours of occasional premature ventricular contractions on the morning of day 5, which did not recur after dronabinol was discontinued. Other mild and self-limited adverse events possibly related to dronabinol included nausea and vomiting (2 subjects), abdominal pain/discomfort (2 subjects), dry mouth (2 subjects), diarrhea (2 subjects), and euphoria (1 subject). One subject with diarrhea had 2 dronabinol doses withheld on the third dosing day.
There was no apparent association between plasma THC concentration and occurrence of the 3 psychological adverse events (increased sadness, depression with suicidal ideation, euphoria) possibly due to dronabinol. Plasma THC concentrations closest to the onset of the event were 9.6, 23.6,and 47.4 ng/mL, respectively. Mean (SD) concentrations at the comparable time point in subjects without a psychological adverse event were 19.0 (5.6), 24.1 (13.8), and 19.2 (7.0) ng/mL, respectively. The small sample size precluded formal statistical testing.
DISCUSSION
This study was designed to determine the lowest rimonabant dose that reliably produced antagonist-elicited cannabis withdrawal. The first dose evaluated, 20 mg, produced only weak evidence of withdrawal and did not meet the prespecified withdrawal criteria. This 20-mg dose was widely prescribed in Europe and elsewhere (largely for treatment of obesity and the metabolic syndrome) without apparently generating reports of adverse events due to cannabis withdrawal. This may be related to the plasma (and brain) rimonabant concentrations and CB1 receptor occupancy levels achieved by this dose.
The 20-mg dose in this study generated a peak plasma rimonabant concentration of 195 (83.4) ng/mL with a Tmax at 1.7 (1.0) hours. These values are comparable to those reported in 8 healthy men after 21 daily doses of 20-mg rimonabant (Cmax = 196 [28.1] ng/mL, Tmax = 2.0 hours [range, 1.5–6 hours]).31 We previously reported mean peak rimonabant concentrations of 478.6 ng/mL after a single 90-mg dose and 307.8 and 334.6 ng/mL after 8 or 15 days, respectively, of daily 40-mg doses.32 These higher concentrations were needed to significantly attenuate the short-term effects of a smoked cannabis cigarette. Similar (or greater) concentrations would presumably be needed for rimonabant to displace THC from CB1 receptors to elicit withdrawal.
Higher rimonabant doses could not be evaluated as planned because rimonabant was withdrawn from worldwide clinical development, forcing premature termination of this study. Only 3 of the planned 5 subjects received 40 mg of rimonabant, not meeting the prespecified criteria and providing weak evidence of withdrawal. This dose (0.41–0.45 mg/kg) generated a rimonabant Cmax of 288 (100.6) ng/mL and Tmax of 1.3 (0.3) hours. These values are comparable to those reported in 8 healthy men after 21 daily doses of 40 mg of rimonabant (Cmax = 326 [92.5], Tmax = 3.0 hours [range, 2–6 hours])31 but still lower than the concentrations associated with attenuation of acute CB1 receptor agonist effects in humans.32
We are not aware of any human brain data on rimonabant concentrations or CB1 receptor occupancy. In Wistar rats, 0.1 mg/kg oral rimonabant occupied approximately one quarter of frontal cortex CB1 receptors 1 hour after dosing, as measured by competition with intravenously administered radiolabeled rimonabant.33 The dose 1 mg/kg occupied approximately half of receptors 1 and 3 hours after dosing but did not immediately reduce food intake. The dose 3 mg/kg occupied approximately two thirds of receptors and did significantly reduce food intake. In Swiss mice, 1 mg/kg oral rimonabant occupied approximately one quarter of brain (minus cerebellum) CB1 receptors after 1 hour and approximately one fifth after 3 hours, as measured by ex vivo displacement of radiolabeled CB1 agonist.34 In a separate mouse study, this same oral dose after 1 and 2 hours blocked approximately 50% of the hypothermic effect of a different CB1 agonist.35 Extrapolating from rodents to humans, these findings suggest that a rimonabant dose at least triple the 20 mg (0.20–0.37 mg/kg) administered in this study might be required to elicit withdrawal.
Our findings suggest that the clinically relevant 20-mg oral rimonabant dose would not have posed a significant risk of eliciting cannabis withdrawal. However, we do not interpret our findings as suggesting that robust antagonist-elicited withdrawal does not exist in humans. Rather, we believe that our failure to demonstrate this phenomenon in the present study was owing to the study’s premature termination and resulting inability to adequately evaluate higher rimonabant doses. This interpretation is supported by the fact that we did observe some evidence of cannabis withdrawal. Three of 5 subjects receiving 20 mg of rimonabant and 1 of 3 subjects receiving 40 mg of rimonabant, compared with none of the 2 subjects receiving placebo, met the prespecified withdrawal criterion of at least a 150% increase in at least 3 of the 6 primary VAS items. Five of the 6 VAS items showed 150% or greater increases in at least 3 of the 8 subjects receiving rimonabant, whereas only 1 VAS item showed such an increase in either placebo subject. Diastolic blood pressure achieved its peak increase significantly sooner after rimonabant than after placebo. Had the study been able to continue as planned to higher rimonabant doses, we believe that robust withdrawal would have been observed.
The failure to observe reliable antagonist-elicited withdrawal was unlikely due to other methodological limitations. Subjects took rimonabant under direct staff observation.Substantial rimonabant plasma concentrations were achieved, peaking 1.6 hours after dosing, well within the 24-hour interval of periodic withdrawal assessments.The prespecified primary VAS items were based on previous studies showing them as significant symptoms during both self-reported and experimentally observed cannabis withdrawal in humans.20,21 Thus, our failure to observe reliable antagonist-elicited withdrawal does not cast doubt on the validity of a human cannabis withdrawal syndrome (CWS).The existence of CWS is now widely ac-cepted20 and CWS is included in the proposed fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (www.dsm5.org).
In conclusion, our results, although derived from a small sample size and only 2 doses of rimonabant, suggest that CB1 receptor antagonists with pharmacological profiles similar to rimonabant, should they become clinically available in the future, might be used at therapeutic doses without substantial risk of eliciting clinically significant withdrawal in cannabis-tolerant patients. Future human experimental studies of antagonist-elicited cannabis withdrawal are warranted to more fully evaluate this phenomenon and the dose ranges over which it occurs.
ACKNOWLEDGMENTS
The authors thank the clinical staff of the Johns Hopkins Behavioral Pharmacology Research Unit and of the Maryland Psychiatric Research Center Treatment Research Program for their work with subjects.
This study was supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse (NIDA); by NIDA Residential Research Support Services contract no. HHSN271200599091CADB (D.L. Kelly, PI); and by Sanofi-Aventis.
This study was conducted under a Cooperative Research and Development Agreement between the National Institutes of Health and Sanofi-Aventis.
Footnotes
Drs Bonnet and Ortemann-Renon work for the study sponsor, Sanofi-Aventis. The other authors are NIDA or Maryland Psychiatric Research Center scientists and have no conflicts to declare. The sponsor contributed to study design and data management but played no role in data analysis or the decision to submit the article for publication. The NIDA investigators collected all data; NIDA and Maryland Psychiatric Research Center investigators prepared the article. The sponsor controlled the rimonabant allocation schedule and reviewed the article.
AUTHOR DISCLOSURE INFORMATION
Drs. Ortemann-Renon and Bonnet are employees of Sanofi-Aventis Recherche. The other authors declare no conflicts of interest.
REFERENCES
- 1.Basavarajappa BS. The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism. Mini Rev Med Chem. 2007;7:769–779. doi: 10.2174/138955707781387920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.De Petrocellis L, DiMarzo V. An introduction to the endocannabinoid system: from the early to the latest concepts. Best Pract Res Clin Endocrinol Metab. 2009;23:1–15. doi: 10.1016/j.beem.2008.10.013. [DOI] [PubMed] [Google Scholar]
- 3.Farhang B, Diaz S, Tang SL, et al. Sex differences in the cannabinoid regulation of energy homeostasis. Psychoneuroendocrinology. 2009;34(suppl 1):S237–S246. doi: 10.1016/j.psyneuen.2009.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009;14:43–65. doi: 10.1517/14728210902736568. [DOI] [PubMed] [Google Scholar]
- 5.Orgado JM, Fernandez-Ruiz J, Romero J. The endocannabinoid system in neuropathological states. Int Rev Psychiatry. 2009;21:172–180. doi: 10.1080/09540260902782828. [DOI] [PubMed] [Google Scholar]
- 6.Pacher P, Mukhopadhyay P, Mohanraj R, et al. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension. 2008;52:601–607. doi: 10.1161/HYPERTENSIONAHA.105.063651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Solinas M, Goldberg SR, Piomelli D. The endocannabinoid system in brain reward processes. Br J Pharmacol. 2008;154:369–383. doi: 10.1038/bjp.2008.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Beardsley PM, Thomas BF, McMahon LR. Cannabinoid CB1 receptor antagonists as potential pharmacotherapies for drug abuse disorders. Int Rev Psychiatry. 2009;21:134–142. doi: 10.1080/09540260902782786. [DOI] [PubMed] [Google Scholar]
- 9.Jagerovic N, Fernandez-Fernandez C, Goya P. CB1 cannabinoid antagonists: structure-activity relationships and potential therapeutic applications. Curr Top Med Chem. 2008;8:205–230. doi: 10.2174/156802608783498050. [DOI] [PubMed] [Google Scholar]
- 10.Lee HK, Choi EB, Pak CS. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents. Curr Top Med Chem. 2009;9:482–503. doi: 10.2174/156802609788897844. [DOI] [PubMed] [Google Scholar]
- 11.Butler H, Korbonits M. Cannabinoids for clinicians: the rise and fall of the cannabinoid antagonists. Eur J Endocrinol. 2009;161:655–662. doi: 10.1530/EJE-09-0511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Le Foll B, Forget B, Aubin HJ, et al. Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from pre-clinical and clinical studies. Addict Biol. 2008;13:239–252. doi: 10.1111/j.1369-1600.2008.00113.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Morrison MF, Ceesay P, Gantz I, et al. Randomized, controlled, double-blind trial of taranabant for smoking cessation. Psychopharmacology (Berl) 2010;209:245–253. doi: 10.1007/s00213-010-1790-2. [DOI] [PubMed] [Google Scholar]
- 14.Scheen AJ, Paquot N. Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders. Best Pract Res Clin Endocrinol Metab. 2009;23:103–116. doi: 10.1016/j.beem.2008.09.001. [DOI] [PubMed] [Google Scholar]
- 15.Soyka M, Koller G, Schmidt P, et al. Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J Clin Psychopharmacol. 2008;28:317–324. doi: 10.1097/JCP.0b013e318172b8bc. [DOI] [PubMed] [Google Scholar]
- 16.United Nations Office on Drugs and Crime. World Drug Report 2009. Vienna, Austria: United Nations Office on Drugs and Crime; 2009. Report No. E.09.XI.12. [Google Scholar]
- 17.Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp Pharmacol. 2005;168:691–717. doi: 10.1007/3-540-26573-2_24. [DOI] [PubMed] [Google Scholar]
- 18.Stewart J, McMahon LR. Rimonabant-induced Δ9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs. J Pharmacol Exp Ther. 2010;334:347–356. doi: 10.1124/jpet.110.168435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Le Foll B, Gorelick DA, Goldberg SR. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology (Berl) 2009;205:171–174. doi: 10.1007/s00213-009-1506-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Budney AJ, Hughes JR, Moore BA, et al. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry. 2004;161:1967–1977. doi: 10.1176/appi.ajp.161.11.1967. [DOI] [PubMed] [Google Scholar]
- 21.Haney M, Ward AS, Comer SD, et al. Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacology (Berl) 2001;155:171–179. doi: 10.1007/s002130000657. [DOI] [PubMed] [Google Scholar]
- 22.Huestis MA, Sampson AH, Holicky BJ, et al. Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther. 1992;52:31–41. doi: 10.1038/clpt.1992.100. [DOI] [PubMed] [Google Scholar]
- 23.Huestis MA, Gorelick DA, Heishman SJ, et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry. 2001;58:322–328. doi: 10.1001/archpsyc.58.4.322. [DOI] [PubMed] [Google Scholar]
- 24.Jones RT, Benowitz N, Bachman J. Clinical studies of cannabis tolerance and dependence. Ann N Y Acad Sci. 1976;282:221–239. doi: 10.1111/j.1749-6632.1976.tb49901.x. [DOI] [PubMed] [Google Scholar]
- 25.Cyr JJ, Kenna-Foley JM, Peacock E. Factor structure of the SCL-90-R: is there one? J Pers Assess. 1985;49:571–578. doi: 10.1207/s15327752jpa4906_2. [DOI] [PubMed] [Google Scholar]
- 26.Ellis BW, Johns MW, Lancaster R, The St, et al. Mary’s Hospital Sleep Questionnaire: a study of reliability. Sleep. 1981;4:93–97. doi: 10.1093/sleep/4.1.93. [DOI] [PubMed] [Google Scholar]
- 27.Heishman SJ, Evans RJ, Singleton EG, et al. Reliability and validity of a short form of the Marijuana Craving Questionnaire. Drug Alcohol Depend. 2009;102:35–40. doi: 10.1016/j.drugalcdep.2008.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lowe RH, Karschner EL, Schwilke EW, et al. Simultaneous quantification of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in human plasma using two-dimensional gas chromatography, cryofocusing, and electron impact-mass spectrometry. J Chromatogr A. 2007;1163:318–327. doi: 10.1016/j.chroma.2007.06.069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Haney M, Ward AS, Comer SD, et al. Abstinence symptoms following oral THC administration to humans. Psychopharmacology (Berl) 1999;141:385–394. doi: 10.1007/s002130050848. [DOI] [PubMed] [Google Scholar]
- 30.Schwilke EW, Schwope DM, Karschner EL, et al. Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC. Clin Chem. 2009;55:2180–2189. doi: 10.1373/clinchem.2008.122119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Turpault S, Kanamaluru V, Lockwood GF, et al. Rimonabant pharmacokinetics in healthy and obese subjects. Clin Pharmacol Ther. 2006;79:P50. [Google Scholar]
- 32.Huestis MA, Boyd SJ, Heishman SJ, et al. Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology (Berl) 2007;194:505–515. doi: 10.1007/s00213-007-0861-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Need AB, Davis RJ, Alexander-Chacko JT, et al. The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats. Psychopharmacology (Berl) 2006;184:26–35. doi: 10.1007/s00213-005-0234-x. [DOI] [PubMed] [Google Scholar]
- 34.Rinaldi-Carmona M, Barth F, Heaulme M, et al. Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. Life Sci. 1995;56:1941–1947. doi: 10.1016/0024-3205(95)00174-5. [DOI] [PubMed] [Google Scholar]
- 35.Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350:240–244. doi: 10.1016/0014-5793(94)00773-x. [DOI] [PubMed] [Google Scholar]