Our DNA Could Affect the Potency of Psychedelics in the Brain

A new study has identified that variation in genes coding for key receptors in our brains may alter the potency of psychedelic drugs. The research suggests that our genetics should be a factor in future clinical trials of these drugs’ therapeutic potential.

Psychedelic drugs such as LSD, psilocybin and mescaline are being explored for their therapeutic potential in various psychiatric applications. A recent clinical trial showed that they were able to equal the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. But the trial showed that, like SSRIs, psychedelics don’t produce similar effects for everyone. What underlies these disparate treatment responses is likely a complex mix of factors, but a team from the University of North Carolina at Chapel Hill School of Medicine has investigated the contribution that our genes may play in affecting our brains’ reactions to psychedelics.

The reception awaiting psychedelics

The gene variants the team identified coded for different variants of the serotonin (5-HT2A) receptor. This is the key receptor that psychedelics bind to – psilocin, the active metabolite that makes magic mushrooms “magic”, is chemically near-identical to serotonin. The variants analyzed, which were all mutations at single points in the genome called single nucleotide polymorphisms (SNPs), were the seven alleles found most in humans, explained Gavin Schmitz, the paper’s first author. Schmitz, speaking to Technology Networks, said that the alleles’ frequency in the human population ranged from 0.003% up to 7.9%.

Working in vitro with human cells, the team used a pair of assays to assess how the different gene forms of the 5-HT2A receptor behaved when binding to any of four commonly studied psychedelics – psilocin, mescaline, 5-MeO-DMT and LSD. “Once 5-HT2A is activated by a drug, it has several options on what to do next,” said Schmitz. “It could signal through G proteins (in this case Gq) or recruit βArrestins [a type of signaling protein], and the relative balance of whether it chooses one option more often than the other depends on the drug. The two assays we used test those pathways independently, which means that we can see how much the 5-HT2A prefers one pathway over another and how that balance changes with different drugs, different SNPs, and over time.”

The team found that, with certain combinations of drug and receptor type, there were significant differences in the drug’s potency – for example, they wrote, “The Ala447Val 5-HT2A receptor displayed a three-fold increase in potency for 5-MeO-DMT”.  One particular receptor showed a nine-fold increase in potency in response to mescaline. While the changes were more modest for most of the combinations examined, both pathways the team explored showed significant differences in response to different receptor alleles.

Clinical implications

“Clinical studies have found a wide variety of responses to psychedelic drugs, with some patients seeing huge benefits after treatment and some seeing no benefits at all. Our study suggests that genes matter in determining how sensitive we are to the effects of psychedelics,” said Schmitz.

He was clear, however, that the differences seen at a cellular level might not be a direct predictor of response at the level of the whole brain in clinical trials. Our understanding of how psychedelics mediate their therapeutic effects is still unclear – which is hardly unique – and some researchers have suggested that the 5-HT2A receptor –  while being key to psychedelics’ hallucinatory effects – might not even be involved in these drugs’ antidepressant effects. For Schmitz, this complicated biology could represent a significant body of future research: “We chose to start with the 5HT2A receptor due to research showing it to be crucial in mediating the psychoactive effects of psychedelics. As other important receptor targets are identified, I would be greatly interested in exploring them too.”

Even prior to our exploration of psychedelics as potential medicines, budding psychonauts have been well aware of the incredible variation that can be produced when the same drug is taken in different settings and with different mindsets. Could the set of genes we are born with also affect how psychedelic hallucinations alter our reality? “I think this is absolutely possible,” concludes Schmitz. “We are all a little bit different from each other and those differences matter especially when it comes to deeply personal experiences.”

Reference: Schmitz GP, Jain MK, Slocum ST and Roth BL. 5‑HT2A SNPs Alter the pharmacological signaling of potentially therapeutic psychedelics. ACS Chem. Neuro. 2022. doi: 10.1021/acschemneuro.1c00815