CB1 blocker rimonabant raised cortisol levels in cannabis-dependent men, hinting at stress axis involvement | Research

The takeaway

In cannabis-dependent men given standardized THC, rimonabant blood levels positively correlated with cortisol increases, suggesting CB1 receptors modulate the human stress hormone system.

Read this if you want to understand the biological connection between cannabis and stress.

Rimonabant-cortisol correlation: r=0.53 (p<0.01)

What the researchers found

Fourteen daily cannabis smokers received escalating THC doses (60-120 mg/day) for 8 days to standardize tolerance, then received rimonabant (20 or 40 mg) or placebo alongside the last THC dose. The study was terminated early when rimonabant was withdrawn from development.

Ten participants completed: five received 20 mg rimonabant, three received 40 mg, and two received placebo. Rimonabant blood concentration positively correlated with cortisol increases (r=0.53, p<0.01). Four of eight rimonabant recipients had cortisol levels at 11:30 AM that exceeded their 8:00 AM levels, the opposite of normal diurnal decline.

Despite the cortisol trend, the 20-40 mg doses did not significantly precipitate frank cannabis withdrawal, consistent with the doses being below the threshold for full antagonism in tolerant individuals.

Why it matters

This was rare human evidence that CB1 receptors modulate the hypothalamic-pituitary-adrenal (HPA) stress axis during chronic cannabis exposure. The cortisol-rimonabant correlation supported the role of endocannabinoids in human stress regulation.

The numbers in context

14 enrolled, 10 completed. Rimonabant-cortisol correlation: r=0.53, p<0.01. 4/8 rimonabant recipients showed reversed diurnal cortisol pattern. Study terminated early due to rimonabant withdrawal from development.

How the study worked

Controlled study with 14 daily cannabis smokers. Standardized THC tolerance over 8 days (60-120 mg/day). Double-blind placebo or rimonabant (20 or 40 mg) with last THC dose. Plasma cortisol, cannabinoid, and rimonabant concentrations measured at 4 timepoints.

What this study cannot tell us

Very small sample (10 completers). Study terminated early. Rimonabant doses may have been too low for full antagonism. No formal withdrawal assessment. Observational cortisol measurements without structured provocation.

How to read the evidence

Small controlled study terminated early due to drug withdrawal from market. Provides suggestive human evidence but very limited sample.

When this study was published

Published in 2012. Rimonabant is no longer in development. The endocannabinoid-stress axis connection continues to be studied through other approaches.

The bigger picture

The cortisol finding connected two important observations: cannabis users often report using cannabis for stress relief, and withdrawal often involves anxiety and irritability. If cannabis suppresses cortisol through CB1 receptors, blocking or removing this suppression would elevate stress hormones.

Questions still open

Would higher rimonabant doses precipitate full withdrawal with larger cortisol spikes? Does chronic cannabis use suppress the HPA axis long-term? Could cortisol elevation during cannabis cessation explain withdrawal anxiety?

Common questions

Does cannabis affect stress hormones?

This study found that blocking cannabinoid receptors in chronic cannabis users was associated with cortisol increases. This suggests cannabis normally helps suppress the stress hormone system through CB1 receptors, and removing this suppression raises cortisol.

Why was the study terminated early?

Rimonabant was withdrawn from development due to psychiatric side effects (depression, anxiety) in other clinical contexts. This study lost its drug supply before completing enrollment.

Read the original research

CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.

The American journal of drug and alcohol abuse, 38(1), 114-9

View on PubMed ↗Publisher’s paper ↗

Citation

Goodwin, Robert S; Baumann, Michael H; Gorelick, David A; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; Schroeder, Jennifer R; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A. (2012). CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.. The American journal of drug and alcohol abuse, 38(1), 114-9. https://doi.org/10.3109/00952990.2011.600398