Rimonabant did not reliably trigger measurable cannabis withdrawal in THC-dependent human volunteers
In 10 daily cannabis smokers given standardized THC, rimonabant at 20 or 40 mg did not reliably elicit cannabis withdrawal by prespecified criteria, though the study was terminated early when rimonabant was withdrawn from development.
Quick Facts
What This Study Found
Ten male daily cannabis smokers received around-the-clock oral THC (40-120 mg/day increasing over 8 days) to standardize cannabis dependence in a closed research unit. On day 9, they received double-blind placebo or rimonabant (a CB1 receptor antagonist) at 20 or 40 mg.
Using the prespecified criterion (150% increase in at least 3 withdrawal visual analog scales within 3 hours), only 3 of 5 subjects in the 20-mg group and 1 of 3 in the 40-mg group met the withdrawal threshold. No placebo subjects met the criterion.
There were no significant associations between withdrawal symptoms and rimonabant plasma levels. The study was terminated prematurely because rimonabant was withdrawn from clinical development (due to psychiatric side effects in other studies).
The authors noted that higher rimonabant doses might produce more reliable withdrawal, but these could not be tested.
Key Numbers
10 completers (14 enrolled). THC: 40-120 mg/day over 8 days. Rimonabant: 20 mg (n=5+1 placebo) or 40 mg (n=3+1 placebo). 3/5 met withdrawal criterion at 20 mg, 1/3 at 40 mg, 0/2 at placebo.
How They Did This
Double-blind, placebo-controlled study in 10 daily cannabis smokers on a closed research unit. 8 days of escalating oral THC to standardize dependence, followed by single-dose rimonabant or placebo on day 9. Withdrawal assessed by visual analog scales, heart rate, and blood pressure for 23.5 hours. Rimonabant and THC plasma levels quantified by mass spectrometry.
Why This Research Matters
This was the first and only study to attempt antagonist-elicited cannabis withdrawal in humans, an important methodology for understanding cannabis dependence physiology.
The Bigger Picture
The premature termination due to rimonabant's withdrawal from the market left a significant gap in understanding antagonist-precipitated cannabis withdrawal in humans.
What This Study Doesn't Tell Us
Very small sample (10 completers). Prematurely terminated. Rimonabant doses may have been too low. Oral THC dosing may not perfectly replicate smoked cannabis dependence. No longer possible to replicate with rimonabant.
Questions This Raises
- ?Would higher CB1 antagonist doses reliably produce human cannabis withdrawal?
- ?Could newer CB1 antagonists without psychiatric side effects be used to study this question?
Trust & Context
- Key Stat:
- Only 4 of 8 rimonabant subjects met prespecified withdrawal criteria
- Evidence Grade:
- Very small randomized study terminated prematurely. First and only human antagonist-elicited cannabis withdrawal study.
- Study Age:
- Published in 2011. Rimonabant was withdrawn from clinical development due to psychiatric side effects; no equivalent human studies have been conducted since.
- Original Title:
- Antagonist-elicited cannabis withdrawal in humans.
- Published In:
- Journal of clinical psychopharmacology, 31(5), 603-12 (2011)
- Authors:
- Gorelick, David A(13), Goodwin, Robert S(6), Schwilke, Eugene(2), Schwope, David M, Darwin, William D, Kelly, Deanna L, McMahon, Robert P, Liu, Fang, Ortemann-Renon, Catherine, Bonnet, Denis, Huestis, Marilyn A
- Database ID:
- RTHC-00487
Evidence Hierarchy
Participants are randomly assigned to treatment or placebo groups to test cause and effect.
What do these levels mean? →Frequently Asked Questions
What happens if you suddenly block cannabinoid receptors?
This study attempted to answer that question. At the doses tested, rimonabant (a CB1 blocker) did not reliably produce measurable withdrawal symptoms, though the study was very small and doses may have been too low.
Why was rimonabant withdrawn?
Rimonabant was being developed as an anti-obesity drug but was withdrawn because it caused serious psychiatric side effects (depression, suicidality) in some patients, unrelated to this cannabis study.
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Cite This Study
https://rethinkthc.com/research/RTHC-00487APA
Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A. (2011). Antagonist-elicited cannabis withdrawal in humans.. Journal of clinical psychopharmacology, 31(5), 603-12. https://doi.org/10.1097/JCP.0b013e31822befc1
MLA
Gorelick, David A, et al. "Antagonist-elicited cannabis withdrawal in humans.." Journal of clinical psychopharmacology, 2011. https://doi.org/10.1097/JCP.0b013e31822befc1
RethinkTHC
RethinkTHC Research Database. "Antagonist-elicited cannabis withdrawal in humans." RTHC-00487. Retrieved from https://rethinkthc.com/research/gorelick-2011-antagonistelicited-cannabis-withdrawal-in
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.