THC-dependent monkeys recognized withdrawal as a distinct drug state, and cannabinoid agonists blocked it | Research

The takeaway

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.

Read this if you are interested in potential medications for managing cannabis withdrawal.

Cannabinoid agonists and clonidine attenuated withdrawal; diazepam and cocaine did not

What the researchers 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.

Why it 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 numbers in context

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 the study worked

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.

What this study cannot 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.

How to read the evidence

Well-controlled primate pharmacology study with strong translational relevance but limited sample size.

When this study was published

Published in 2010. Cannabis withdrawal pharmacotherapy research has continued, with some human trials of agonist approaches.

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.

Questions still open

Could lower-potency cannabinoid agonists serve as step-down treatments for cannabis dependence? Would clonidine be effective for cannabis withdrawal management in humans?

Common 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.

Read the original research

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

View on PubMed ↗Publisher’s paper ↗

Citation

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