On the safety of psychedelics

The acute toxicity of psychedelics is considered low. Reports of fatal overdoses associated with their use are rare (Haden & Woods, Reference Haden and Woods2020; Darke et al., Reference Darke, Duflou, Peacock, Farrell, Hall and Lappin2024; Thomas, Reference Thomas2024), with deaths primarily linked to relatively high doses (i.e. ≥ 20 times the typical dose) or the combination of psychedelics with other drugs or ethanol (Schlag et al., Reference Schlag, Aday, Salam, Neill and Nutt2022; Lake & Lucas, Reference Lake and Lucas2024; Kopra et al., Reference Kopra, Penttinen, Rucker and Copeland2025). Clinical studies conducted in supervised settings have also demonstrated low addictive potential (Johnson et al., Reference Johnson, Richards and Griffiths2008; Johansen & Krebs, Reference Johansen and Krebs2015; Johnson et al., Reference Johnson, Griffiths, Hendricks and Henningfield2018; Schlag et al., Reference Schlag, Aday, Salam, Neill and Nutt2022; Hinkle et al., Reference Hinkle, Graziosi, Nayak and Yaden2024). Compared to ethanol, opioids, cocaine, crack, amphetamines, and some psychostimulants, they have a low risk of addiction and intoxication (Johnson et al., Reference Johnson, Griffiths, Hendricks and Henningfield2018). Noteworthy, clinical evidence suggests that psychedelics can alleviate psychological and physiological symptoms associated with dependence on other psychoactive substances (Vamvakopoulou & Nutt, Reference Vamvakopoulou and Nutt2024; Yao et al., Reference Yao, Guo, Lu, Liu, Huang, Diao, Li, Zhang, Kosten, Shi, Bao, Lu and Han2024).

Challenging emotional experiences (e.g. anxiety and panic attacks), sensory and spatial distortions, headache, nausea and vomiting, and elevations in heart rate and blood pressure are changes induced by psychedelics as transient effects observed after administering usual doses but infrequently manifest in protocols using microdoses (Nichols, Reference Nichols2016; Polito & Stevenson, Reference Polito and Stevenson2019; Schlag et al., Reference Schlag, Aday, Salam, Neill and Nutt2022; Wsół, Reference Wsół2023; Murphy et al., Reference Murphy, Muthukumaraswamy and de Wit2024; Neumann et al., Reference Neumann, Dhein, Kirchhefer, Hofmann and Gergs2024; Yerubandi et al., Reference Yerubandi, Thomas, Bhuiya, Harrington, Villa Zapata and Caballero2024) or when used in controlled settings with appropriate inclusion criteria (Rhee et al., Reference Rhee, Davoudian, Sanacora and Wilkinson2023; Hinkle et al., Reference Hinkle, Graziosi, Nayak and Yaden2024; Klaiber et al., Reference Klaiber, Humbert-Droz, Ley, Schmid and Liechti2024; Romeo et al., Reference Romeo, Kervadec, Fauvel, Strika-Bruneau, Amirouche, Verroust, Piolino and Benyamina2024; Simon et al., Reference Simon, Olsen, Hoyte, Black, Reynolds, Dart and Monte2024; Sabé et al., Reference Sabé, Sulstarova, Glangetas, De Pieri, Mallet, Curtis, Richard-Lepouriel, Penzenstadler, Seragnoli, Thorens, Zullino, Preller, Böge, Leucht, Correll, Solmi, Kaiser and Kirschner2025). These relatively limited adverse reactions are associated with stimulating various 5-HT receptors (Johnson et al., Reference Johnson, Richards and Griffiths2008; Family et al., Reference Family, Hendricks, Williams, Luke, Krediet, Maillet and Raz2022; Holze et al., Reference Holze, Caluori, Vizeli and Liechti2022). For example, the potential cardiovascular risk associated with serotonergic psychedelics is attributed to their interaction with 5-HT_1B, 5-HT_2B, and 5-HT₄ receptors (Wsół, Reference Wsół2023). However, no associations have been established between the lifetime use of classical psychedelics and the development of cardiometabolic diseases (Simonsson et al., Reference Simonsson, Osika, Carhart-Harris and Hendricks2021).

The relationship between psychedelic use and the risk of seizures is not fully understood, as clinical studies typically exclude individuals with a history of seizures or convulsions. While psychedelics may theoretically increase the risk in predisposed individuals due to cortical 5-HT_2A receptor hyperstimulation, most studies suggest that these substances have a low epileptogenic potential when used in controlled settings. The risk may be elevated when psychedelics are combined with factors common in athletic environments, such as sleep deprivation, stimulant use, or high-stress conditions, particularly in susceptible individuals. However, further investigation is needed to understand better the underlying mechanisms and associated risk factors (Freidel et al., Reference Freidel, Kreuder, Rabinovitch, Chen, Huang and Lewis2024; Lewis et al., Reference Lewis, Jaeger, Girn, Omene, Brendle and Argento2024; Soto-Angona et al., Reference Soto-Angona, Fortea, Fortea, Martínez-Ramírez, Santamarina, López, Knudsen and Ona2024). Based on this, caution is advised for athletes with a history of seizures and those using medications (e.g. bupropion) or supplements (e.g. high-dose caffeine) that may lower the seizure threshold.

The use of psychedelics, particularly MDMA, has been associated with an increased risk of hyponatremia in humans, primarily due to increased antidiuretic hormone (also known as vasopressin) release from the posterior pituitary and excessive fluid intake, leading to water retention and sodium dilution (Atila et al., Reference Atila, Straumann, Vizeli, Beck, Monnerat, Holze, Liechti and Christ-Crain2024). This mechanism is attributed to MDMA’s elevation of hypothalamic 5-HT and dopamine levels, stimulating vasopressin release and promoting water retention via vasopressin-2 receptors in the kidneys. Excessive water intake, driven by hyperthermia, dry mouth, and stimulant effects in physically demanding or hot environments, may exacerbate sodium dilution. Although this effect is self-limiting and observed mainly acutely, this condition may be particularly concerning for endurance athletes. Temporary hyponatremia outside of competition may contribute to longer-term consequences, potentially predisposing them to a higher risk of injuries or reduced performance in subsequent training or competitions.

Evidence from both rodent and human studies has demonstrated an association between MDMA use and an increased risk of hyperthermia and rhabdomyolysis. MDMA-treated rodents exhibited significant increases in body temperature, sustained muscle contraction, and muscle damage resembling rhabdomyolysis. These effects were related to increases in neurotransmitters, primarily 5-HT and dopamine, and activation of the sympathetic nervous system (Sprague et al., Reference Sprague, Brutcher, Mills, Caden and Rusyniak2004; Duarte et al., Reference Duarte, Leão, Magalhães, Ascensão, Bastos, Amado, Vilarinho, Quelhas, Appell and Carvalho2005; Rusyniak et al., Reference Rusyniak, Tandy, Hekmatyar, Mills, Smith, Bansal, MacLellan, Harper and Sprague2005; Sprague et al., Reference Sprague, Moze, Caden, Rusyniak, Holmes, Goldstein and Mills2005; de Bragança et al., Reference de Bragança, Moreau, de Brito, Shimizu, Canale, de Jesus, Silva, Gois, Seguro and Magaldi2017). In humans, clinical and observational studies have reported similar effects, especially in intoxication or recreational settings involving prolonged physical activity, crowded environments, and inadequate thermoregulation (Screaton et al., Reference Screaton, Singer, Cairns, Thrasher, Sarner and Cohen1992; Lehmann et al., Reference Lehmann, Thom and Croft1995; Halachanova et al., Reference Halachanova, Sansone and McDonald2001; Sue et al., Reference Sue, Lee and Huang2002; Vanden Eede et al., Reference Vanden Eede, Montenij, Touw and Norris2012; Doyle et al., Reference Doyle, Meyer, Breen and Hunt2020). This could be relevant for endurance athletes if their MDMA use and physical exercise are not adequately spaced apart, as MDMA-induced hyperthermia and rhabdomyolysis can be exacerbated by the physiological demands of prolonged exertion, increasing the risk of severe complications and impairing athletic performance. Although the cited articles did not assess athletes under the acute effects of psychedelic substances, their findings indirectly underscore the importance of understanding the risks associated with MDMA use in physically demanding contexts, as well as the need for proper monitoring of signs and symptoms.

Evidence indicates that 5-HT is a key neuromodulator of locomotor activity (Bacqué-Cazenave et al., Reference Bacqué-Cazenave, Bharatiya, Barrière, Delbecque, Bouguiyoud, Di Giovanni, Cattaert and De Deurwaerdère2020; Flaive et al., Reference Flaive, Fougère, van der Zouwen and Ryczko2020). As reviewed by Werle and Bertoglio (Reference Werle and Bertoglio2024), published studies have demonstrated the biphasic effects of psychedelic substances on locomotion. In the open-field test, rats and mice exhibit either hyperlocomotion or hypolocomotion, depending on the dose. These effects are mediated by mechanisms involving the activation of 5-HT_1A, 5-HT_2C, and 5-HT_2A receptors (in the case of MDMA, they also involve the release of 5-HT and dopamine). Each substance has its particularities, although hypolocomotor effects (suggestive of sedation) generally predominate at moderate to high doses (Werle & Bertoglio, Reference Werle and Bertoglio2024). While it is unlikely and strongly discouraged for individuals to participate in sports while under the acute influence of psychedelics, it is worth noting that rodent studies suggest psilocybin, LSD, DMT, ayahuasca, and MDMA can influence locomotor activity.

Psychedelics and mental health

Psychedelics can provide significant benefits across multiple domains of mental health and well-being in healthy individuals (Lebedev et al., Reference Lebedev, Kaelen, Lövdén, Nilsson, Feilding, Nutt and Carhart-Harris2016; Schmid & Liechti, Reference Schmid and Liechti2018; Hutten et al., Reference Hutten, Mason, Dolder, Theunissen, Holze, Liechti, Feilding, Ramaekers and Kuypers2020a; Perkins et al., Reference Perkins, Pagni, Sarris, Barbosa and Chenhall2022). Of particular relevance to athletes are several potential effects, including reduced pain (Ramaekers et al., Reference Ramaekers, Hutten, Mason, Dolder, Theunissen, Holze, Liechti, Feilding and Kuypers2021; Askey et al., Reference Askey, Lasrado, Maiarú and Stephens2024; Strand et al., Reference Strand, Whitney, Johnson, Dunn, Attanti, Maloney, Misra, Gomez, Viswanath, Emami and Leathem2025) and improvements in sleep (Allen et al., Reference Allen, Jeremiah, Murphy, Sumner, Forsyth, Hoeh, Menkes, Evans, Muthukumaraswamy, Sundram and Roop2024). Additionally, psychedelics may enhance stress management by reducing anxiety levels and promoting greater emotional resilience (Griffiths et al., Reference Griffiths, Johnson, Richards, Richards, McCann and Jesse2011; Arruda Sanchez et al., Reference Arruda Sanchez, Ramos, Araujo, Schenberg, Yonamine, Lobo, de Araujo and Luna2024).

The growing interest and acceptance of psychedelic substances have driven clinical trials, advancing our understanding of their potential benefits (Nichols, Reference Nichols2016; Reiff et al., Reference Reiff, Richman, Nemeroff, Carpenter, Widge, Rodriguez, Kalin and McDonald2020; Nutt & Carhart-Harris, Reference Nutt and Carhart-Harris2021; McClure-Begley & Roth, Reference McClure-Begley and Roth2022). Their contribution to alleviating symptoms of depression, anxiety, posttraumatic stress disorder (PTSD), eating disorders, and substance use disorders has been documented (Reiff et al., Reference Reiff, Richman, Nemeroff, Carpenter, Widge, Rodriguez, Kalin and McDonald2020; Barber & Aaronson, Reference Barber and Aaronson2022; Brewerton et al., Reference Brewerton, Wang, Lafrance, Pamplin, Mithoefer, Yazar-Klosinki, Emerson and Doblin2022; Cavarra et al., Reference Cavarra, Falzone, Ramaekers, Kuypers and Mento2022; Cuerva et al., Reference Cuerva, Spirou, Cuerva, Delaquis and Raman2024; Dos Santos & Hallak, Reference Dos Santos and Hallak2024; Doss et al., Reference Doss, DeMarco, Dunsmoor, Cisler, Fonzo and Nemeroff2024; Zaretsky et al., Reference Zaretsky, Jagodnik, Barsic, Antonio, Bonanno, MacLeod, Pierce, Carney, Morrison, Saylor, Danias, Lepow and Yehuda2024). Table 1 presents the details and primary findings of human studies examining the effects of psilocybin, LSD, DMT, ayahuasca, and MDMA on the mental health of individuals diagnosed with the aforementioned psychiatric conditions. Noteworthy, the association of psychedelics with psychotherapeutic support (i.e. psychedelic-assisted psychotherapy) has been shown to improve the integration of psychedelic experiences (Luoma et al., Reference Luoma, Chwyl, Bathje, Davis and Lancelotta2020).

Some of the studies reviewed (Table 1) also report that these substances are associated with significant and long-lasting symptom reduction, with therapeutic effects persisting for weeks or months following only a few administrations, even in patients resistant to typical pharmacological treatment. Psychedelics have also presented a favourable safety profile, as indicated by the relatively low incidence of severe adverse reactions when administered under controlled clinical conditions. Such features may be particularly relevant for health care in athletes, who often endure high levels of physical and mental stress and are vulnerable to various psychiatric disorders (Edwards, Reference Edwards2024). Hypothetically, psychedelic therapy could serve as a valuable tool for enhancing well-being in this population with minimal risk of impairing performance.

However, it is essential to address the methodological limitations of the studies published to date, as well as the gaps that still need to be clarified to enable a responsible application of psychedelic therapies in clinical practice. Some reviewed studies included small sample sizes and lacked double-blind methodologies or inactive placebos, which limits the generalisability of the observed results and increases the chance of confirmation bias. Furthermore, the majority of participants were White or Caucasian, which may limit the extrapolation of findings to other ethnic groups with distinct cultural or genetic characteristics, thus impacting the representativeness of these results when psychedelics are applied on a larger scale. Another issue is the variability in study protocols (e.g. dosage, number of administrations, and intervals between treatments). Greater methodological rigour and standardisation are needed to understand better the actual clinical impact of psychedelic therapy on both the general population and athletes. Future research should also incorporate more objective evaluation methods, ideally including physiological or neurobiological measurements that can be correlated with the health status (or psychiatric disorder under investigation).

Mental health issues in athletes

Studies indicate that the prevalence of psychiatric disorders in high-performance athletes (both amateur and professional) may be similar or even higher than in the general population, which likely arises from intense physical and emotional stressors often experienced (Gouttebarge et al., Reference Gouttebarge, Castaldelli-Maia, Gorczynski, Hainline, Hitchcock, Kerkhoffs, Rice and Reardon2019; Reardon et al., Reference Reardon, Hainline, Aron, Baron, Baum, Bindra, Budgett, Campriani, Castaldelli-Maia, Currie, Derevensky, Glick, Gorczynski, Gouttebarge, Grandner, Han, McDuff, Mountjoy, Polat, Purcell, Putukian, Rice, Sills, Stull, Swartz, Zhu and Engebretsen2019; Glick et al., Reference Glick, Stillman and McDuff2020; Marí-Sanchis et al., Reference Marí-Sanchis, Burgos-Balmaseda and Hidalgo-Borrajo2022; McDonald et al., Reference McDonald, Losty and MacCarthy2023; Smith et al., Reference Smith, Buadze, Colangelo and Liebrenz2023; Thuany et al., Reference Thuany, Viljoen, Gomes, Knechtle and Scheer2023; Beable, Reference Beable2024). Among them are the high demand for physical and sports performance, overtraining, interpersonal conflicts in competitions, the imbalance between personal life and training, injuries, and early retirement (Chang et al., Reference Chang, Putukian, Aerni, Diamond, Hong, Ingram, Reardon and Wolanin2020). Furthermore, due to self-pressure to demonstrate mental resilience, athletes may not report their health concerns, accept professional assistance, or adhere to treatment. Additionally, athletes may often avoid pharmacological treatment due to concerns about doping, potential adverse reactions, and the effects of medication on athletic performance (Reardon, Reference Reardon2016; Bomfim, Reference Bomfim2020). As a result, a cycle of untreated suffering can develop, compromising both mental health and physical aspects. Early identification of these factors and appropriate clinical intervention are essential to ensure performance and longevity in sports practice, as well as the psychological well-being of athletes (Glick et al., Reference Glick, Stillman, Reardon and Ritvo2012; Chang et al., Reference Chang, Putukian, Aerni, Diamond, Hong, Ingram, Reardon and Wolanin2020). Consequently, there is growing interest in sports research to assess the mental health of athletes such as long-distance runners, cyclists, swimmers, triathletes, and others (Berger et al., Reference Berger, Best, Best, Lane, Millet, Barwood, Marcora, Wilson and Bearden2024).

Drugs currently available for the management of psychiatric disorders in athletes present significant limitations (Morris, Reference Morris2015; Reardon & Creado, Reference Reardon and Creado2016; Tso & Pelliccia, Reference Tso and Pelliccia2022). Antidepressants and anxiolytics currently approved for clinical use are administered daily and can cause side effects that negatively affect athletic performance, such as drowsiness, changes in appetite, and weight gain (Reardon, Reference Reardon2016; Reardon & Creado, Reference Reardon and Creado2016; Edwards, Reference Edwards2024). In addition, individual variability in response to these medications can hinder treatment effectiveness. For example, while approximately 15% of participants in clinical trials experience a significant antidepressant effect beyond that of a placebo (Stone et al., Reference Stone, Yaseen, Miller, Richardville, Kalaria and Kirsch2022), around 30% of individuals diagnosed with major depressive disorder are resistant to conventional treatment, further increasing the social and economic burden of this condition (McIntyre et al., Reference McIntyre, Alsuwaidan, Baune, Berk, Demyttenaere, Goldberg, Gorwood, Ho, Kasper, Kennedy, Ly-Uson, Mansur, McAllister-Williams, Murrough, Nemeroff, Nierenberg, Rosenblat, Sanacora, Schatzberg, Shelton, Stahl, Trivedi, Vieta, Vinberg, Williams, Young and Maj2023). In this scenario, psychedelic therapy could emerge as either a complementary or an alternative for the treatment of psychiatric disorders in athletes.

Psychedelics to maintain and improve mental health in athletes

Several clinical studies have demonstrated the efficacy of psychedelic-assisted psychotherapy (Table 1; Nichols, Reference Nichols2016; Reiff et al., Reference Reiff, Richman, Nemeroff, Carpenter, Widge, Rodriguez, Kalin and McDonald2020; Nutt & Carhart-Harris, Reference Nutt and Carhart-Harris2021; Cavarra et al., Reference Cavarra, Falzone, Ramaekers, Kuypers and Mento2022; Knudsen, Reference Knudsen2023). Following approval by the Therapeutic Goods Administration in 2023, Australia became the first country to authorise and regulate the medicinal use of psilocybin and MDMA for the treatment of depression and PTSD, respectively (Nutt et al., Reference Nutt, Crome and Young2024). Similarly, Oregon and Colorado became the first American states to legalise psilocybin, issuing official licences to specialised mental healthcare service centres for use (Korthuis et al., Reference Korthuis, Hoffman, Wilson-Poe, Luoma, Bazinet, Pertl, Morgan, Cook, Bielavitz, Myers, Wolf, McCarty and Stauffer2024).

To date, the potential of psychedelics to enhance mental health or treat psychiatric disorders in athletes remains unknown. However, considering the evidence from the general population (Table 1), several aspects of psychedelic therapy may be beneficial for these individuals (Carhart-Harris & Goodwin, Reference Carhart-Harris and Goodwin2017; Barber & Aaronson, Reference Barber and Aaronson2022; Holze et al., Reference Holze, Singh, Liechti and D’Souza2024). In healthy athletes, the administration of psychedelics may offer benefits in promoting mental health and well-being, aiding in the management of psychological and emotional challenges. By enhancing resilience and emotional flexibility, psychedelic therapy could mitigate the effects of everyday stressors in high-performance sports, including intensive training routines, self-imposed demands for physical performance, and sustained competitiveness. Moreover, in athletes diagnosed with psychiatric disorders, psychedelic-assisted psychotherapy could offer some advantages over conventional treatments. Unlike daily medications, only a few sessions spaced over days to weeks are typically sufficient to promote long-term mental health benefits that are maintained over several months (Yao et al., Reference Yao, Guo, Lu, Liu, Huang, Diao, Li, Zhang, Kosten, Shi, Bao, Lu and Han2024). Furthermore, the half-life of these substances lasts only a few hours, not producing withdrawal symptoms. Although psychedelic therapy may result in adverse reactions, they are transient and manifest mainly in the following hours after administration. Thus, potential concerns associated with impaired sports performance can be reduced, even if athletes are in training or competition periods (Reardon & Creado, Reference Reardon and Creado2016; Edwards, Reference Edwards2024). Yousefi et al. (Reference Yousefi, Lietz, O’Higgins, Rippe, Hasler, van Elk and Enriquez-Geppert2025) have meta-analysed psilocybin’s acute effects on executive functions and attention. Psilocybin increased reaction times dose-dependently without significantly affecting accuracy, suggesting an impairment in executive function that may be relevant to specific sports. However, its impact on performance is potentially less concerning, as athletes are not expected to compete while under the influence of psychedelics.

Several psychedelic substances produce prosocial effects in rodent and human studies (Dumont et al., Reference Dumont, Sweep, van der Steen, Hermsen, Donders, Touw, van Gerven, Buitelaar and Verkes2009; Hysek et al., Reference Hysek, Schmid, Simmler, Domes, Heinrichs, Eisenegger, Preller, Quednow and Liechti2014; Kamilar-Britt & Bedi, Reference Kamilar-Britt and Bedi2015; Griffiths et al., Reference Griffiths, Johnson, Richards, Richards, Jesse, MacLean, Barrett, Cosimano and Klinedinst2018; De Gregorio et al., Reference De Gregorio, Popic, Enns, Inserra, Skalecka, Markopoulos, Posa, Lopez-Canul, He, Lafferty, Britt, Comai, Aguilar-Valles, Sonenberg and Gobbi2021; Bhatt & Weissman, Reference Bhatt and Weissman2024). While systematic research on psychedelics in sports is limited, their potential prospective effects may include improved social dynamics during training or competition, team cohesion, reduced anxiety, enhanced resilience among athletes, and sports-related mild traumatic brain injury (e.g. concussion) (VanderZwaag et al., Reference VanderZwaag, Garcia-Romeu and Garcia-Barrera2024). However, the use of psychedelics in sports raises potential issues. Serotonergic psychedelics and related compounds produce varying effects in tests of negative social interactions, often assessing aggression, in rodents through their actions on 5-HT_2A and 5-HT_1A receptors (Odland et al., Reference Odland, Kristensen and Andreasen2022). Future studies must establish optimal dosages, contexts, and protocols that maximise potential benefits while minimising risks.

Scientific evidence on the interactions between psychedelic substances and antidepressants, antipsychotics, anxiolytics, and mood stabilisers remains limited. However, it has been reported that psychedelics and certain psychiatric medications may share overlapping pharmacological targets, molecular pathways interactions, and hepatic metabolism via similar enzymes (Sarparast et al., Reference Sarparast, Thomas, Malcolm and Stauffer2022; Rhee et al., Reference Rhee, Davoudian, Sanacora and Wilkinson2023; Halman et al., Reference Halman, Kong, Sarris and Perkins2024). Consequently, drug interactions between psychedelic substances and medications already used by athletes should be considered, as they may potentiate or attenuate the actions of both substances. Therefore, adequate clinical monitoring will be essential to mitigate the risks of adverse reactions, toxicity, or inadequate management of psychiatric symptoms.

Effects of psychedelics on physical and physiological parameters

Administration of the psychedelic substance DOI has been shown to reduce circulating levels of total cholesterol and low-density lipoprotein (LDL) in a high-fat diet-fed apolipoprotein E knockout mice model without affecting food intake or body weight. DOI administration was also associated with a reduction in the increased serum levels of the pro-inflammatory cytokine CXCL10 induced by high-fat diet-fed and reduced expression of pro-inflammatory marker genes in the aortic arch (Flanagan et al., Reference Flanagan, Sebastian, Battaglia, Foster, Maillet and Nichols2019a). On the other hand, preclinical studies have shown potentially conflicting results of the psilocybin administration on metabolic parameters and body weight regulation. Although the administration of a high dose of psilocybin was associated with a modest but significant reduction in body weight, decreased consumption of the high-calorie diet, and decreased central adiposity in a rodent model of obesity (Huang et al., Reference Huang, Pham, Panenka, Honer and Barr2022), neither a single nor repeated administration of psilocybin had significant metabolic effects. It did not lower body weight or food intake in diet-induced obese mice or genetic mouse models of obesity (Fadahunsi et al., Reference Fadahunsi, Lund, Breum, Mathiesen, Larsen, Knudsen, Klein and Clemmensen2022). Moreover, increased creatine kinase, aspartate aminotransferase, and chloride have been reported in male and female mice treated with psilocybin (Shakir et al., Reference Shakir, Pedicini, Bullock, Hoen, Macias, Freiman, Pletnikov, Tamashiro and Cordner2024). Preclinical studies have shown that MDMA treatment may increase serum levels of total and LDL cholesterol, corticosterone, aspartate transaminase, alanine transaminase, or glucose in rodents (Graham et al., Reference Graham, Herring, Schaefer, Vorhees and Williams2010; Shahraki & Irani, Reference Shahraki and Irani2014; Golchoobian et al., Reference Golchoobian, Nabavizadeh, Roghani, Foroumadi and Mohammadian2017), although hypoglycaemia has also been reported (Soto-Montenegro et al., Reference Soto-Montenegro, Vaquero, Arango, Ricaurte, García-Barreno and Desco2007; Golchoobian et al., Reference Golchoobian, Nabavizadeh, Roghani, Foroumadi and Mohammadian2017).

In addition to regulating body weight, lipid metabolism is also essential for cellular mechanisms related to inflammation and nociception/pain, and the anti-inflammatory and immunomodulatory properties of psychedelics have also been reported (Flanagan & Nichols, Reference Flanagan and Nichols2022). Lipid mediators, including arachidonic acid (AA), can be metabolised by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes and converted to pro-inflammatory metabolites such as prostaglandins, thromboxane, leukotrienes, and hydroxyeicosatetraenoic acids. In rodents, the psychedelic bufotenine has been shown to induce an anti-nociceptive effect and promote the downregulation of inflammatory mediators from COX, LOX, CYP450, linoleic acid, docosahexaenoic acid, and other pro-inflammatory pathways (Wang et al., Reference Wang, Xu, Shen, Zhou, Lv, Ma, Li, Wu and Duan2021a; Shen et al., Reference Shen, Lv, Yang, Deng, Liu, Zhou, Zhu and Ma2022). Askey et al. (Reference Askey, Lasrado, Maiarú and Stephens2024) have reviewed the psilocybin potential as an anti-nociceptive agent, focusing on preclinical animal models and exploring serotonergic mechanisms and neuroplastic actions that improve functional connectivity in brain regions involved in chronic pain. They also discuss its broader effects on pain and associated emotional and inflammatory components. The review by Strand et al. (Reference Strand, Whitney, Johnson, Dunn, Attanti, Maloney, Misra, Gomez, Viswanath, Emami and Leathem2025) has examined psilocybin, LSD, and ketamine as potential treatments for chronic pain. It focuses on their pharmacology, effects on neuropathic pain, clinical implications, safety profiles, and patient responses.

Preclinical and clinical data also indicate that psychedelics increase the release of anti-inflammatory interleukins (e.g. IL-10) and reduce the expression and activity of other pro-inflammatory markers, including IL-6, IL-1β, tumour necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-kB). Thus, administration of these substances may attenuate the activation of genes and downstream signalling pathways that contribute to inflammation (dos Santos, Reference dos Santos2014; Boxler et al., Reference Boxler, Streun, Liechti, Schmid, Kraemer and Steuer2018; Flanagan & Nichols, Reference Flanagan and Nichols2022; Mason et al., Reference Mason, Szabo, Kuypers, Mallaroni, de la Torre Fornell, Reckweg, Tse, Hutten, Feilding and Ramaekers2023; Low et al., Reference Low, Ng, Lim, Goh and Kumari2025). DOI can inhibit TNF-α-induced inflammation by mitigating the expression of genes encoding intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and IL-6 through serotonin 5-HT_2A receptor activation in both in vitro and in vivo (Yu et al., Reference Yu, Becnel, Zerfaoui, Rohatgi, Boulares and Nichols2008; Nau et al., Reference Nau, Yu, Martin and Nichols2013). Furthermore, DOI administration blocked the activation and translocation of NF-kB and decreased nitric oxide synthase activity (Yu et al., Reference Yu, Becnel, Zerfaoui, Rohatgi, Boulares and Nichols2008).

In vitro studies have demonstrated that psilocybin-containing mushroom extracts inhibited lipopolysaccharide (LPS)-induced increases in TNF-α and IL-1β, besides decreasing COX-2 concentrations in treated human U937 macrophage cells (Nkadimeng et al., Reference Nkadimeng, Steinmann and Eloff2021; Laabi et al., Reference Laabi, LeMmon, Vogel, Chacon and Jimenez2024). In healthy volunteers, a single dose of psilocybin reduced plasma levels of TNF-α immediately after administration, and IL-6 and C-reactive protein were reduced in the psilocybin group seven days later. The persisting reductions in pro-inflammatory markers correlated with clinical improvement of mood and sociability (Mason et al., Reference Mason, Szabo, Kuypers, Mallaroni, de la Torre Fornell, Reckweg, Tse, Hutten, Feilding and Ramaekers2023).

Possible opposite effects have been reported regarding MDMA. Acute administration of MDMA appears to promote an anti-inflammatory effect. It impairs the secretion of IL-1β and TNF-α induced by LPS administration in rodents (Connor et al., Reference Connor, Kelly, McGee and Leonard2000), besides suppressing innate IFN-γ production by increasing IL-10 levels (Boyle & Connor, Reference Boyle and Connor2007). On the other hand, in human plasma samples collected at different time points after a single oral administration of MDMA, an increase in cortisol and lipidic mediators of inflammation was observed, suggesting stimulation of inflammatory pathways (Boxler et al., Reference Boxler, Streun, Liechti, Schmid, Kraemer and Steuer2018).

Immunomodulatory effects of psychedelic substances and other chemical compounds derived from ayahuasca have also been reported (dos Santos, Reference dos Santos2014; Galvão-Coelho et al., Reference Galvão-Coelho, de Menezes Galvão, de Almeida, Palhano-Fontes, Campos Braga, Lobão Soares, Maia-de-Oliveira, Perkins, Sarris and de Araujo2020). Harmine has been proposed to exert anti-inflammatory and antioxidant effects through several mechanisms, such as AMPK/Nrf2 pathway activation, reduced caspase-3 expression by repressing the Bax/Bcl2 ratio, inhibition of the c-Jun N-terminal kinase (JNK), downregulation of LC3B II/I, p38 MAPK, TLR4, and NF-κB levels. Furthermore, it appears to increase the expression of p62, Bcl-2, Beclin1, ULK1, and p-mTOR (Hamsa & Kuttan, Reference Hamsa and Kuttan2010; Liu et al., Reference Liu, Wu, Gong, Wang, Zhu, Tong, Chen, Ling and Huang2017a; Niu et al., Reference Niu, Yao, Li, Zang, Li, Zhao, Liu and Zhi2019; Ma et al., Reference Ma, Li, Yao, Liu, Yu, Zang, Wang, Zhou, Wen, Luo, Li and Niu2024; Tabaa et al., Reference Tabaa, Tabaa, Rashad, Elballal and Elazazy2024). Harmine also attenuated bone destruction induced by an inflammatory response. It shifted the polarisation of macrophages from M1 to M2 phenotypes both in vitro and in vivo in a murine model (Wang et al., Reference Wang, Wang, Wang, Ge, Xu, Zheng, Jiang, Zhao, Xu, Wang, Zhu and Geng2021b). A three-day ayahuasca treatment prevented anxiety and oxidative stress induced by an inflammatory insult in rats. Additionally, it increased cortical levels of the anti-inflammatory cytokine IL-4 and BDNF (de Camargo et al., Reference de Camargo, Joaquim, Machado, de Souza Ramos, da Rosa, de Novais Junior, Mathias, Maximiano, Strickert, Nord, Gava, Scarpari, Martins, Lins, Chaves, da Silva, de Oliveira, da Silva, Fernandes, Tiscoski, Piacentini, Santos, Inserra, Bobinski, Rezin, Yonamine, Petronilho and de Bitencourt2024).

Although the precise molecular mechanisms related to the effects of psychedelics on immunity and inflammatory responses remain to be elucidated, the involvement of 5-HT_2A receptor activation has been proposed. 5-HT_2A receptor is widely distributed in tissues and cells, regulating innate and adaptive immune responses, such as the spleen, thymus, circulating lymphocytes, T cells, eosinophils, and mononuclear cells (Herr et al., Reference Herr, Bode and Duerschmied2017; Thompson & Szabo, Reference Thompson and Szabo2020). While the 5-HT_2A receptor activation by 5-HT primarily contributes to inflammation, psychedelics appear to recruit anti-inflammatory intracellular signalling pathways through activation of the same receptor, possibly by stabilising it in a slightly different structural and functional conformation, that is, biased agonism (Raote et al., Reference Raote, Bhattacharya, Panicker and Chattopadhyay2007; Shan et al., Reference Shan, Khelashvili, Mondal, Mehler and Weinstein2012; Flanagan et al., Reference Flanagan, Foster, Galbato, Lum, Louie, Song, Halberstadt, Billac and Nichols2024). The anti-inflammatory effects of psychedelics resulting from the activation of the 5-HT_2A receptor have also been associated with improved respiratory and neurological function, demonstrating benefits in animal models of asthma (Stankevicius et al., Reference Stankevicius, Ferraz-de-Paula, Ribeiro, Pinheiro, Ligeiro de Oliveira, Damazo, Lapachinske, Moreau, Tavares de Lima and Palermo-Neto2012; Nau et al., Reference Nau, Miller, Saravia, Ahlert, Yu, Happel, Cormier and Nichols2015; Flanagan et al., Reference Flanagan, Sebastian, Battaglia, Foster, Cormier and Nichols2019b; Flanagan et al., Reference Flanagan, Billac, Landry, Sebastian, Cormier and Nichols2020) and attenuating the functional consequences of neuroinflammation (Zhong et al., Reference Zhong, Tao and Yang2015; Liu et al., Reference Liu, Li, Tan, Wang, Fan and Huang2017b; Sun et al., Reference Sun, Yang, Zhang, Zhang, Lu, Hu, Liu, Zhou and Chen2019; Nardai et al., Reference Nardai, László, Szabó, Alpár, Hanics, Zahola, Merkely, Frecska and Nagy2020; Xin et al., Reference Xin, Ma, Chen, Zhou, Dong, Wang and Ji2021; Goulart da Silva et al., Reference Goulart da Silva, Daros, Santos, Yonamine and de Bitencourt2022; Zanikov et al., Reference Zanikov, Gerasymchuk, Ghasemi Gojani, Robinson, Asghari, Groves, Haselhorst, Nandakumar, Stahl, Cameron, Li, Rodriguez-Juarez, Snelling, Hudson, Fiselier, Kovalchuk and Kovalchuk2023; Zheng et al., Reference Zheng, Lin, Lu, Cao, Liu, Lin, Yang, Zhang, Tu, Pan, Hu and Zhang2023; Floris et al., Reference Floris, Dabrowski, Zanda and Daws2024).

A significant knowledge gap in psychedelic research, particularly regarding their potential use in athletes, is the lack of studies evaluating their effects on physical health and metabolic parameters. Based on the evidence outlined above and its potential translational implications, treating athletes with psychedelic substances may offer benefits. The improved mental well-being and emotional control associated with psychedelic therapy could contribute to performance by making them more focused and resilient. At the same time, these substances’ anti-inflammatory and analgesic effects could mitigate physical stress, reduce muscle fatigue, and facilitate recovery after prolonged or intense exercise. By reducing inflammation, psychedelics could also improve mental health and reduce symptoms in individuals with psychiatric disorders such as depression or anxiety, as convergent evidence points to an increase in inflammatory markers in these clinical conditions and the significant role of inflammation in their pathophysiology (Bauer & Teixeira, Reference Bauer and Teixeira2019; Beurel et al., Reference Beurel, Toups and Nemeroff2020; Zeng et al., Reference Zeng, Chourpiliadis, Hammar, Seitz, Valdimarsdóttir, Fang, Song and Wei2024). Since research on the use of psychedelic substances in sports contexts is incipient (Fig. 1), far more studies are needed before potentially establishing guidelines on their safe and effective use.

Figure 1. An overview of the current landscape of psychedelics and athletic performance.

Psychedelics in sports competitions: legal and regulatory considerations

Psychedelic substances have been classified as prohibited or controlled substances in most countries, posing challenges for establishing potential guidelines that ensure treatment efficacy and safety under appropriate regulatory oversight. In sports competitions, the World Anti-Doping Agency (WADA; https://www.wada-ama.org/en/prohibited-list) does not list psychedelics as ‘prohibited substances’, except for MDMA, which is classified as a stimulant amphetamine.

For a substance or method to be included in WADA’s Prohibited Substances List under the World Anti-Doping Code, it must meet at least two of the following three criteria: (1) it enhances or has the potential to enhance sports performance, (2) it poses an actual or potential risk to athlete health, and (3) it violates the spirit of sport as defined in the Code (https://www.wada-ama.org/en/resources/world-anti-doping-code-and-international-standards/world-anti-doping-code). To date, no clinical evidence has suggested that psychedelics act as ergogenic aids. WADA regularly updates its prohibited and restricted substances list based on evolving scientific evidence. For example, while cannabis/Δ⁹-tetrahydrocannabinol remains prohibited in competition due to its potential to impair performance, pose safety risks, and violate the ’spirit of sport’, cannabidiol (CBD) has been permitted, as it lacks these properties. As research on psychedelics progresses, the regulatory status of specific compounds in sports may be reevaluated, potentially leading to updates similar to the removal of CBD from the prohibited list.

Conclusions and suggestions for future research

Several clinical studies have highlighted the mental health benefits of psychedelics and their potential role as therapeutic adjuncts to improve the quality of life, but significant considerations remain. A critical knowledge gap in evaluating these substances’ effects on physical health in humans persists. Similarly, the impact of psychedelics on physiological responses relevant to athletic performance, such as muscular strength, motor coordination, locomotion, endurance, cardiorespiratory capacity, fluid and electrolyte balance, hormonal regulation, fatigue, and reflexes, remains largely unexplored scientifically. Moreover, it is worth noting the ethical and legal concerns associated with performance-enhancing substances and the importance of distinguishing between the use of psychedelics within and outside the acute performance/sports context.

Rodent research can provide a valuable foundation for understanding the potential effects of psychedelic therapy on physical performance in humans (Fig. 2). The rotarod test has been used to assess motor coordination and balance in rodents. The gait analysis test provides a detailed assessment of movement patterns and gait symmetry, which is crucial for identifying motor coordination changes (Carter et al., Reference Carter, Morton and Dunnett2001; Deacon, Reference Deacon2013). Muscular strength is typically evaluated through the grip strength test, which measures the animal’s grip force by stimulating traction of the forelimbs or hind limbs (Munier et al., Reference Munier, Pank, Severino, Wang, Zhang, Vergnes and Reue2022). It provides a direct measure of muscle strength, relevant for assessing whether psychedelics could influence aspects of muscular endurance in humans, an essential factor in the performance of athletes. The treadmill running test (Dougherty et al., Reference Dougherty, Springer and Gershengorn2016; Castro & Kuang, Reference Castro and Kuang2017) is a tool for exploring the effects of psychedelic substances on endurance and cardiorespiratory capacity. Rodents are encouraged to run on a treadmill, allowing for analysis of aerobic capacity, fatigue, and prolonged exercise tolerance. These data help understand the potential of psychedelics to enhance aerobic performance and to observe possible indirect cardiorespiratory impacts from their administration. Stress resilience is also essential for high-performance athletes, and the forced swim test is a tool for assessing stress-coping strategy in rodents (Slattery & Cryan, Reference Slattery and Cryan2012; Commons et al., Reference Commons, Cholanians, Babb and Ehlinger2017). In this test, the duration of immobility in a forced swim scenario reflects the animal’s ability to persist under adverse conditions. Several psychedelics have been shown to decrease immobility and increase active behaviours, including swimming and climbing (Cameron et al., Reference Cameron, Benson, Dunlap and Olson2018; Hibicke et al., Reference Hibicke, Landry, Kramer, Talman and Nichols2020; Odland et al., Reference Odland, Kristensen and Andreasen2022; Rakoczy et al., Reference Rakoczy, Runge, Sen, Sandoval, Wells, Nguyen, Roberts, Sciortino, Gibbons, Friedberg, Jones and McMurray2024). Metabolic parameters and overall physical condition can be monitored through assessments such as food and water intake (to evaluate impacts on basal metabolism and caloric needs) and body condition scoring, which provides a qualitative assessment of the animal’s overall physical state by monitoring body composition and body mass index.

Figure 2. Helpful behavioural and physiological responses in rodents for inferring the physical effects of psychedelic drugs in humans.

Overall, these methods could provide preclinical evidence to elucidate the influence of psychedelics on motor, metabolic, and cardiorespiratory functions, as well as their impact on stress resilience. This knowledge could inform the design of safer and more effective clinical protocols to explore the potential benefits of psychedelics as adjunctive therapies in enhancing the mental health and physical performance of athletes and non-athletes. Such studies could also illuminate the underlying mechanisms of action, identify potential effects on organs and tissues beyond the central nervous system, and investigate potential sex differences or genetic and metabolic influences (Rakoczy et al., Reference Rakoczy, Runge, Sen, Sandoval, Wells, Nguyen, Roberts, Sciortino, Gibbons, Friedberg, Jones and McMurray2024; Werle & Bertoglio, Reference Werle and Bertoglio2024).