AM404, a compound that boosts endocannabinoid levels and was being studied as a potential anti-smoking medication, was found to be self-administered by squirrel monkeys, raising abuse potential concerns.
Read this if you are interested in the development of endocannabinoid-based medications and their safety profiles.
AM404 was self-administered by monkeys and triggered relapse to THC, anandamide, and cocaine seeking.
What the researchers found
AM404 is an anandamide transport inhibitor that was being studied for its ability to reduce nicotine-seeking behavior. This study tested whether AM404 itself might be rewarding and found that it was.
Squirrel monkeys readily self-administered AM404 intravenously, with the classic inverted U-shaped dose-response curve seen with drugs of abuse (peak responding at 10 micrograms/kg). AM404 also triggered reinstatement of drug-seeking behavior in monkeys previously trained to self-administer THC, anandamide, or cocaine.
Both effects were blocked by rimonabant (CB1 antagonist), confirming they were mediated through the endocannabinoid system. The FAAH inhibitor URB597 enhanced AM404's reinforcing effects, supporting a role for anandamide in driving self-administration.
Another anandamide transport inhibitor (VDM11) also maintained self-administration, suggesting this is a class effect rather than specific to AM404.
Why it matters
Endocannabinoid-boosting compounds are being explored as potential treatments for various conditions including addiction and pain. This study raises an important safety flag: compounds that increase brain endocannabinoid levels may themselves carry abuse potential, because the endocannabinoid system is part of the brain's reward circuitry.
The numbers in context
AM404 self-administration peaked at 10 micrograms/kg/injection. AM404 reinstated drug-seeking previously reinforced by THC, anandamide, or cocaine. Both effects blocked by rimonabant (0.3 mg/kg). URB597 (0.3 mg/kg) potentiated AM404 reinforcing effects.
How the study worked
Squirrel monkey intravenous self-administration study using fixed-ratio schedules. Monkeys with prior experience self-administering anandamide or cocaine were tested with AM404 substitution. Reinstatement experiments tested whether AM404 could trigger relapse to previously extinguished drug-seeking. Pharmacological antagonism with rimonabant confirmed mechanism. The FAAH inhibitor URB597 was used to test whether enhancing anandamide levels potentiated the effects.
What this study cannot tell us
Primate self-administration does not necessarily predict human abuse patterns. The monkeys had prior experience with other drugs, which could sensitize them to reward from AM404. The clinical relevance depends on whether therapeutic doses in humans would reach reinforcing levels. AM404 also has some direct activity at other targets (TRPV1 receptors).
How to read the evidence
Preliminary evidence from primate self-administration studies. The findings are consistent across multiple measures but have not been tested in humans.
When this study was published
Published in 2016. The abuse potential of endocannabinoid modulators remains an important consideration in drug development.
The bigger picture
The drug development strategy of boosting natural endocannabinoids (rather than using direct cannabinoid agonists like THC) was seen as a potentially safer therapeutic approach. This study complicates that narrative by showing that indirectly increasing endocannabinoid levels can still activate the reward system enough to produce self-administration in primates.
Questions still open
- Are all endocannabinoid-boosting compounds potentially addictive, or can some avoid this risk? Would lower therapeutic doses in humans avoid reinforcing effects? Does the route of administration matter (intravenous versus oral)? Should abuse potential testing be standard for all endocannabinoid modulators?
Common questions
Can boosting natural endocannabinoids be addictive?
What does this mean for endocannabinoid-based medications?
Read the original research
Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys.
Psychopharmacology, 233(10), 1867-77
Citation
Schindler, Charles W; Scherma, Maria; Redhi, Godfrey H; Vadivel, Subramanian K; Makriyannis, Alexandros; Goldberg, Steven R; Justinova, Zuzana. (2016). Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys.. Psychopharmacology, 233(10), 1867-77. https://doi.org/10.1007/s00213-016-4211-3
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