People with different genetic variants of a particular serotonin receptor may be predisposed to stronger or weaker psychedelic trips. Tripping on psychedelics is an unpredictable experience that can catapult you into a state of bliss, plunge you into a pit of despair, or simply send you spiraling through a wormhole of confusion. While it’s widely accepted that the nature of these chemical escapades is influenced by a range of psychological and environmental factors, new research indicates that some people may be genetically predisposed to have stronger trips than others. Exactly which drugs count as "psychedelic" is the subject of some debate, although neuroscientists generally reserve the term for those substances that bind to the serotonin 2A (5-HT2A) receptor. As they lock onto the receptor’s binding sites, these mind-bending molecules set off a cascade of effects that result in epic alterations of consciousness. However, not everyone’s serotonin 2A receptors function equally. Genetic variations – or single nucleotide polymorphisms (SNPs) – alter the shape and performance of these psychedelic gateways. To investigate how these SNPs impact the strength of certain mind-altering drugs, a team of researchers measured the responses of seven common variations of the 5-HT2A receptor when combined with different psychedelics in the lab. Publishing their findings in the journal ACS Chemical Neuroscience, they explain how they tested the reactions of these seven SNPs to LSD, mescaline, a magic mushroom compound called psilocin, and the potent tryptamine 5-MeO-DMT – found in some plants and the excretions of the Colorado River Toad. Results indicated that many of these gene variations altered how the 5-HT2A receptor responds to these four substances. “Significantly, the in vitro pharmacological effects of the SNP drug actions at 5-HT2AR are drug specific,” write the researchers. Compared to the regular variant of the serotonin 2A receptor, two SNPs – known as Ala230Thr and His452Tyr – displayed a seven-fold decrease in signaling potency when interacting with psilocin. Meanwhile, the Ala447Val variant showed a three-fold increase in potency for 5-MeO-DMT. “Four polymorphic 5-HT2A receptors exhibited statistically significant changes in mescaline potency,” explain the authors. “Of these, the largest effect was observed for the Ser12Asn 5-HT2A receptor, which displayed a 9-fold increase in potency for mescaline.” Interestingly, none of the SNPs produced changes in LSD signaling potency, although some did influence the trajectory of acid trips. For instance, Ala230Thr appears to react most strongly during the early stages of LSD stimulation, while His452Tyr “limits the potency and efficacy of LSD at later time points.” Another variant called Asp48Asn showed an increased response to psilocin, but a weakened reaction to mescaline when compared to the regular version of the 5-HT2A receptor. Summarizing these observations, the study authors explain that “patients and populations with certain polymorphisms may be differentially amenable to psychedelic-assisted treatments.” In other words, some people may be naturally susceptible to stronger or weaker trips when ingesting certain drugs. “Taken together, these results may have relevance for the design and interpretation of future clinical trials,” they conclude. Source
