How Psilocybin Is Processed in the Body: A Systematic Review

Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), a serotonergic psychedelic belonging to the 5-hydroxytryptaminergic class, was first isolated from Psilocybe mushrooms by Albert Hofmann in 1957 and subsequently synthesized by him in 1958 [1]. Initially utilized in psychiatric research during the early to mid-1960s, the clinical use of psilocybin as a treatment for mental health conditions was curtailed following its classification as a Schedule 1 substance in the United States in 1970 [2,3]. Research into psilocybin’s potential therapeutic effects resumed in the mid-1990s, with the compound now considered as the preferred agent for clinical studies on serotonergic psychedelics due to its shorter duration of action of 4–6 h compared to similar classical psychedelic substances [4,5,6,7]. Current research on psilocybin emphasizes its administration in controlled, supportive settings to achieve therapeutic benefits. These studies aim to utilize psychospiritual experiences induced by psilocybin, channeling them into durable therapeutic interventions for individuals with mental health conditions [8,9].

Pharmacokinetics refers to the study of the processes underlying the absorption, distribution, metabolism, and excretion of a drug within the body over time [10]. Understanding pharmacokinetics is essential for the safe and effective use of any drug, as it provides critical information about how the drug is processed within the body to confer its therapeutic availability on target organ systems [11]. This knowledge helps determine appropriate dosing regimens, predict therapeutic efficacy and duration, identify potential side effects, generate contraindications, and understand individual variability in drug response. Additionally, pharmacokinetics plays a vital role in drug development, informing the design of clinical trials and ensuring that medications are used safely and efficiently in clinical practice [11]. Psilocybin is a prodrug that undergoes rapid metabolism in the body to its active form, psilocin (N,N-dimethyl-4-hydroxytryptamine), mostly through gut and hepatic dephosphorylation [12]. The pharmacokinetics of psilocybin and psilocin are influenced by various factors, including the rate of absorption, systemic distribution, and elimination via urine and feces [13]. The role of cytochrome P450 (CYP) enzymes, specifically the CYP 450 family, is critical in the metabolism of psilocin [13]. These enzymes, which are involved in the oxidative metabolism of a wide range of substances, may contribute to the interindividual variability observed in psilocybin’s pharmacokinetic profile [14]. Understanding the interaction between psilocybin, psilocin, and the CYP 450 enzymes is essential for predicting potential drug–drug interactions, optimizing dosing strategies, and minimizing adverse effects in clinical settings.

Research into the pharmacokinetic properties of psilocybin and its interactions with CYP 450 enzymes has been limited. As psilocybin continues to gain attention in clinical and therapeutic settings, a thorough understanding of these interactions becomes increasingly important, particularly for individuals on polypharmacy regimens, including other serotonergic-modulating medications such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). This systematic review aims to synthesize the available evidence on the pharmacokinetics of psilocybin in humans, with a particular focus on the role of CYP 450 enzymes in its metabolism, and to explore the implications for its clinical use.

This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [15], and the protocol was registered with PROSPERO (CRD42025633390).

The database search yielded 2997 articles, from which 1149 duplicates were automatically removed, leaving 1848 articles for screening. Following title and abstract review, 41 studies proceeded to full-text assessment, and 14 were ultimately included in this review (Figure 1, Table 1) [13,19,20,21,22,23,24,25,26,27,28,29,30,31].

In this review on the pharmacokinetics of psilocybin, significant variability was observed across studies, influenced by factors such as dose, species, and route of administration. Psilocybin was found to be rapidly absorbed, with Tmax typically reported around 2 h following oral administration and much shorter with intravenous dosing. Extensive distribution was noted, with a high volume of distribution (up to 1016 L in humans), indicating widespread tissue penetration. Psilocybin was metabolized to its active compound, psilocin, primarily through the actions of CYP2D6 and CYP3A4 enzymes, with further metabolism producing secondary compounds such as 4-HIAA and psilocin-O-glucuronide. Elimination was shown to occur predominantly via renal excretion, with the half-life of psilocin ranging from 2 to 4.8 h following oral administration. These findings highlight the complexity of psilocybin’s pharmacokinetics and provide important insights for its therapeutic use.

IV administration of psilocybin led to a markedly shorter Tmax for psilocin, compared to psilocin Tmax after oral psilocybin administration. This rapid conversion of psilocybin to psilocin, with a Tmax of just 2 min, is due to the direct absorption of psilocybin into the bloodstream, bypassing first-pass hepatic metabolism [32]. In contrast, the oral administration of psilocybin results in delayed psilocin absorption due to the time required for the compound to pass through the gastrointestinal system, in addition to undergoing first-pass metabolism in the liver [32]. If first-pass metabolism was not involved, we would expect IV administration to result in lower psilocin levels and higher psilocybin levels relative to the oral route [33]. However, the rapid conversion of psilocybin to psilocin after IV administration highlights the difference in absorption and metabolism between the two routes. While this rapid absorption may enhance therapeutic efficacy in situations requiring a quick onset of action, the limitations of IV administration—such as its invasive nature, the need for specialized medical infrastructure, and the potential for adverse reactions due to rapid changes in plasma concentration—restrict its practical use in routine therapy [34]. Additionally, the wide range of Cmax values observed across studies underscores variability in psilocybin metabolism, influenced by individual factors like enzymatic activity and study conditions. Dose-dependent increases in Cmax confirm the predictability of psilocybin’s pharmacokinetics, but interindividual and inter-species differences, such as higher plasma concentrations in animal studies, highlight the need for caution when extrapolating these results to humans [13,21,22,24,29,31]. These findings emphasize the potential importance of personalized dosing strategies and the need for further research to optimize psilocybin’s therapeutic use.

The oral administration of psilocybin results in a higher Vd compared to IV administration. This difference is likely influenced by various factors, including metabolism, plasma protein binding, the route of administration, and the drug’s intrinsic properties [13,20,21,22,24,27]. While a high Vd may suggest extensive tissue distribution, it does not necessarily indicate a reduced potential for toxicity. In some cases, drugs with high Vds can be highly toxic due to prolonged retention in tissues and difficulty eliminating them [35,36]. Additionally, the high Vd may indicate extensive distribution into the central nervous system (CNS), which is beneficial for its therapeutic effects, especially in treating psychiatric conditions [37]. However, this extensive distribution could present challenges in monitoring and the slower elimination of the drug, which may require careful management in clinical settings [38]. Additionally, oral administration leads to a longer t1/2 of 2–4.8 h compared to approximately 1.2 h for IV administration. This difference reflects faster systemic clearance rates of 3126 ± 719 mL/min for IV dosing versus more variable oral clearance rates, which range from 60.6 µg/h to 263 L/h [39]. The longer half-life observed with oral dosing may play a role in the sustained therapeutic effects seen in psychiatric treatments, though the exact relationship between pharmacokinetics and clinical duration remains unclear. In contrast, the shorter half-life of IV administration could be advantageous for conditions requiring precise dosing and the rapid cessation of effects, though its clinical implications warrant further investigation [40]. Additionally, cost-effectiveness may be an important consideration, as oral administration is generally more accessible and less resource-intensive compared to IV delivery, which requires medical supervision and specialized equipment. Renal excretion is the primary elimination pathway for psilocin, emphasizing the critical role of kidney function in its clearance and explaining why clinical trials commonly exclude individuals with renal failure to avoid potential accumulation and toxicity. This exclusion highlights the need for caution when considering psilocybin therapy in populations with chronic renal disease [41,42]. Additionally, the variability in clearance rates and half-life across species highlights the complexity of psilocybin’s metabolism and excretion. Future research should address the challenges by optimizing dosing strategies and evaluating safety in diverse patient populations, including those with renal impairment.

Psilocybin is metabolized via multiple enzymatic pathways, starting with alkaline phosphatase to psilocin followed by CYP450, MAO-A, and UGTs, which play a significant role in its pharmacokinetics and potential drug interactions. Psilocybin undergoes rapid metabolism after administration, primarily converting to its active metabolite, psilocin, through enzymatic pathways. Psilocin, the primary mediator of its psychoactive effects, is further metabolized into secondary metabolites such as 4-hydroxyindole-3-acetic acid (4-HIAA) and psilocin-O-glucuronide. The involvement of CYP450 enzymes, particularly CYP2D6 and CYP3A4, highlights the potential for drug–drug interactions, as substances that inhibit or induce these enzymes could significantly alter psilocybin’s pharmacokinetics [43]. This enzymatic metabolism not only underscores the potential for variability in individual responses but also emphasizes the need for caution when psilocybin is used in combination with other medications [43]. The CYP450 enzyme family, responsible for metabolizing a broad range of medications, is particularly relevant for interactions involving psilocybin [44]. Studies have highlighted possible interactions between psilocybin and various drug classes, including anxiolytics, antipsychotics, mood stabilizers, antidepressants, and recreational substances [45]. For example, co-administration with antipsychotics such as chlorpromazine, risperidone, and haloperidol has been shown to attenuate psilocybin-induced effects, such as visual perceptual changes and the sensation of ego dissolution, with some antipsychotics also influencing working memory performance [46,47,48]. Psilocybin primarily exerts its effects through agonism at serotonin 2A receptors (5-HT2A) [49]. Medications with 5-HT2A antagonist properties, such as risperidone, have been shown to partially or completely block psilocybin’s subjective effects [46,47,48]. Additionally, selective serotonin reuptake inhibitors (SSRIs), like escitalopram, which increase extracellular serotonin by inhibiting its reuptake, may attenuate psilocybin’s acute effects and potentially influence treatment-related outcomes, such as reductions in depression symptoms [19,45]. This attenuation occurs due to receptor competition between elevated endogenous serotonin and psilocin at serotonin receptors [19]. Interestingly, despite prior expectations, escitalopram pretreatment did not significantly reduce psilocybin’s core subjective effects but did significantly mitigate some physiological reactions, such as increased blood pressure and pupil dilation [19,50]. Notably, mood stabilizers such as lithium and lamotrigine warrant special consideration, as case reports suggest that their combination with psilocybin or other psychedelics may increase the risk of adverse effects, including seizures and manic episodes [51,52].

An important consideration in the metabolism of psilocybin is the distinction between synthetic, purified psilocybin, and naturally occurring psilocybin derived from fungal sources. Naturally sourced psilocybin contains a complex mixture of other tryptamines, such as baeocystin and norbaeocystin, which may also interact with CYP enzymes. These additional tryptamines could compete for enzymatic processing, potentially altering the pharmacokinetics of psilocybin and its active metabolite, psilocin. In contrast, synthetic psilocybin, being a purified compound, follows a more predictable metabolic pathway without interference from other bioactive constituents. However, some studies suggest that naturally sourced psilocybin may produce more robust symptom improvement [53], indicating that the presence of additional bioactive compounds could enhance therapeutic effects rather than hinder them.

Psilocybin’s potential as a psychiatric treatment is due to its pharmacological effects on the serotonergic system and its ability to affect neural networks implicated in mental health disorders. By modulating 5-HT2A receptor activity, psilocybin alters functional connectivity, particularly within the default mode network (DMN), which plays a key role in self-referential thinking and emotional regulation [54,55]. Decreased DMN activity has been associated with a shift in perspective and increased mental flexibility, which may be beneficial in conditions characterized by rigid thought patterns, such as depression [55,56,57]. Psilocybin has also been shown to promote structural neuroplasticity, enhancing dendritic spine density and synaptic strength in preclinical models [58]. These findings align with clinical studies suggesting that psilocybin’s therapeutic effects may extend well beyond the acute psychedelic experience. Despite its classification as a Schedule 1 substance, interest in psilocybin has increased due to evidence from clinical trials demonstrating its potential benefits and a relatively favorable safety profile when administered in controlled settings [59,60]. Understanding psilocybin’s pharmacokinetics, including its metabolism, is essential for optimizing dosing strategies and identifying potential drug–drug interactions. Future research should aim to refine its clinical use, particularly in patient populations with varying metabolic profiles, to maximize therapeutic benefits while minimizing risks.

This systematic review has several limitations that should be acknowledged. First, the included studies exhibited significant heterogeneity in methodologies, including variability in psilocybin dosages, routes of administration, study designs, and populations (e.g., human versus animal models). This variability limited our ability to perform a meta-analysis and may have influenced the consistency of reported pharmacokinetic outcomes. Second, the small sample sizes in several human studies (totaling only 112 participants across six studies) may reduce the generalizability of findings to broader populations, particularly in clinical settings. Third, only one study examined intravenous administration, and none were conducted in clinical samples, limiting the applicability of findings to therapeutic contexts. Additionally, there was a lack of dose–response studies, and no study comprehensively assessed both pharmacokinetics and pharmacodynamics. Reporting inconsistencies further hindered comparisons across studies, highlighting the need for standardized guidelines. Given these gaps, future research should prioritize larger, well-controlled trials with standardized methodologies and diverse populations. Moreover, adherence to established pharmacodynamic reporting guidelines, such as those recommended by the Food and Drug Administration or the European Medicines Agency for psychedelic drug development, could improve consistency and comparability across studies.

This systematic review provides a comprehensive synthesis of psilocybin’s pharmacokinetics, highlighting key findings across absorption, distribution, metabolism, and excretion. Oral administration remains the most commonly studied route, with absorption characterized by Tmax values around 2 h and dose-dependent Cmax levels. Distribution data indicate a large volume of distribution for psilocin, supporting extensive tissue uptake. Metabolism primarily involves CYP enzymes, particularly CYP2D6 and CYP3A4, with secondary contributions from UGTs and MAO-A, resulting in both active and inactive metabolites. Excretion studies consistently identify renal clearance as the primary elimination pathway. Despite variability in reported pharmacokinetic parameters due to differences in study design, populations, and dosing regimens, these findings underscore the complexity of psilocybin metabolism and its potential for drug–drug interactions.

Future research should focus on refining psilocybin’s pharmacokinetic profile across diverse populations, including individuals with varying genetic polymorphisms of CYP enzymes. Further studies are needed to evaluate potential drug–drug interactions, particularly with medications metabolized by CYP2D6 and CYP3A4. Additionally, investigating alternative routes of administration, such as intranasal or sublingual delivery, may optimize bioavailability and therapeutic outcomes. Standardizing study methodologies, including consistent dosing protocols and analytical techniques, will be essential for enhancing comparability across studies. Finally, exploring pharmacokinetic–pharmacodynamic relationships in clinical populations will help optimize dosing strategies for psychiatric and neurological disorders.

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pharmaceutics17040411/s1↗. Table S1. Full search strategy. Table S2. Risk of bias assessment results.

Conceptualization: S.M., H.A.-S., A.P., T.T. and V.B.; Methodology: all authors; Validation: all authors; Formal Analysis: S.M., H.A.-S., A.P. and T.T.; Investigation: S.M., H.A.-S., A.P. and T.T.; Resources: V.B.; Data Curation: S.M., H.A.-S., A.P., T.T. and V.B.; Writing—Original Draft Preparation: S.M., H.A.-S., A.P. and T.T.; Writing—Review and Editing: all authors; Supervision: V.B. All authors have read and agreed to the published version of the manuscript.

Richard Zeifman received funding from the NYU Langone Psychedelic Medicine Research Training program (funded by MindMed) and the Canadian Institutes of Health Research (Grant Number: 202110MFE-472921-HTB-272687). Jennifer Swainson, Lisa Burback, Olga Winkler, and Yanbo Zhang are supported by the Academic Medicine and Health Services Program (AMHSP), a joint program funded by the University of Alberta and Alberta Health Services to ensure physicians affiliated with Alberta’s faculties of medicine are compensated for providing patient care along with their work related to research, innovation, education, administration, and leadership. Jennifer Swainson has received honoraria for speaking or advisory roles from Abbvie, Bausch Health, Biron, Eisai, Idorsia, Janssen, Lundbeck, Novo Nordisk, and Otsuka. Rakesh Jetly is the CMO of Mydecine Innovation Group. Venkat Bhat is supported by an Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research funding from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. David Erritzoe is acting as a paid scientific advisor for Aya Biosciences, Lophora Aps, Clerkenwell Health, Mindstate Design Lab. Manish Jha has received contract research grants from Acadia Pharmaceuticals, Neurocrine Bioscience, Navitor/Supernus and Janssen Research and Development; has received honorarium to serve as Section Editor of the Psychiatry and Behavioral Health Learning Network and as Guest Editor for Psychiatric Clinics of North America from Elsevier; has received consultant fees from Eleusis Therapeutics US, Janssen Global Services, Janssen Scientific Affairs, Boehringer Ingelheim and Guidepoint Global; has received fees to serve on Data Safety and Monitoring Board for Worldwide Clinical Trials (Eliem, Skye and Inversargo), Vicore Pharma and IQVIA (Click); and honoraria for educational presentations from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, H.C. Wainwright and Company and Global Medical Education. Raimar Loebenberg is the director of BioNXT. Muhammad I. Husain has led contracted research for COMPASS Pathfinder Limited and has provided consultancy to Mindset Pharma Inc., Psyched Therapeutics, and Wake Network.

This research received no external funding.