Our DNA Could Affect the Potency of Psychedelics in the Brain
A deeper understanding of this phenomenon could help explain patient variability and advance precision psychiatry.
A study has identified that variation in genes coding for key receptors in our brains may alter the potency of psychedelic drugs and result in “immunity to psychedelics”. The research suggests that our genetics should be a factor in 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 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.
This variability raises an important question for clinical practice: why do individuals respond so differently to the same drug? One emerging explanation lies in the concept of immunity to psychedelics. Rather than referring to immunity in the classical immunological sense, the term describes a reduced or absent pharmacological response due to genetic variation in receptor targets. 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.
Genetic drivers of immunity to psychedelics
The gene variants the team identified coded for different variants of the serotonin (5-HT2A) receptor. This is one of the key receptors 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.
These findings support the hypothesis that genetic variation can contribute to immunity to psychedelics by either diminishing or exaggerating drug potency at the cellular level.
Experimental methods for assessing drug–receptor interactions
The study of genetic variation and immunity to psychedelics relied heavily on in vitro pharmacological techniques. Two complementary assays were employed to investigate 5-HT2A receptor signaling dynamics:
- Gq signaling assay: This measures activation of the canonical Gq protein pathway. When the 5-HT2A receptor is stimulated by a ligand, Gq activation triggers intracellular calcium release, which can be quantified using calcium-sensitive fluorescent indicators.
- β-arrestin recruitment assay: β-arrestins regulate receptor desensitization and internalization but also act as signaling scaffolds. Recruitment assays, often employing bioluminescence resonance energy transfer or enzyme complementation technologies, detect β-arrestin binding to activated receptors.
Running these assays in parallel enabled the researchers to measure signaling bias – the preference of a receptor–drug complex to activate one pathway over another. This methodology provides a mechanistic framework to understand how SNPs reshape psychedelic pharmacology.
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.”
Credit: iStock.
Toward precision psychiatry and personalized medicine
Understanding genetic variation underlying immunity to psychedelics represents a step toward precision psychiatry. By stratifying patients based on genetic profiles, clinical trials could more accurately measure drug efficacy, minimizing confounding from non-responders.
In practice, this could mean:
- Genetic screening: Identifying receptor variants before therapy to guide treatment choice.
- Dose optimization: Adjusting psychedelic dose based on receptor sensitivity.
- Drug development: Designing novel ligands that retain efficacy across receptor variants.
Such approaches would align with broader movements in personalized medicine, where therapies are increasingly tailored to individual genetic and molecular profiles.
Ethical considerations will also play a role. Genetic screening introduces questions of privacy, accessibility and fairness in treatment allocation. Nonetheless, integrating genomics into psychedelic therapy may ultimately enhance efficacy and safety.
The concept of immunity to psychedelics underscores the complexity of translating psychedelic compounds into reliable therapies. By leveraging advanced pharmacological assays and incorporating genetic insights into trial design, researchers are laying the groundwork for precision approaches to psychedelic therapy.
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.”
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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