Cannabinoid Cross-Tolerance in Monkeys Did Not Extend to Every Drug
Cross-tolerance is a measured relationship between particular drugs and particular effects. A squirrel-monkey experiment with repeated AM411 exposure found major changes in responses to cannabinoid agonists, alongside selective changes for some dopamine-related drugs. Other tested drug responses remained unchanged.
One repeated treatment, several comparison drugs
Researchers repeatedly administered the long-acting CB1 agonist AM411 and measured responding maintained by a stimulus-shock termination schedule. They compared drug dose-response relationships before and during chronic treatment. This was an animal operant-behavior experiment, not a test of human driving or an assay of intoxication in blood.
The pattern was selective
The supplied abstract reports large rightward shifts for several cannabinoid agonists, including THC, and smaller rightward shifts for methamphetamine and a dopamine D2 agonist. Several other dopamine-related and opioid drugs did not show comparable shifts. Sensitivity to the behavior-disrupting effects of CB1 antagonists increased.
Why the distinction matters
An altered response to one drug cannot establish universal tolerance to every intoxicant. A shift in the dose needed to disrupt scheduled responding also does not identify the dose needed to impair judgment, memory or driving. Enhanced sensitivity to an antagonist is a different observation from reduced sensitivity to an agonist.
The findings support investigation of interactions between cannabinoid and dopamine signaling. They do not establish that chronic cannabis users are protected from stimulant or opioid effects. AM411 is an experimental cannabinoid agonist, and the treatment history and behavioral endpoint must remain part of any comparison.
Related: interpreting cannabis tolerance claims.
Research cited
Desai RI; Thakur GA; Vemuri VK; Bajaj S; Makriyannis A; Bergman J. Analysis of tolerance and behavioral/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs. The Journal of pharmacology and experimental therapeutics (2013). doi:10.1124/jpet.112.198374. Findings discussed from the study abstract.
