Lysergic Acid Diethylamide (LSD)

LSD is a semi‑synthetic ergoline first described in 1938. It is an intensely potent, long‑acting agonist at 5‑HT_2A receptors with additional activity at 5‑HT_1A, 5‑HT_2B/C, D₂, and several adrenergic sites Liechti 2021.

Contemporary investigations are assessing LSD for treatment‑resistant depression, anxiety associated with life‑threatening illness, substance‑use disorders, and cluster headache. Sublingual “microdose” regimens are also under examination, although dose–response data remain preliminary Holze 2021.

After oral or sublingual dosing LSD is rapidly absorbed and undergoes extensive hepatic biotransformation, yet the parent compound persists in plasma for 8–12 h at conventional psychoactive doses of 100–200 µg Dolder 2017.

CYP2D6 encodes a polymorphic hepatic cytochrome P450 responsible for O‑ and N‑dealkylation of roughly 25 percent of prescribed drugs. In vitro work demonstrated that CYP2D6 catalyses N‑demethylation of LSD to nor‑LSD Luethi 2019. Additional isoforms (CYP3A4, CYP1A2, CYP2C9, CYP2E1) contribute, but genetic variability in these enzymes exerts lesser or inconsistent influence on LSD exposure.

Functional variation in CYP2D6 produces the canonical metabolizer phenotypes: poor (PM), intermediate (IM), normal (NM), and ultrarapid (UM). These categories correspond to absent, reduced, normal, or elevated enzyme activity, respectively McInnes 2023.

The only published human pharmacogenetic study pooled 81 healthy volunteers from four randomized crossover trials. LSD (100–200 µg p.o.) was administered, and plasma exposure was stratified by CYP2D6 diplotype Liechti 2021. Participants lacking functional CYP2D6 (PM) showed:

• ≈ 75 percent increase in LSD area under the curve.
• Prolongation of elimination half‑life from median 2.6 h (NM) to 4.6 h (PM).
• Higher peak scores on validated psychometric scales (5D‑ASC, MEQ30) and delayed return to baseline.

No significant pharmacokinetic effect was detected for CYP1A2, CYP2C9, CYP2C19, or CYP2B6 haplotypes in the same dataset, suggesting a dominant role for CYP2D6.

CYP2D6 Ultrarapid Metabolizer (UM)

• Effect: Accelerated clearance; plasma exposure falls below population mean.
• Implication: Psychoactive effects may resolve sooner and be less intense.
• Side effects: No increase predicted, though reduced efficacy could drive redosing in uncontrolled settings.

CYP2D6 Normal Metabolizer (NM)

• Effect: Reference pharmacokinetics.
• Implication: Clinical trials use this phenotype as baseline.
• Side effects: Typical profile of transient anxiety, tachycardia, mydriasis.

CYP2D6 Intermediate Metabolizer (IM)

• Effect: AUC modestly elevated; simulations suggest 15–30 percent prolongation of subjective effects.
• Implication: Slightly greater intensity and duration but rarely clinically problematic.
• Side effects: Potential for residual insomnia next day.

CYP2D6 Poor Metabolizer (PM)

• Effect: Substantially reduced metabolic clearance; exposure increased ≈ 75 percent.
• Implication: Heightened likelihood of dysphoric reactions, anxiety surges, and extended recovery period.
• Side effects: Greater cardiovascular stimulation and perceptual disturbances; case reports document panic reactions at standard 100 µg doses.

Indeterminate / Not Available

• Effect: Unknown
• Implication: No specific guidance; follow standard dosing with clinical monitoring.

CYP2D6 Dosing Guideline

CYP2D6 PM frequency varies by ancestry: ≈ 8 percent in Europeans, 1–2 percent in East Asians, and up to 10 percent in some Near‑Arabian groups. The reduced‑function *10 allele reaches 45 percent frequency in East Asian populations, producing a high prevalence of IM status Youssef 2022. UM status, driven by gene duplications, is most common in North Eastern Africa and parts of the Middle East (up to 28 percent) Tan 2024. These distributions predict that clinical trials conducted predominantly in European volunteers may underestimate variability in ethnically diverse settings.

• Liechti ME et al. Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD. Scientific Reports 2021. DOI
• Luethi D et al. Cytochrome P450 enzymes contribute to the metabolism of LSD to nor‑LSD and 2‑oxo‑3‑hydroxy‑LSD. Biochemical Pharmacology 2019. PDF
• Holze F et al. Pharmacokinetics and pharmacodynamics of LSD microdoses in healthy participants. Clinical Pharmacology & Therapeutics 2021. DOI
• McInnes GT et al. Does ethnicity impact CYP2D6 genotype–phenotype relationships? Clinical and Translational Science 2023. Link
• Youssef MA et al. Frequencies of CYP2D6 genetic polymorphisms in Arab populations. Human Genomics 2022. Link
• Tan J et al. Variation landscape of CYP2D6 in a multi‑ethnic Asian cohort. Scientific Reports 2024. PDF
• Dolder PC et al. Pharmacokinetics and pharmacodynamics of LSD in healthy subjects. Clinical Pharmacokinetics 2017. Link