Psychedelic Therapy: Promise, Precaution and the Genetics Behind Individual Response

The recent BBC report on the growing interest in psychedelic-assisted therapy highlights a remarkable shift in mental health research. From individuals attending ayahuasca retreats in South America to NHS-supported clinical trials investigating psilocybin for depression, psychedelic medicines are moving from the fringes of healthcare into serious scientific discussion.¹ However, while the potential is exciting, a cautious and evidence-led approach remains essential.

At Chxhealth, we believe that personalised medicine should be guided by science rather than hype. Psychedelics may eventually become an important therapeutic tool for some patients, but they are unlikely to be a universal solution, and biological differences between individuals may play a major role in determining both effectiveness and safety.

Why are people turning to psychedelics?

Many patients seeking psychedelic therapy share a similar story. They have often tried conventional approaches such as antidepressants, counselling, cognitive behavioural therapy (CBT) or other psychological interventions, but continue to struggle with depression, anxiety, trauma or existential distress. The BBC article describes individuals who felt that traditional treatments had failed to address deeply rooted emotional problems and who sought alternative approaches abroad.

Researchers hypothesise that psychedelics may temporarily disrupt rigid patterns of brain activity, allowing patients to reassess entrenched thoughts, behaviours and emotional responses.² Clinical studies have reported improvements in treatment-resistant depression and major depressive disorder, particularly when psychedelic administration is combined with structured psychological support.¹

Importantly, the therapeutic model is not simply about taking a drug. Modern psychedelic-assisted therapy typically involves:

• Careful patient screening
• Psychological preparation
• Supervised dosing sessions
• Post-treatment integration therapy

The psychological support component may be as important as the psychedelic compound itself.

The cautionary reality

Despite media enthusiasm, several leading researchers have emphasised that psychedelic therapy is not a "silver bullet". Benefits are not universal, some studies have produced mixed results, and long-term outcomes remain under investigation.¹ Potential risks include:

• Acute anxiety or panic reactions
• Psychotic episodes in vulnerable individuals
• Cardiovascular effects
• Dangerous interactions with prescription medications
• Exposure to unsafe or unregulated retreat environments

Reports of serious adverse events and even deaths at poorly regulated retreats demonstrate why supervised medical environments are critical.

Why might psychedelics work for some people but not others?

One of the most intriguing questions in psychedelic medicine is why response rates vary so dramatically. While psychological factors undoubtedly matter, biological differences may also contribute substantially.

Psilocybin metabolism

Psilocybin itself is largely a prodrug. After ingestion it is rapidly converted into psilocin, the molecule primarily responsible for psychedelic effects.³ The simplified pathway is:

Psilocybin → alkaline phosphatases & esterases → psilocin → UGT glucuronidation → psilocin-glucuronide → renal excretion

Additional metabolism involves:

Psilocin → MAO-A → 4-HIAA metabolites  |  Psilocin → CYP2D6 / CYP3A4 → oxidised metabolites

Research suggests involvement of the following genes in psilocin metabolism: CYP2D6, CYP3A4, MAO-A and UGT enzymes.^3,4

Genetic variability

Many of these enzymes show substantial genetic variation between individuals.

CYP2D6

CYP2D6 is one of the most genetically variable drug-metabolising enzymes in humans. Individuals may be:

• Poor metabolisers
• Intermediate metabolisers
• Normal metabolisers
• Ultra-rapid metabolisers

Differences in CYP2D6 activity may alter psilocin clearance, affecting drug exposure, duration of effect and side-effect risk. Although current studies have not demonstrated a definitive clinical effect of CYP2D6 genotype on psilocin plasma concentrations, further research is ongoing.^4,5

CYP3A4

CYP3A4 contributes to psilocin metabolism and is influenced by genetics, other medications, grapefruit products and herbal supplements. Co-administration of CYP3A4 inhibitors could theoretically increase psychedelic exposure.^3,4

Serotonin receptor genetics

The primary target of psilocin is the serotonin 5-HT_2A receptor.² Variation in genes such as HTR2A, HTR1A and SLC6A4 could theoretically influence sensitivity to psychedelic experiences and therapeutic outcomes. While the evidence is still emerging, receptor-level genetics may eventually help explain why one patient experiences profound benefit while another reports little effect.⁵

Ayahuasca: an even more complex biological story

Ayahuasca presents additional challenges because it combines N,N-dimethyltryptamine (DMT) with monoamine oxidase inhibitors (MAOIs). Normally, orally administered DMT is rapidly broken down by MAO-A:

DMT → MAO-A → indole metabolites → inactivation

Ayahuasca contains β-carbolines such as harmine and harmaline that inhibit MAO-A. This changes the pathway:

DMT + MAO-A inhibition → increased bioavailability → prolonged psychedelic effects

The result is dramatically increased DMT exposure and longer-lasting psychoactive effects.⁶ However, MAO inhibition introduces additional risks:

• Drug interactions
• Blood pressure changes
• Serotonin toxicity when combined with certain antidepressants
• Unpredictable responses between individuals

This reinforces the importance of medical oversight.⁶

Could genetics help identify suitable candidates?

As psychedelic medicine develops, pharmacogenomics may become increasingly relevant. Potential future screening could include:

• CYP2D6 genotype
• CYP3A4 variants
• MAOA polymorphisms
• Serotonin receptor genes (HTR2A)
• Serotonin transporter variants (SLC6A4)

Such testing might eventually help clinicians identify greater risk of adverse effects, reduced likelihood of response, drug-interaction concerns and optimal dosing strategies. At present, however, evidence is not yet strong enough to recommend routine genetic testing specifically for psychedelic therapy. More research is needed before these markers can guide clinical practice.^3,4,5

A Chxhealth perspective

The current resurgence of psychedelic research is scientifically fascinating and may ultimately provide valuable new treatments for patients with depression, PTSD and other mental health conditions. Early trial results are encouraging, and the NHS research programmes described by the BBC represent an important step toward evidence-based evaluation.¹

Nevertheless, enthusiasm should not outpace evidence. Psychedelic therapy remains experimental. Not all patients respond. Some may experience adverse effects. Genetic differences in metabolism, receptor biology and neurotransmitter pathways may prove to be important determinants of outcome, but the science is still evolving.

The future may lie not simply in psychedelic medicine, but in precision psychedelic medicine, where genomics, pharmacology and psychological assessment are integrated to identify the right treatment for the right patient at the right time. Until then, caution, robust clinical evidence and professional supervision should remain central to any discussion about psychedelic therapies.

Explore your own genetics

Concerned about your results? Chxhealth offers evidence-based testing designed to help you better understand your metabolism, nutrition and overall health. While we do not offer testing for psychedelic therapy, the same principle of precision medicine runs through everything we do. Explore our genetic testing to understand more about your individual biology.

This article is informational and does not constitute medical advice. Chxhealth is a biomarker and genetic data provider; we do not diagnose, treat or prescribe, and we do not provide or endorse psychedelic substances or therapy. Psychedelics are controlled substances in the UK. Never start, stop or combine any treatment without speaking to a qualified healthcare professional.

References

1. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637–1648. Available here.
2. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264–355. Available here.
3. Thomann J, Kolaczynska KE, et al. In vitro and in vivo metabolism of psilocybin's active metabolite psilocin. Front Pharmacol. 2024;15:1391689. Available here.
4. Meshkat S, Al-Shamali H, Perivolaris A, et al. Pharmacokinetics of psilocybin: a systematic review. Pharmaceutics. 2025;17(4):411. Available here.
5. Halman A, et al. Harnessing pharmacogenomics in clinical research on psychedelic-assisted therapy. Clin Pharmacol Ther. 2025. Available here.
6. The pharmacological interaction of compounds in ayahuasca: a systematic review. Braz J Psychiatry. Available here.