Ch. II — Chemistry and pharmacology

Chapter II of Post-2010 Psychedelics: An Expert-Panel Review. For the executive summary and full table of contents, start there.

This chapter establishes the chemical scaffolds and pharmacokinetic profiles of the five compound classes that recur across the remainder of the review: psilocybin/psilocin, N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, “mebufotenin” in pharma usage), and the grey-market fluoroethyl lysergamides addressed in detail in Chapter VIII. All structural and pharmacokinetic claims here are foundational; later chapters reference but do not re-derive them.

2.1 Classification framework

The five compounds covered share a single pharmacological commonality — 5-HT2A receptor agonism (Ch III) — but partition cleanly into two structural superfamilies, with a small but consequential third compartment.

Indolealkylamines are arylethylamines in which the aromatic system is an indole. They subdivide into:

• Simple tryptamines, in which the aminoethyl side chain projects from indole C3 with no ring fusion (psilocybin/psilocin, DMT, 5-MeO-DMT, bufotenine, serotonin itself). Substitution patterns of pharmacological interest cluster at the indole 4- and 5-positions (4-OH, 4-PO, 5-OMe, 5-OH) and at the terminal amine (N,N-dimethyl, N-isopropyl-N-methyl). The minimal tryptamine scaffold is biosynthetically derived from L-tryptophan.¹
• Ergolines, in which the tryptamine skeleton is fused into a tetracyclic ring system through additional C–C bonds, locking the aminoethyl group into a defined conformation. LSD is a diethylamide of d-lysergic acid; lisuride, ergotamine, and the fluoroethyl lysergamides discussed in §2.6 occupy the same scaffold.²

Phenethylamines — mescaline, the 2C-x and DOx series, 25x-NBOMe compounds — replace the indole with a substituted benzene ring. They are not the focus of this chapter (the post-2010 clinical pipeline is dominated by tryptamines and ergolines), but the conceptual point matters: hallucinogenic activity tolerates substantial scaffold variation, which is the structural foundation for §3.3’s discussion of biased agonism. Brandt and colleagues’ analytical chemistry programme has catalogued >100 hallucinogenic chemotypes binding 5-HT2A with submicromolar affinity.³

The five classes covered here are therefore: psilocybin/psilocin (4-substituted simple tryptamines), DMT (unsubstituted simple tryptamine), 5-MeO-DMT (5-substituted simple tryptamine), LSD (ergoline), and the fluoroethyl lysergamides (modified ergolines). All five activate 5-HT2A; they differ markedly in route of administration, kinetic profile, secondary receptor engagement, and — by consequence — subjective profile and clinical handling.

2.2 Psilocybin and psilocin

Structure. Psilocybin is 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT). Psilocin is its dephosphorylated active metabolite, 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT). Psilocybin itself is essentially a prodrug: oral psilocybin is dephosphorylated rapidly by alkaline phosphatase (and possibly nonspecific esterases) in the intestinal mucosa and liver to free psilocin, which is the species that crosses the blood–brain barrier and engages 5-HT2A.⁴⁵ The 4-phosphate group confers water solubility and oral bioavailability; psilocin alone is poorly stable in aqueous solution because the 4-hydroxyindole oxidises.

Isolation and synthesis. Albert Hofmann isolated and characterised both compounds in 1957–1958 from Psilocybe mexicana and reported the structure and a chemical synthesis in Experientia (1958) and Helvetica Chimica Acta (1959).⁶⁷ The modern reference large-scale synthesis is Shirota, Hakamata and Goda (2003), who reported a chromatography-free route from 4-hydroxyindole at gram scale via the zwitterionic N,O-dibenzylphosphate intermediate, with the final psilocybin obtained in ~85% yield over the key step.⁸ Kargbo, Sherwood and colleagues (2020, ACS Omega) subsequently described a kilogram-scale GMP-compatible second-generation route via direct phosphorylation of psilocin — eliminating the protecting-group strategy of Shirota — which is the chemistry that underpins Compass Pathways’ COMP360 and (with adaptations) Filament Health’s PEX010 supply.⁹

Stability. Psilocybin is thermally and pH-stable enough to survive normal pharmaceutical handling; psilocin is markedly less so. Free 4-hydroxyindoles oxidise to coloured quinones on standing — the bluing of bruised Psilocybe fruiting bodies is the macroscopic manifestation of this chemistry. Formulated psilocybin tablets are typically stored cold and protected from light, but they are not pathologically labile.

Pharmacokinetics. Oral psilocybin is rapidly converted to psilocin. In Holze et al.’s 2023 escalating-dose study (15, 25, 30 mg in healthy adults), maximum plasma psilocin concentrations were reached at a T_max of 1.7–2.0 h (median ~2 h), with terminal elimination half-life of 1.4–1.8 h, and complete return to baseline subjective effects by ~6 h.⁵ Meshkat et al.’s 2025 systematic review (14 studies; 8 laboratory, 6 clinical; 112 healthy participants pooled) reported T_max 1.8–4 h and half-life 1.5–4 h across studies, with the variability partly reflecting assay sensitivity, dose, and food state; one investigation reported psilocin bioavailability of 52.7 ± 20%.¹⁰ The dosing intervals used in current Phase 3 programmes (Compass COMP360 25 mg; Usona PSIL201 25 mg; Reunion luvesilocin/RE104 — an O-glutaryl psilocin prodrug with a different PK envelope) are calibrated against this 4–6 h “therapy window.” Elimination is predominantly renal, with psilocin-O-glucuronide the principal urinary metabolite; CYP2D6 and CYP3A4 contribute secondary oxidative pathways to 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol, with MAO-A a minor contributor.¹⁰

2.3 N,N-dimethyltryptamine (DMT)

Structure. DMT is the simplest of the bioactive tryptamines: tryptamine itself, dimethylated at the terminal amine. It carries no ring substitution. The compound is biosynthesised from tryptamine by indole-N-methyltransferase (INMT), with co-substrate S-adenosyl-L-methionine; INMT is expressed in mammalian (including human) peripheral tissues, and the biosynthetic capacity is documented, though whether endogenous DMT reaches behaviourally meaningful concentrations in the human CNS remains contested.¹¹

Sources and synthesis. DMT is widely distributed in plant species, most prominently in Mimosa hostilis (=M. tenuiflora) root bark, Psychotria viridis leaves (chacruna, the standard ayahuasca admixture), and several Acacia and Anadenanthera species. The first chemical synthesis was reported by the Canadian chemist Richard H. F. Manske in 1931 (Canadian Journal of Research, “A Synthesis of the Methyltryptamines and Some Derivatives”) via reductive methylation of tryptamine; Manske did not test the compound pharmacologically.¹² Its psychoactivity was characterised by Stephen Szára in Budapest in 1956.

Oral inactivity and ayahuasca. Free DMT is rapidly degraded in the gut and liver by monoamine oxidase A (MAO-A), to which N,N-dialkylated tryptamines lacking ring substitution at the 4-position are excellent substrates. Oral DMT alone is therefore essentially inactive; the ayahuasca preparation pairs DMT-containing P. viridis with Banisteriopsis caapi vine, which contains the β-carboline harmine and harmaline — competitive, reversible MAO-A inhibitors (RIMAs). This pharmacological pairing renders DMT orally bioavailable and is the chemical basis of the long, gut-mediated ayahuasca experience.¹³

Parenteral and inhaled PK. When MAO is bypassed (IV bolus, IV infusion, vaporised inhalation, intramuscular injection), DMT enters and exits the brain very rapidly. In the Liechti-group bolus + infusion study (Vogt et al., 2023, Translational Psychiatry; 27 healthy participants, five regimens), 15 mg and 25 mg IV boluses produced very intense psychedelic effects peaking within ~2 min, while infusions without bolus produced slowly rising dose-dependent effects that plateaued at ~30 min and resolved within 15 min of cessation; the early plasma half-life was ~5–6 min.¹⁴ Continuous infusion paradigms (the “extended DMT” model now pursued by atai VLS-01, Small Pharma SPL026, and Algernon’s AP-188) achieve steady-state plasma exposure for 30–90 minutes, decoupling subjective duration from the natural metabolic half-life.¹⁵ DMT’s session length is dialled by infusion engineering rather than dose, a route-of-administration lever absent from oral psilocybin and LSD.

2.4 Lysergic acid diethylamide (LSD)

Structure. LSD is the N,N-diethyl amide of d-lysergic acid. The ergoline core is a tetracyclic fusion of an indole and a partially-reduced quinoline; the C8 position carries the diethylamide group, and the C5/C8 chiral centres define stereochemistry. Four stereoisomers are possible: (5R,8R)-LSD — pharmacologically active “d-LSD”; (5R,8S)-iso-LSD; (5S,8S)-l-LSD; and (5S,8R)-l-iso-LSD. Only d-LSD is appreciably active at 5-HT2A. The C8 chiral centre is configurationally labile under mildly basic or acidic conditions, particularly in solution; d-LSD epimerises to iso-LSD on standing, which is one reason for the strict cold/dark/dry storage and routine HPLC quality control in clinical-grade material.²

Synthesis. Hofmann first synthesised LSD-25 in 1938 at Sandoz, the 25th compound in a series of lysergic acid amides screened as analeptics. The classical Hofmann–Stoll route condenses d-lysergic acid (obtained semi-synthetically from ergot alkaloids or by fermentation of Claviceps species) with diethylamine via an acyl chloride, mixed anhydride, or — more cleanly — propionate-mixed anhydride or a phosphoryl-activated intermediate. Modern routes (Garbaccio et al.; the MindMed and Onsero GMP processes underpinning MM120 and the BetterLife BETR-001) use carbodiimide or POCl3-based amide couplings with the carboxylate epimerisation kept below detection.

Stability. LSD’s photolability is famous: it is essentially fluorescent under UV, and degrades over hours of incident light to lumi-LSD and related photoproducts. Heat, oxygen, and trace alkali drive C8 epimerisation. Pharmaceutical formulations (MM120 oral solution; MindMed and Lykos MAPP3 era IV preparations; Holze-group oral capsule) are stabilised with ascorbate and held cold.

Dose–response. LSD’s dose–response curve is unusually flat at the high end. Subjective psychedelic threshold is ~10 µg base (the cleanest definition coming from Holze et al.’s microdose escalation: 5 µg null, 10 µg significant, 20 µg robust).¹⁶ The therapeutic dose range used in 2023–2026 trials clusters at 100–200 µg base. MM120’s dose-response anomaly — 100 µg outperforming 200 µg on some Phase 2b GAD endpoints — is consistent with the broader literature that higher LSD doses do not produce proportionally larger antidepressant or anxiolytic outcomes, possibly because subjective intensity beyond a ceiling becomes anxiogenic or interferes with therapeutic process.

Pharmacokinetics. LSD’s PK in oral capsule formulation (Holze et al. 2019, 2021): T_max ≈ 1.5 h, terminal plasma t½ ≈ 3.6 h (range 2.4–7.3 h across subjects), subjective duration 8–11 h for 100–200 µg base.¹⁷¹⁸ CYP-mediated oxidation produces 2-oxo-3-hydroxy-LSD (O-H-LSD), the principal urinary metabolite. CYP2D6 contributes; CYP2D6 poor metabolisers show modestly elevated AUC and prolonged subjective effects (Vizeli et al. 2021).¹⁹ These kinetics define the long, single-session clinical paradigm used in MM120-Voyage and Holze’s anxiety trial — LSD requires a near-full-day dosing visit, in contrast to the ~6 h psilocybin window.

2.5 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)

Structure. 5-MeO-DMT — increasingly designated “mebufotenin” in pharma usage (Beckley/atai BPL-003; GH Research GH001) — is N,N-dimethyltryptamine bearing a methoxy group at the indole 5-position. The structural relationship to bufotenine (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT) is exactly the O-methylation of the 5-hydroxyl. The pharmacological consequences of that single methylation are not trivial: 5-MeO-DMT crosses the blood–brain barrier substantially more readily than bufotenine (the 5-OH being a hydrogen-bond donor that reduces lipophilicity), and 5-MeO-DMT’s receptor profile differs in clinically meaningful ways from both bufotenine and N,N-DMT.

Sources and synthesis. 5-MeO-DMT is endogenous to multiple plant species, including Anadenanthera peregrina seeds — the source of yopo snuff, a ritual snuff with documented use among the Yanomami, Piaroa and other Orinoco/Caribbean Indigenous communities — and Virola species in the Amazon. The animal source that has attracted disproportionate attention is the parotoid gland secretion of the Sonoran Desert toad Incilius alvarius (formerly Bufo alvarius); the dried secretion is 5–15% 5-MeO-DMT by mass. The conservation, ecological, and ethical dimensions of toad-secretion sourcing — including the now-documented “fabricated ancestrality” of the Comcáac/Seri attribution and the Comcáac council’s formal objections — are discussed in Ch X §10.6. Synthesis from 5-methoxytryptamine via reductive dimethylation (formaldehyde/NaBH3CN or formaldehyde/formic acid) is straightforward and is the route underlying GH Research’s GH001 and Beckley/atai’s BPL-003. Industrial synthesis does not, however, resolve the colonial-knowledge-extraction question: the documented Indigenous antecedents (Amazonian yopo, post-1980s syncretic toad-medicine practice) and the absence of structural reciprocity agreements from any of the commercial-stage 5-MeO-DMT developers (GH Research, AtaiBeckley) are part of the picture even where the molecule reaches the patient via a wholly synthetic route. The reciprocity framework is developed in Ch X §10.7; the synthesis decoupling argument is taken up in Ch XIII §13.6.

Pharmacokinetics. Like free N,N-DMT, 5-MeO-DMT is MAO-A-susceptible and is also a CYP2D6 substrate; the latter converts 5-MeO-DMT to bufotenine, which is itself bioactive. Oral 5-MeO-DMT alone is essentially inactive without MAOI co-administration; inhaled (vaporised free base) or insufflated routes bypass first-pass metabolism. Onset is on the order of seconds for inhaled administration, with peak subjective effects at 1–3 minutes and total duration 15–30 minutes for vaporisation; insufflated administration extends onset to 5–15 min and duration to 30–60 min.²⁰ GH001 (inhalable aerosol) and BPL-003 (intranasal benzoate salt) exploit these kinetic differences to bracket a “single-session” 30–60 minute experience that fits a clinical room more neatly than ayahuasca or LSD.

Receptor profile distinct from psilocin. 5-MeO-DMT has higher 5-HT1A affinity relative to 5-HT2A than psilocin or DMT: published binding ratios place 5-HT1A/5-HT2A affinity for 5-MeO-DMT at roughly 1:10 versus ~1:100 or weaker for psilocin and N,N-DMT.²⁰ The 5-HT1A component is widely invoked to account for the qualitatively distinct subjective profile of 5-MeO-DMT — non-visual, ego-dissolving, “white-light” — relative to the predominantly visual, narrative content of psilocybin or LSD. This is mechanistically loose but clinically consequential: the 2025 GH001 Phase 2b result (−15.5 MADRS placebo-adjusted at Day 8, n=81) is unusually large among psychedelic trials, and it is worth marking that this effect was produced by a compound with a different receptor balance than COMP360.

2.6 Fluoroethyl lysergamides — structural scaffold note

Detailed pharmacology, grey-market sociology, and a critical naming-collision finding belong to Chapter VIII. This section provides only the structural scaffold context Chapter III needs.

The ergoline scaffold tolerates substitution at two loci of consistent pharmacological consequence:

• N1 (indole nitrogen) acylation produces 1-acyl-LSD analogues that function as LSD prodrugs: hydrolysis of the N1-acyl group by serum or hepatic esterases regenerates LSD in vivo. ALD-52 (1-acetyl-LSD), 1P-LSD (1-propionyl-LSD), 1B-LSD (1-butanoyl-LSD), 1cP-LSD (1-cyclopropanoyl-LSD), and 1V-LSD (1-valeroyl-LSD) are the main grey-market examples; the Brandt/Halberstadt “Return of the lysergamides” analytical series, Parts I–VII, characterises them.^3212223 In vitro, N1-acyl compounds show reduced direct 5-HT2A affinity (5–10× lower than LSD) but mouse head-twitch and self-report data align with equimolar LSD after a brief hydrolytic lag — the prodrug interpretation. 1cP-LSD has been shown in human serum incubations to release LSD with kinetics consistent with esterase-mediated cleavage.
• N6 alkyl substitution modifies receptor selectivity directly without prodrug activation. Replacing the N6-methyl of LSD with ethyl gives ETH-LAD; with allyl, AL-LAD; with propyl, PRO-LAD. These changes shift 5-HT2A vs 5-HT1A/2C balance and modulate subjective profile and duration without depending on metabolic activation. The N6-alkyl track is the substrate on which fluorination is engineered.

The actual verified fluoroethyl-class compounds. Two patent-disclosed compounds matter for this review:

• FLUORETH-LAD (FE-LAD, TRALA-15), 6-(2-fluoroethyl)-6-nor-lysergic acid diethylamide — an N6-haloalkyl analogue first proposed by the Shulgins in TiHKAL but never synthesised by them, with the first reported synthesis and in-vitro pharmacology in patent WO 2022/008627 A2 (Compass Pathfinder; Matthias Grill, inventor; filed 2021-07-07, published 2022-01-13).²⁴ The patent reports affinity at human 5-HT1A and 5-HT2A comparable to LSD with substantially reduced affinity at 5-HT2C and dopamine D1/D2/D4 — a claimed selectivity improvement over LSD. Patent binding data are sponsor-generated and not journal-peer-reviewed; independent receptor-binding replication of FLUORETH-LAD has not appeared as of 2026-05-13.
• FP-LAD (PROF-LAD, F-PRO-LAD, TRALA-16), 6-(3-fluoropropyl)-6-nor-lysergic acid diethylamide — the three-carbon homologue of FLUORETH-LAD (a fluorinated PRO-LAD, not a 1-propionyl + N6-fluoroethyl hybrid). Patent disclosures in US 2023/0414583 (MindMed; Trachsel and Liechti, inventors) and Gilgamesh WO 2022/226408 A1 report nanomolar 5-HT2A agonism (EC50 ≈ 0.48 nM, ~93% efficacy) with low single-digit nM Ki values across 5-HT2A/2B/2C. A 2025 independent synthesis (Hamilton Morris / Lizard Labs) reported mouse head-twitch potency ~one-fifth that of LSD on a milligram basis. As with FLUORETH-LAD, peer-reviewed replication is absent.

Naming-collision caution. Grey-market and Wikipedia sources occasionally use “1FE-LSD” in ways that imply an N1-fluoroethyl-LSD. There is no peer-reviewed or patent-disclosed N1-fluoroethyl-LSD analogue as of the freeze date. The abbreviation “1Fe-LSD” actually denotes 1-(ferrocenecarbonyl)-LSD (SYN-L-234; WIPO WO 2024/028495, Synex Holdings BV) — an iron-containing organometallic N1-acyl LSD prodrug in the same logical class as 1P-LSD and 1cP-LSD. The “Fe” is the chemical symbol for iron, not “fluoroethyl.” Ch VIII §8.5 develops this naming-collision finding in full; the panel should read assertions of an “N1-fluoroethyl-LSD” in secondary sources with caution.

The pharmaceutical rationale for fluorination on the N6-alkyl track is twofold: metabolic stabilisation (C–F bonds resist CYP-mediated hydroxylation) and modulation of lipophilicity and binding-pocket H-bonding. The grey-market rationale is regulatory arbitrage. Chapter VIII develops the full picture.

2.7 Metabolism overview

Across the five compound classes the major metabolic pathways are:

• MAO-A oxidative deamination dominates clearance of free tryptamines (N,N-DMT, 5-MeO-DMT, psilocin, bufotenine), generating the corresponding indole-3-acetaldehyde, then indole-3-acetic acid derivatives. This is the chemistry that renders all free tryptamines orally inactive without MAOI co-administration. Psilocybin escapes the issue because its 4-phosphate is hydrolysed peripherally only after intestinal absorption — though psilocin itself is then MAO-susceptible, hence its short half-life.
• CYP2D6 contributes to 5-MeO-DMT clearance (producing bufotenine) and to LSD oxidation; CYP2D6 poor metabolisers exhibit elevated LSD AUC.¹⁹ CYP1A2 and CYP3A4 contribute to LSD oxidation to nor-LSD and O-H-LSD. Psilocin clearance is dominated by glucuronidation (UGT1A10 in the intestine, UGT1A9 in the liver) rather than CYP, which is why CYP-based drug–drug interaction concerns for psilocin are modest.⁴
• Glucuronidation is the principal Phase II clearance pathway for psilocin and for hydroxylated LSD metabolites.
• COMT is a minor contributor for ring-hydroxylated metabolites (4-hydroxy-psilocin pathways, bufotenine).

Interspecies differences matter for translation. Rodent UGT1A profiles differ substantially from human; rat psilocin half-lives are reported shorter than human. CYP2D6 is functionally absent in dogs and varies with strain in mice; preclinical PK studies should be interpreted with the species expression pattern in mind.

Clinical drug–drug interaction implications.

• SSRIs and SNRIs: chronic 5-HT2A receptor occupancy and downregulation may attenuate psychedelic effects. Becker et al. (2022 Eur Neuropsychopharmacol; 2024 Neuropsychopharmacology) report blunted but not abolished psilocybin acute effects in escitalopram-treated participants — subjective intensity reductions on the order of 30–50% — but no consistent attenuation of late-stage antidepressant outcome. Current clinical trial protocols typically require SSRI taper before dosing: COMP005/006 require a 2-week SSRI washout (6 weeks for fluoxetine to accommodate the active metabolite norfluoxetine’s 4–16 day half-life); Usona PSIL201 requires a 4-week washout; MindMed MM120 requires 2 weeks for short-half-life SSRIs and longer for fluoxetine; Lykos MDMA-AT required a 5-half-life taper before dosing. Real-world implications: roughly half of TRD patients in the registrational target population are on a stable SSRI/SNRI regimen with documented partial response, often augmented by atypical antipsychotic or bupropion; the screening-exclusion fraction from SSRI-non-tolerability of washout (depression relapse during taper; suicidality emergence; medication-supervision feasibility) is non-trivial and is not consistently reported in the trial publications. ICER and FDA Patient-Focused Drug Development consultations have flagged this as a real-world-access concern.
• MAOIs: co-administration with ayahuasca-grade β-carbolines or pharmaceutical MAOIs (phenelzine, tranylcypromine, isocarboxazid; selegiline at higher doses; moclobemide reversible-MAOI) converts orally-inactive tryptamines (5-MeO-DMT, N,N-DMT) into orally-active long-duration experiences. Pharmaceutical MAOI co-administration with parenteral psychedelics also risks serotonin syndrome and hypertensive crisis; this is a hard contraindication. The MAOI-using TRD population (small but not zero; selegiline and moclobemide users in particular) is excluded from current registrational trials.
• Lithium: case reports (Honyiglo 2019; Nayak 2021) describe seizures and serotonin-syndrome-like presentations with psilocybin + lithium co-use, with approximately 8–12 published cases of seizures in psilocybin + lithium combinations. Lithium is a standard exclusion in current trials (COMP005/006, MM120, MAPP1/2) and a documented harm-reduction concern. The aetiological link is unconfirmed but the case-series risk-signal is sufficient for the per-protocol exclusion; the lithium-using bipolar-II TRD population is largely excluded from psychedelic trial samples.
• Psychotic-disorder history and family history: personal history of psychotic disorder, current or past manic episode, and first-degree family history of psychotic disorder or bipolar I disorder are standard exclusions across the registrational corpus. Severe cardiovascular disease (uncontrolled hypertension; ischaemic heart disease; QT-prolongation risk factors; structural heart disease) is excluded across the 5-MeO-DMT and LSD programmes specifically because of acute hypertensive response. The aggregate screening-exclusion fraction across the FDA-relevant TRD population — patients who have failed ≥2 antidepressants in the current episode — is on the order of 30–50% on DDI grounds alone (SSRI-non-tolerability of washout + lithium + MAOI + psychotic-disorder-history exclusions), a real-world access constraint that the registrational labelling cannot resolve. The economic-access framing is taken up in Ch V §5.7.
• CYP2D6 strong inhibitors (paroxetine, fluoxetine, bupropion) and CYP3A4 inducers/inhibitors warrant pre-dose review for LSD, 5-MeO-DMT, and DMT.

FDA DDI labelling expectations. The DDI sections above describe pharmacology; the regulatory question is what FDA will require in the approved labelling of psilocybin (and analogous classical psychedelics). Under FDA’s 2020 In Vitro Drug Interaction Studies guidance and 2020 Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions guidance, sponsors of a novel chemical entity are expected to characterise: (i) the molecule as victim — quantitation of CYP and transporter contributions to clearance (UGT1A9/1A10 dominate psilocin glucuronidation; CYP2D6 and CYP3A4 contribute secondary oxidative pathways to 4-hydroxy-indole-3-acetic acid and 4-hydroxytryptophol metabolites; MAO-A contributes minor clearance); (ii) the molecule as perpetrator — induction and inhibition of major CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) and transporters (P-gp, OATP1B1/1B3, BCRP), with in-vitro data triggering or excluding clinical DDI studies; (iii) protein-binding and serum-binding displacement DDIs; (iv) PK-of-DDI-modifier studies in CYP2D6 poor/extensive metabolisers for psilocin and LSD. The Compass COMP360 NDA package plausibly contains all of this; the public-record literature (Holze 2023; Meshkat 2025 review) covers the substrate side but not the perpetrator side at the FDA-expected level of completeness.

Beyond CYP-mediated DDIs, two pharmacodynamic-DDI categories will be load-bearing in the labelling discussion. First, the 5-HT2A serotonergic overlap with SSRIs, SNRIs, MAOIs, lithium, and triptans is the question of whether FDA expects a labelled serotonin-syndrome warning analogous to triptans, SSRIs, or other 5-HT-active drugs. The trial-protocol exclusion of MAOIs and the trial-protocol washout requirement for SSRIs (2 weeks; 6 weeks for fluoxetine) suggest the labelling will include at minimum a Precaution (and plausibly a Warning) on co-administration with serotonergic drugs and a Contraindication or strong Warning on MAOI co-administration. Second, the lithium-psilocybin seizure case-series (Honyiglo 2019; Nayak 2021; ~8–12 published cases of seizures in psilocybin + lithium combination) is the test case for whether the labelling will be a Contraindication (excludes use in lithium-treated patients entirely, materially reducing the bipolar-II TRD addressable market) or a Warning/Precaution (allows risk-benefit-managed use with lithium washout or monitoring). The aetiological link is unconfirmed but the case-series risk-signal is sufficient for trial-protocol exclusion; whether it crosses the bar for labelled Contraindication versus Warning has substantial impact on the addressable patient population — the bipolar-II TRD population (Aaronson 2024 open-label data; Ch XII §12.7) is meaningfully larger than zero, and a Contraindication forecloses it while a Warning preserves it under managed use.

The screening-exclusion fractions estimated in this section (30–50% of the FDA-relevant TRD population excluded on DDI grounds alone in current trials) may compress in the post-approval real-world setting depending on whether the FDA-approved labelling positions key co-medications as Contraindications (excludes use) or Warnings (allows managed use). The economic-access framing developed in Ch V §5.7 and the REMS-architecture framing in Ch XI §11.2c both depend on which labelling category FDA settles on, and the public record does not yet disclose this.

2.8 Comparative dosing and pharmacokinetics

The table below consolidates §2.2–2.5 for cross-reference. Doses are typical clinical or research doses (not recreational), routes are those used in 2024–2026 clinical programmes where applicable, and PK values are pooled from the studies cited inline above.

Two clinical–operational implications drop out of this table:

1. Session-length engineering is now a central design lever. The 8-hour LSD session is a cost and logistical burden that has motivated pursuit of compressed-duration alternatives — luvesilocin (RE104) targets ~4 h, GH001 ~30 min, BPL-003 ~60 min. The clinical-effectiveness consequences of compression are discussed in Ch V/VI.
2. MAO-A pharmacology governs route selection. The MAO-A-susceptibility of free tryptamines forces parenteral or inhaled delivery for DMT and 5-MeO-DMT; psilocybin’s prodrug architecture is what makes it the most operationally tractable classical psychedelic for outpatient clinical use. This is not an accident — it is the structural reason psilocybin, not DMT, has driven the post-2010 clinical pipeline.

The systems-level and circuit-level consequences of receptor engagement at these PK envelopes are taken up in Chapter IV; the receptor-level mechanisms underlying differential subjective and therapeutic profiles — biased agonism, the partial-vs-full agonism question, the non-hallucinogenic frontier — are developed in Chapter III.

References

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