Rimonabant did not reliably trigger measurable cannabis withdrawal in THC-dependent human volunteers | Research

The takeaway

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reliably elicit cannabis withdrawal by prespecified criteria, though the study was terminated early when rimonabant was withdrawn from development.

Read this if you are interested in the pharmacology of cannabis dependence and withdrawal.

Only 4 of 8 rimonabant subjects met prespecified withdrawal criteria

What the researchers 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 The study was terminated prematurely because rimonabant was withdrawn from clinical development (due to psychiatric side effects in other studies).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.

Why it 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 numbers in context

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 the study worked

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.

What this study cannot 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.

How to read the evidence

Very small randomized study terminated prematurely. First and only human antagonist-elicited cannabis withdrawal study.

When this study was published

Published in 2011. Rimonabant was withdrawn from clinical development due to psychiatric side effects; no equivalent human studies have been conducted since.

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.

Questions still open

Would higher CB1 antagonist doses reliably produce human cannabis withdrawal? Could newer CB1 antagonists without psychiatric side effects be used to study this question?

Common 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.

Read the original research

Antagonist-elicited cannabis withdrawal in humans.

Journal of clinical psychopharmacology, 31(5), 603-12

View on PubMed ↗Publisher’s paper ↗

Citation

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