THC-dependent monkeys recognized withdrawal as a distinct drug state, and cannabinoid agonists blocked it
Rhesus monkeys chronically treated with THC learned to discriminate the withdrawal state produced by rimonabant, which was reversed by THC and other cannabinoid agonists but not by diazepam or cocaine.
Quick Facts
What This Study Found
Monkeys receiving chronic THC were trained to discriminate the cannabinoid antagonist rimonabant (which precipitates withdrawal) from vehicle. The withdrawal discrimination was dose-dependent.
Several drugs were tested for their ability to block the withdrawal signal. THC and the cannabinoid agonist CP55940 fully blocked it. The cannabinoid agonist WIN 55212-2 and the alpha-2 adrenergic agonist clonidine partially blocked it. Diazepam (a benzodiazepine) and cocaine did not block it.
Simply stopping THC treatment also triggered the withdrawal discrimination, along with physical signs like head shaking and increased nighttime activity.
The drug discrimination approach was more pharmacologically selective than observing physical withdrawal signs, as head shaking was reduced by all test compounds including those that did not block the subjective withdrawal experience.
Key Numbers
Chronic THC: 1 mg/kg every 12 hours. Rimonabant discrimination ED50: 0.25 mg/kg. THC and CP55940 fully attenuated; WIN 55212-2 and clonidine partially attenuated; diazepam and cocaine did not attenuate withdrawal discrimination.
How They Did This
Controlled primate study using drug discrimination under a fixed-ratio schedule of stimulus-shock termination in rhesus monkeys receiving chronic THC (1 mg/kg every 12 hours). Multiple agonist and non-cannabinoid drugs tested for ability to attenuate withdrawal discrimination.
Why This Research Matters
The study suggested that cannabinoid agonist replacement therapy (analogous to methadone for opioids) and possibly clonidine could help manage the subjective experience of cannabis withdrawal, informing potential treatment development.
The Bigger Picture
The primate model provided stronger translational evidence than rodent studies for developing cannabis withdrawal pharmacotherapies, supporting cannabinoid agonist replacement and alpha-2 adrenergic approaches.
What This Study Doesn't Tell Us
Primate model with small numbers of animals. The discriminative stimulus paradigm measures one aspect of withdrawal. Rimonabant-precipitated withdrawal may differ from natural withdrawal. Clinical translation not yet tested.
Questions This Raises
- ?Could lower-potency cannabinoid agonists serve as step-down treatments for cannabis dependence?
- ?Would clonidine be effective for cannabis withdrawal management in humans?
Trust & Context
- Key Stat:
- Cannabinoid agonists and clonidine attenuated withdrawal; diazepam and cocaine did not
- Evidence Grade:
- Well-controlled primate pharmacology study with strong translational relevance but limited sample size.
- Study Age:
- Published in 2010. Cannabis withdrawal pharmacotherapy research has continued, with some human trials of agonist approaches.
- Original Title:
- Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.
- Published In:
- The Journal of pharmacology and experimental therapeutics, 334(1), 347-56 (2010)
- Authors:
- Stewart, Jennifer L(2), McMahon, Lance R(7)
- Database ID:
- RTHC-00457
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Could medications help with cannabis withdrawal?
This study found that cannabinoid agonist drugs and clonidine (a blood pressure medication) reduced withdrawal effects in monkeys, while sedatives and stimulants did not, pointing toward specific pharmacological approaches.
What is agonist replacement therapy?
Similar to using methadone for heroin withdrawal, agonist replacement uses a controlled dose of a similar drug to manage withdrawal symptoms while the person gradually reduces use. This study supported this approach for cannabis dependence.
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Cite This Study
https://rethinkthc.com/research/RTHC-00457APA
Stewart, Jennifer L; McMahon, Lance R. (2010). Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.. The Journal of pharmacology and experimental therapeutics, 334(1), 347-56. https://doi.org/10.1124/jpet.110.168435
MLA
Stewart, Jennifer L, et al. "Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.." The Journal of pharmacology and experimental therapeutics, 2010. https://doi.org/10.1124/jpet.110.168435
RethinkTHC
RethinkTHC Research Database. "Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in..." RTHC-00457. Retrieved from https://rethinkthc.com/research/stewart-2010-rimonabantinduced-delta9tetrahydrocannabinol-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.