Chronic Cannabinoid Treatment Caused Massive Tolerance and Cross-Tolerance With Dopamine Drugs | Research

The takeaway

Chronic CB1 receptor activation in monkeys produced up to 250-fold tolerance to cannabinoid agonists and cross-tolerance to methamphetamine and dopamine drugs, while increasing sensitivity to cannabinoid antagonists.

Read this if you are interested in why tolerance develops to cannabis and how it interacts with other brain systems.

Up to 250-fold tolerance to cannabinoids and 10-fold cross-tolerance to dopamine drugs

What the researchers found

Squirrel monkeys chronically treated with the potent CB1 agonist AM411 developed enormous tolerance to cannabinoid agonists, with up to 250-fold rightward shifts in potency. At the same time, they became much more sensitive to CB1 antagonists (100-fold leftward shift for SR141716A), providing evidence of physical dependence.

Critically, cross-tolerance developed with methamphetamine (4.8-fold) and the dopamine D2 agonist NPA (10-fold), but not with other dopamine or opioid drugs. The differences in tolerance magnitude among cannabinoid agonists may reflect differences in their pharmacological efficacy (how strongly they activate the receptor).

Why it matters

The cross-tolerance between the cannabinoid and dopamine systems provides strong evidence that these systems interact functionally. This has implications for understanding why cannabis users may have blunted responses to natural rewards and why stimulant effects may be altered in cannabis users.

The numbers in context

Tolerance: >250-fold for AM411, methanandamide. >45-fold for AM4054, WIN55,212.2, THC. Antagonist sensitivity: >100-fold for SR141716A, >20-fold for AM4113. Cross-tolerance: 4.8-fold for methamphetamine, 10-fold for NPA. No change for other DA drugs, morphine, or naltrexone.

How the study worked

Behavioral pharmacology study in squirrel monkeys using a fixed-ratio schedule of shock avoidance. Chronic treatment with AM411 (1.0 mg/kg/day, intramuscular). Dose-response curves for CB1 agonists, antagonists, dopamine-related drugs (methamphetamine, SKF82958, SCH23390, NPA, haloperidol), and opioid drugs (morphine, naltrexone) compared before and during chronic treatment.

What this study cannot tell us

Primate behavioral pharmacology with small sample sizes typical of the field. The doses and chronic treatment regimen may not reflect human cannabis use. The behavioral measure (shock avoidance) is a specific assay that may not capture all aspects of drug effects. Only one chronic treatment dose was tested.

How to read the evidence

Primate behavioral pharmacology study with comprehensive dose-response data; moderate evidence for CB1-D2 interaction.

When this study was published

Published in 2013. The CB1-dopamine interaction continues to be an important area of addiction neuroscience.

The bigger picture

This study provides behavioral pharmacological evidence for the long-suspected link between cannabinoid and dopamine signaling. The selective cross-tolerance with methamphetamine and D2 agonists, but not other dopamine or opioid drugs, points to specific shared mechanisms between CB1 and D2 receptor pathways.

Questions still open

Does chronic human cannabis use produce similar cross-tolerance with dopamine-mediated processes? Could the CB1-D2 interaction explain cannabis-associated amotivation? Would dopamine medications be less effective in chronic cannabis users?

Common questions

Why does cannabis tolerance develop?

Chronic CB1 receptor activation causes the receptors to become less responsive (desensitize) and to be removed from cell surfaces (internalize). This study showed the magnitude of tolerance can be enormous, up to 250-fold for some agonists, meaning much higher doses are needed to produce the same effect.

What does cross-tolerance with dopamine drugs mean?

Cross-tolerance means that tolerance to one drug also reduces the effect of a different drug. The finding that chronic cannabinoid treatment reduced responses to methamphetamine and a dopamine D2 agonist suggests the cannabinoid and dopamine systems are functionally linked. This could help explain why chronic cannabis users sometimes report feeling less motivated or responsive to natural rewards.

Read the original research

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, 344(2), 319-28

View on PubMed ↗Publisher’s paper ↗

Citation

Desai, Rajeev I; Thakur, Ganesh A; Vemuri, V Kiran; Bajaj, Shama; Makriyannis, Alexandros; Bergman, Jack. (2013). 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, 344(2), 319-28. https://doi.org/10.1124/jpet.112.198374