Editorial Emerging therapeutic opportunities for psychedelic and related drugs

Editorial Emerging therapeutic opportunities for psychedelic and related drugs | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL British Journal of Pharmacology This is a preprint and has not been peer reviewed. Data may be preliminary. 1 April 2026 V1 Latest version Share on Editorial Emerging therapeutic opportunities for psychedelic and related drugs Authors : Susan Wonnacott 0000-0002-3775-7563 [email protected] , Gary Stephens 0000-0002-8966-4238 , and Trevor Sharp 0000-0001-7434-9713 Authors Info & Affiliations https://doi.org/10.22541/au.177505774.48075799/v1 212 views 129 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult to treat conditions that extend beyond neuropsychiatric disorders provided the impetus for this Themed Issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical trials, and insight into the regulatory processes that determine clinical approval. In this Editorial we introduce these aspects and provide an overview of current controversies and challenges in the field, as well as highlighting the exciting potential that these drugs offer. Emerging therapeutic opportunities for psychedelic and related drugs Sue Wonnacott, Gary Stephens & Trevor Sharp ABSTRACT Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult to treat conditions that extend beyond neuropsychiatric disorders provided the impetus for this Themed Issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical trials, and insight into the regulatory processes that determine clinical approval. In this Editorial we introduce these aspects and provide an overview of current controversies and challenges in the field, as well as highlighting the exciting potential that these drugs offer. LINKED ARTICLES This article is part of a themed issue Emerging therapeutic opportunities for psychedelic and related drugs . To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/…… Abbreviations 4-AcO-DMT, 4-acetoxy-N,N-dimethyltryptamine DMT, N,N-dimethyltryptamine; LSD, lysergic acid diethylamide MDA, 3,4-Methylenedioxyamphetamine MDD, major depressive disorder MDMA, 3,4-methylenedioxymethamphetamine MHRA, Medicines and Healthcare products Regulatory Agency PTSD, post-traumatic stress disorder SUD, substance use disorder TRD, treatment resistant depression INTRODUCTION This Themed Issue was originally inspired by a symposium at the 19th World Congress of Basic and Clinical Pharmacology (WCP2023) July 2–7, 2023 in Glasgow that was chaired by Danny Hoyer; speakers included David Nutt and Emma Robinson. The session marked the burgeoning interest in the clinical potential of psychedelic drugs. Natural products with psychedelic properties have a long history of recreational use; pharmaceutical industry interest in their potential is not new but such agents have only now reached the stage of being submitted to regulatory authorities for approval as prescribed medicines. Lysergic acid diethylamide (LSD) was the first synthesised in 1938 by Albert Hofmann at Sandoz laboratories in Switzerland, following a search of ergot alkaloids for a respiratory stimulant. Famously, Hofmann returned to LSD in 1943 and ingested 0.25mg of the drug, precipitating a psychedelic experience during his cycle ride home from work. This is celebrated by an event known as ’Bicycle Day’ which even today is held every year on April 19 th . Hofmann went on to isolate and identify both psilocybin and its active metabolite psilocin from psychoactive mushrooms ( Psilocybe mexicana ) and developed a method for their de novo synthesis (Hofmann et al. 1958). Beginning in the 1950s, the profound subjective experience of psychedelic drugs inspired the work of many writers and artists including Aldous Huxley, Allen Ginsberg and Henri Michaux. Interestingly, a series of intricate drawings by Michaux, which illustrate his experiences with mescaline, were recently exhibited at the Courtauld Institute in London (https://courtauld.ac.uk/wp-content/uploads/2025/02/Micahux-for-website.pdf). The drawings were made a few hours or days after the mescaline episode had passed. Michaux considered that the experiences offered a “portal into the inner workings of the mind” and inferred that they reflected a persistent perturbation of brain function. Before the development of any brain imaging technology, Michaux’s remarkable drawings contributed to the notion that such drugs might induce profound brain changes beneficial for treating complex mental illnesses. Now, some 70 years later, with a greater knowledge of their neurochemical and psychopharmacological action, the therapeutic potential of psychedelic drugs, and related agents such as 3,4-methylenedioxymethamphetamine (MDMA), is on the cusp of being realised. Today, interest in the therapeutic uses of these drugs has expanded beyond the psychotic illnesses considered by Michaux’s medical contemporaries to embrace a wide range of conditions including major depressive disorder (MDD) and treatment resistant depression (TRD), anxiety disorders, pain states and inflammation. This Themed Issue presents a timely collection of reviews and research papers that provide a snapshot of the therapeutic prospects, challenges and limitations of psychedelic drugs and their derivatives. The intriguing molecular and pharmacological mechanisms that determine the clinical efficacy of these extraordinary compounds is critically discussed. Chemical diversity and a multiplicity of labels for psychedelic and related drugs The plethora of natural and synthetic substances with psychedelic properties has led to a confusing array of terminology. Currently, researchers have to navigate a diversity of commonly used terms such as ‘entactogen’, ‘empathogen’, ‘psychoplastogen’, ‘hallucinogen’, and perhaps the less commonly used term, ‘deliriant’ (Alexander et al., (2024); Hoyer, 2025; see Table 1). This problem has become further exacerbated by the emergence of psychedelic analogues with ‘non-psychedelic’ or ‘non-hallucinogenic’ properties. Some of these descriptors relate to the subjective experience evoked by the drug (entactogen, empathogen) and arguably are less helpful since they can only be revealed when the substance is ultimately tested in humans. Other descriptors relate to the promotion of neuroplasticity (psychoplastogen, plastogen) but this encompasses drugs across many different pharmacological classes and therapeutic uses (psychedelics, ketamine-like anaesthetics, conventional antidepressants, lithium, scopolamine, AMPAkines etc). Psychostimulants such as amphetamine, which increase release of dopamine, noradrenaline and often 5-HT, do not fit well into the psychedelic drug classification as they typically do not produce hallucinations or profound changes in perception. Chemical structure can aid pharmacological nomenclature, especially when understanding the molecular basis of receptor action (Gumpper & Nicholls, 2024), but this information does not predict in a simple way whether a drug will have psychedelic properties or not (e.g. many ergolines are psychedelic but some are not). The term ‘psychotomimetic’ can capture psychedelics, ketamine-like anaesthetics and MDMA-like drugs but is less used since it implies that drugs “mimic psychosis”, which is now considered inaccurate or potentially misleading. Here, we use the descriptor ”psychedelic drugs” as an appropriate term to encompass the compounds considered in this Themed Issue. The theme of this Special Issue on psychedelic drugs is very much focused on agents with agonist activity at 5-HT (serotonin) receptors. Here, the preface ‘5-HT-ergic’ (or ‘serotoninergic’) defines the scope and at the same time provides a grounding around a pharmacological principle (receptor activity). Whilst it remains the work of advisory bodies to provide definitive guidelines, we advocate the use of standard pharmacological descriptors such as ‘agonist’, ‘partial agonist’, ‘selective’, ‘non-selective’ and ‘indirect’, all set in the context of a particular neurotransmitter (here 5-HT), to provide the basis for a straightforward systematic nomenclature that we feel the field needs (Table 1). Thus, uncontroversially, a drug such as psilocin (4-hydroxy-N,N-dimethyltryptamine) is a non-selective 5-HT 2A receptor agonist, and MDMA is an indirect 5-HT receptor agonist. When combined with (but separated from) a descriptor of functional effects (‘psychedelic’, non-psychedelic’, ‘neuroplasticity-inducing’ etc), then a more complete picture emerges. 5‑HT 2A receptor agonist 5‑HT 2A receptor agonist May be non‑selective across 5‑HT and other receptor subtypes. Agonist efficacy may be assay‑dependent. LSD Psilocin N,N-dimethyl-tryptamine (DMT) Mescaline Psychedelic drug Hallucinogen Psychoplastogen 5‑HT 2A receptor weak partial agonist 5‑HT 2A receptor weak partial agonist May be non‑selective across 5‑HT and other receptor subtypes. Agonist efficacy may be assay‑dependent. Lisuride Tabernanthalog 2-Br-LSD Ergotamine Non-psychedelic drug Non-hallucinogen Psychoplastogen Indirect 5‑HT agonist 5-HT releasing agent Many 5-HT releasing agents also release catecholamines at higher doses. 5-HT reuptake inhibitors may be considered indirect 5-HT agonists. MDMA 3,4-Methylene-dioxyamphetamine (MDA) Psychedelic/related drug Entactogen Empathogen Non‑serotonergic dissociative anaesthetic Non-competitive NMDA receptor antagonist Ketamine Phencyclidine Psychoplastogen Psychostimulant Catecholamine releasing agents and uptake inhibitor Amphetamine, Methylphenidate Cocaine Psychomotor stimulant Deliriant Muscarinic receptor antagonist Certain anticholinergics produce delirium only when taken in excessive doses. Muscimol (source Amanita muscaria) is often considered a deliriant but GABA A receptor agonism is its principle pharmacological effect. Scopolamine Atropine Anticholinergics Table 1. Proposed psychedelic and related drug terminology . Note that the concept that weak partial agonists at the 5 HT 2A receptor are non-hallucinogens is novel and not yet widely accepted. A role for biased agonism at the 5 HT 2A receptor is a potential alternative explanation for non-hallucinogenic 5 HT 2A receptor agonists (see text for further discussion). Does 5-HT pharmacology explain the long-lasting clinical benefits of psychedelic and related drugs? The exciting therapeutic prospects for psychedelic and related drugs raises the question of how these agents achieve their clinical effects. There is a clear consensus that the 5-HT 2A receptor is a key target of psychedelic drugs. However, what makes these drugs more effective, for example, than conventional antidepressants? And how is evidence of their rapid and persistent therapeutic benefit, which reportedly lasts for days or weeks after only a single drug dose, explained in terms of their pharmacology? These questions are addressed in two reviews that consider the molecular interactions between drug and receptor (Gumpper & Nichols, 2024) and their neuropsychopharmacology (Sharp & Ippolito, 2025). Various hypotheses have been proposed to account for their rapid action, including pre- versus postsynaptic actions, off-target effects and differential downstream signaling pathways, and these are evaluated by Sharp & Ippolito (2025). The therapeutic effectiveness of psychedelic drugs is often attributed to the promotion of neuroplasticity to strengthen or remodel synapses and networks, but the precise mechanisms remain uncertain. A challenge for the drug development pipeline is to generate effective psychedelic analogues that lack the hallucinatory properties of classical psychedelics while preserving their therapeutic potential. Drug discovery in this area is summarized by Qureshi et al. (2025). The disorientating experience of drugs like psilocybin will likely limit their therapeutic use to specialized clinical settings that bring associated financial and logistical restraints. Interestingly, a new generation of non-hallucinogenic 5-HT 2A receptor agonists has emerged, despite clear evidence that the 5-HT 2A receptor mediates the hallucinatory properties of classical psychedelic drugs (Sharp & Ippolito, 2025). One possible explanation for these seemingly paradoxical findings is biased agonism . That is, the therapeutic and psychedelic properties are both 5-HT 2A receptor-mediated but involve distinct signaling pathways such that drugs with appropriate signaling bias can exhibit preference for therapeutic versus psychedelic effects. However, recent pharmacological studies (Wallach et al, 2023; Ippolito et al 2025) provide tantalizing evidence that low signaling efficacy (ie weak partial agonism) may determine the non-hallucinatory properties of these compounds, rather than biased agonism (Table 1). An alternative theory involves location bias , whereby intracellular 5-HT 2A receptors are responsible for cortical plasticity that underpins the long-lasting benefits of psychedelic drug therapy (Vargas et al., 2023). This could stimulate a new avenue of drug discovery to selectively target intracellular 5-HT receptors (Hoyer, 2025). By contrast, evidence for a quite different mechanism in which psychedelic drugs evoke direct positive allosteric modulation of the neurotrophin receptor TrkB has been reported (Molinar et al., 2023; Ascone et al., 2026). Whilst potentially ground-breaking, this idea now needs further investigation given a recent study that failed to confirm any direct interaction between psychedelic drugs and TrkB (Jain et al, 2025). It will be of interest to see how the controversy over this purported pharmacological target of these drugs is resolved. 4 Progress and challenges in the clinical application of psychedelic and related drugs It is a big step from the concept that psychedelic drugs provoke a potentially beneficial and long-lasting perturbation in the brain, to granted approval of a prescribed medicine. The success of translation from preclinical to clinical trials is highly unpredictable (see Bespalov et al 2016), in part because animal models of complex psychiatric illnesses have a poor record of construct, face and predictive validity (Belzung & Lemoine, 2011, Van den Berg, 2022). Moreover, the psychiatric illnesses themselves are heterogeneous in terms of symptoms and outcomes, and are mechanistically ill-defined and poorly understood, all of which makes clinical studies challenging. Nevertheless, in many respects important progress is being made in fast-tracking psychedelics towards their development as medicines. Preclinical studies: In addition to the limitations noted above, the psychedelic experience is challenging to model in animals. The rodent head-twitch response is the most widely used measure of hallucinatory effects and psychedelic potency: this and other rodent assays for evaluating the effects of psychedelic drugs and their antidepressant-like actions are critically evaluated by Alexander et al. (2024). Clearly there are limitations in the current assays in terms of modelling human depressive disorders; in particular, TRD (for which psychedelic drugs may offer a longed-for treatment) is not well represented. Alexander and colleagues advocate models more grounded in cognitive constructs of human emotional processing, notably affective biases and impaired reward learning. Similarly, given the likely importance of prosocial effects of MDMA in treating anxiety disorders and post-traumatic stress disorder (PTSD), the potential of modelling prosocial behaviour in animals is discussed by Casey & Heifets (2025). Much research around these conditions is focused on understanding the neural circuitry of fear learning, extinction and recall, and Wang et al. (2025) describe an interesting example of an ethologically-based model of fear learning, based on predator odour-evoked vocalisations in rats, to investigate effects of the psychedelic 4-acetoxy-N, N-dimethyltryptamine (4-AcO-DMT). Changes in emotional processing also contribute to pain perception and are likely relevant to mechanisms involved in psychedelic drug-induced improvements in chronic pain (Askey et al., 2024). While pain may seem to be more tractable for modelling in preclinical assays, the diversity of clinical pain states and their multifactorial basis, including the central modulation of pain perception, also presents challenges. As considered by Askey et al. (2024), the prevailing consensus is that psilocybin has clear effects in animal studies of pain. This is further supported by recent studies: Hammo et al. (2025) convincingly demonstrate that psilocybin relieves mechanical allodynia and anxiodepressive-like states in mice, via actions at both 5-HT 1 and 5-HT 2A receptors, likely via a central (cortical) mechanism. Askey et al. (2026 in press) report that psilocybin facilitates gabapentin-mediated analgesia in the spared nerve injury mouse model. However, another study recently reported that psilocybin had no analgesic properties when tested in mouse models of inflammatory pain, spared nerve injury or acid-induced muscle pain (except for cold sensitivity in a neuropathic pain model) (Gregory et al., 2026). These results mirror a recent report from the same authors that psilocybin had no effect on anxiety- and depressive-like behaviours or fear extinction learning (Lu et al., 2026 preprint). Whilst further research is needed to understand these discrepancies, potential confounds include variation in experimental design (drug dosing, timing etc), as well as sex differences which are recognised as an important variable in pain studies (Mogil, 2020). Central and peripheral inflammation is now well known to influence pain perception. In this regard, anti-inflammatory actions of psychedelic drugs offer another mechanism by which they can act in pain conditions Askey et al. (2024), as well as other medical conditions with an inflammatory basis, such as asthma, as discussed by Qureshi et al. (2025). Indeed, neuroinflammation impacts a wide range of neuropsychiatric conditions including MDD (Hoyer, 2025). Clinical trials : Somewhat unusually for drugs targeted for development, the safety of many psychedelic drugs in humans is well established from their long history of recreational use. Whilst their psychotropic properties have the potential for causing psychological trauma (and persistent, high dose use of MDMA has been linked to neurotoxic effects), as a class these substances have good tolerability, low toxicity and low addiction liability. This background has led directly to a burgeoning number of therapeutic (Phase II and III) clinical trials for psychedelic and related drugs (Hoyer, 2025; see Psychedelic Drug Development Tracker). Trial design is variable, and combination treatments (such as psilocybin or MDMA plus psychotherapy) can limit comparison of data across different trials. However, some robust observations are emerging. In particular psilocybin has shown rapid-acting antidepressant activity in TRD (Alexander et al., 2024; Nutt et al. 2025), with one positive Phase III trial completed (Goodwin et al 2022) and a second reported to meet endpoints in the general press as of February 2026. Encouraging results for MDMA for the treatment of PTSD have also been reported (Casey & Heifets, 2025; Nutt et al. 2024). From clinical trials and supporting evidence, psilocybin and MDMA are currently the leading contenders for translation to the clinic for MDD and TRD, and PTSD, respectively. LSD and an LSD analogue are also in Phase III trials for MDD and GAD, respectively. Positive clinical trial outcomes also support the pursuit of these and other psychedelic and related drugs for pain (Askey et al. 2024) and inflammatory indications (Qureshi et al. 2025). Substance use disorder (SUD), the compulsive use of addictive substances, is another prevalent and poorly managed condition that is also being considered as a target for psychedelic drug therapy. Wittenkeller et al. (2025) review some of the current work in this area. At the time of writing they report on 34 on-going Phase I and II clinical trials for psychedelic drugs to treat SUD. Currently, alcohol abuse is the most common form of SUD being examined, with four of the trials targeting SUD comorbid with MDD or PTSD. These early trials will provide key information not only on therapeutic potential but also practical aspects around feasibility, compliance and safety regimes. Clinical approval : While positive clinical trial data may be a prerequisite for eventual clinical approval, a complex regulatory process follows with an uncertain outcome. In the United States, psilocybin and MDMA were granted Breakthrough Therapy Designation status by the FDA for MDD and PTSD in 2019 (Casey & Heifets, 2025), with LSD achieving this designation for generalized anxiety disorder in 2024 (Hoyer, 2025). However, FDA approval for MDMA for PTSD was declined in August 2024, citing concerns regarding functional unblinding and “issues with trial design and misconduct”. In the UK, synthetic psilocybin formulated as COMP360 (Compass Pathways) received a drug “innovation passport” from the UK Medicines and Healthcare products Regulatory Agency (MHRA). This formulation has made the strongest move towards the clinic, with a second successful Phase 3 trial announced in the first quarter of 2026 (see above). A potentially instructive ‘proof-of-concept’ is supplied herein by Nutt et al. (2024), who takes the reader through this approval process, not only for the clinical use of psilocybin for TRD and MDMA for PTSD, but also approval of psilocybin for therapeutic use in Australia in 2023. This account by David Nutt and colleagues illustrates the hurdles, pitfalls and restrictions that can be encountered during the decision-making process and provides insight that may be relevant for the success of future applications. The success of another powerful psychotropic agent, ketamine, achieving world-wide approval for TRD (Miller et al., 2026) sets an important precedent for the direction of travel of psychedelic drugs. 5 Concluding remarks As demonstrated by the collection of articles in this Themed Issue, these are exciting times for research on psychedelic and related drugs. Recent research has delivered a paradigm shift in our understanding of both the pharmacological mechanisms underlying the effects of these agents and their potential for bringing real clinical benefit in a diversity of neuropsychiatric conditions. More challenging to come is the hoped for translation of their therapeutic promise into clinical approval. Concerns, especially from regulatory bodies regarding how a psychedelic drug trial can be fully blinded, are being met by including the use of active controls, such as the NMDA receptor antagonist dextromethorphan, or inclusion of sub-hallucinogenic drug doses (Aday et al., 2025). However, in the event that psychedelic drugs receive a global welcome as prescribed drugs, it is difficult to envisage their use outside highly specialized clinical settings. There are advocates for treatment protocols involving repeated ‘microdosing’ with sub-hallucinogenic doses (Totomanova et al., 2025) but this approach is countered by clinical reports that the intensity of psychedelic experience is correlated with therapeutic outcome, consistent with an altered state of consciousness being required for full clinical benefit. On the other hand, evidence from studies on the emerging generation of non-hallucinogenic psychedelic analogues suggests that the therapeutic effects and psychedelic experience are separable. If the latter proves to be correct then this could be a game-changer in terms of realizing the full therapeutic potential of the pharmacology of psychedelic and related drugs. Author Contributions S. Wonnacott, G Stephens, T, Sharp: Conceptualisation (equal); Project administration (equal); Writing - original draft (equal); writing - review and editing (equal). Conflict of Interest statement The authors declare no competing interests. Data availability statement Not applicable - Editorial, no original data produced. Author affiliations Sue Wonnacott , Department of Life Sciences, University of Bath, Bath BA2 7AY, UK. Email: [email protected] Gary J. Stephens, School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, UK. Email: [email protected] Trevor Sharp, University Department of Pharmacology, Mansfield Road,Oxford OX1 3QT, UK. Email: [email protected] References Aday, J.S., Simonsson, O., Schindler, E.A.D., D’Souza, D.C. (2025). Addressing blinding in classic psychedelic studies with innovative active placebos. Int. J. Neuropsychopharmacol ., 28 :pyaf023. doi: 10.1093/ijnp/pyaf023. Alexander, L., Anderson, D., Baxter, L., Claydon. M., Rucker, J., & Robinson, E.S.J. (2024). Preclinical models for evaluating psychedelics in the treatment of major depressive disorder. Br. J. Pharmacol .,. doi: 10.1111/bph.17370. Epub ahead of print. PMID: 39467003. 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Collection British Journal of Pharmacology Authors Affiliations Susan Wonnacott 0000-0002-3775-7563 [email protected] University of Bath Department of Life Sciences View all articles by this author Gary Stephens 0000-0002-8966-4238 University of Reading Reading School of Pharmacy View all articles by this author Trevor Sharp 0000-0001-7434-9713 University of Oxford Department of Pharmacology View all articles by this author Metrics & Citations Metrics Article Usage 212 views 129 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Susan Wonnacott, Gary Stephens, Trevor Sharp. Editorial Emerging therapeutic opportunities for psychedelic and related drugs. Authorea . 01 April 2026. DOI: https://doi.org/10.22541/au.177505774.48075799/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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