Hallucinogenic compounds such as DMT, mescaline, and psilocybin can produce weak and transient self-administration in rhesus monkeys previously trained to self-administer MDMA. No compound generated reliable responding, and no subject self-administered DOI at rates above those for saline. In some sessions, 3 out of 4 subjects responded at rates between 0.75 and 3.0 responses per second when DMT, mescaline, or psilocybin were available, earning a majority of infusions and appearing intoxicated. This pattern suggests these hallucinogens may have weak reinforcing effects or mixed reinforcing and aversive properties.
The chiral nature of the MDMA molecule produces two enantiomers, each biologically active. Reviewing the author's research and other publications, no differences between racemic MDMA and its enantiomers in maintaining behavior were noted. Blocking the 5-HT2A receptor shifted the dose-effect function rightward for S(+)-MDMA but insurmountably reduced the reinforcing effects of R(-)-MDMA. Long-term self-administration can lead to chronic tolerance, with S(+)-MDMA somewhat less susceptible than the racemate or R(-)-enantiomer. PET neuroimaging showed negligible dopamine transporter occupancy after R(-)-MDMA but reasonable interaction after S(+)-MDMA. Non-human primate studies caution that results with enantiomers may not inform about the racemate and vice versa.
A single dose of the psychedelics LSD or DOI did not reduce opioid consumption or withdrawal signs in mice that had become dependent on fentanyl analogs. Mice drinking water avoided the bitter taste of quinine, but mice consuming fentanyl solutions continued drinking despite the adulteration, a behavior unchanged by psychedelic treatment. Fifteen days later, neither LSD nor DOI altered naloxone-precipitated jumping or restlessness, but both drugs lessened withdrawal-associated heightened sensitivity to heat. These results do not support a single psychedelic exposure as a treatment for opioid use disorder, though they suggest possible persistent effects on pain perception during withdrawal.