Psilocybin as a Disease-Modifying Drug

A Salutogenic Approach in Psychiatry

Background: Treatment with so-called psychedelic drugs, including psilocybin, lysergic acid diethylamide (LSD), and others, is among the most promising recent developments in psychiatry. This review focuses on psilocybin, a substance found in all mushrooms of the genus Psilocybe, because the largest amount of available evidence relates to this drug.

Methods: This review is based on pertinent publications (since 1969) that were retrieved by a selective search carried out in August 2024 in the PubMed and ScienceDirect databases employing the keywords “psilocybin” AND “long-term effects” AND “mental disorders”, with an emphasis on randomized, controlled clinical trials (RCTs).

Results: The available RCTs document the efficacy of psilocybin mainly against depression, including otherwise medically refratory depression. Most of the trials revealed a strong effect, with Cohen’s d ranging from 0.67 to 2.6; they used a variety of depression scales and follow-up intervals. Evidence was also found for the efficacy of psilocybin against substance use disorders (alcohol in particular) and symptoms of anxiety accompanying life-threatening somatic illnesses, such as cancer. Initial uncontrolled studies have also shown significant improvement after the administration of psilocybin for other indications.

Conclusion: Treatment with psilocybin differs fundamentally from classic psychopharmacotherapy. Its potentially transdiagnostic, rapid, and sustainable efficacy and its positive effect on further dimensions of mental health beyond the patient’s symptoms and psychopathology imply that it may have disease-modifying and salutogenic mechanisms of action. Psychotherapy accompanied by the administration of psychedelic drugs may turn out to be the first disease-modifying treatment in the history of psychiatry.

In Germany, the treatment of people with mental disorders is provided in more than 400 psychiatric and 250 psychosomatic clinics, with around 55 000 and 11 000 beds, respectively. The annual number of cases totals almost one million and has more than doubled since 1990. In no other medical discipline is the hospital bed occupancy rate anywhere near as high (around 95%) (1). In addition, there is also a dense network of outpatient treatment facilities that still does not meet demand. Since 1990, antidepressant prescription figures have not only more than doubled in Germany, where around 5 million people are taking antidepressants at any given time – and this figure has not yet plateaued (2). The prevalences of depression and other mental disorders remain high (3) and even appear to have significantly increased over the past 15 years in particular (4).

Yet at the same time, the effectiveness of available antidepressants may be considered moderate at best (5). Under naturalistic conditions, less than 50% of patients treated with selective serotonin reuptake inhibitors (SSRI) respond to treatment, and only 30% achieve remission (6). However, even if common outcome measures do indicate such remission, for many patients this does not reflect a state of mental health in which the individual can develop their abilities, cope with the stresses of everyday life, work productively, and contribute to their community (7). After unsuccessful treatment for depression, only about one quarter of patients achieve complete remission on changing to a different antidepressant (8). Even after four different consecutive treatments, only two thirds of the patients reach remission, and recurrence rates are high (8). Furthermore, many patients suffering from mental disorders are also under long-term treatment, even though this only inadequately controls their symptoms and results in significant side effects. Finally, the evidence indicates that pharmacotherapy leads to resistance to treatment (9) which develops in the course of therapy in 20 to 30% of patients (10). The long-term course of the disease can also be adversely affected; after discontinuing antidepressant treatment, the time until relapse is significantly shortened compared with the naturalistic course (11). Only one of three patients value the benefit of an antidepressant more highly than the risks and side effects associated with its administration (12).

From a pathogenetic point of view, on the other hand, almost all mental disorders are considered chronic: Once they have developed, treatment after alleviation of the acute condition is then aimed at preventing recurrence and only in the second instance at the patient’s full recovery.

All currently available psychotropic drugs must be considered symptomatic forms of therapy. Their use is based on the assumption that specific molecular dysfunctions underlie mental disorders which can be treated by long-term medication (similar to type 1 diabetes, for example). According to this concept, mental disorders are regarded as “metabolic disorders of the brain”. “Classic” antidepressants, however, do not eliminate the cause of the disorder or fundamentally modify the course of the disease. The long-held serotonin or monoamine hypothesis of depression, which was derived from the mechanism of action of common antidepressants after their development and postulated a depletion of serotonin levels as the etiological origin of depression, is now being increasingly called into question (13). However, treatment of mental illnesses lacks disease-modifying pharmacological approaches and an overall salutogenic concept. Disease modification implies not only treating the biological causes of a disorder but also reducing mortality and avoiding hospitalization in the long term (14). Salutogenesis is a concept that studies the origins of health and seeks to understand those factors that contribute towards people developing resilience when confronted with stressors which enables them to remain healthy or regain their health. Unlike pathogenesis, which is concerned with the development of disease, salutogenesis looks at the sources of well-being and health (15, 16).

Of all drugs, classic (or serotonergic) psychedelics could fulfill the criteria of disease modification. This is all the more remarkable given that research on them already started more than seventy years ago, only then to come almost to a standstill for decades because they were declared “Substances with no evidence-based medical benefit” by regulation with classification as “Schedule 1 substances” under the UN Convention on Psychotropic Substances (Vienna, 1971). As a result, drugs such as psilocybin continue to be listed as non-marketable narcotics according to the German narcotics law. Classic psychedelics, including tryptamines such as psilocybin, can induce profound changes of perception, emotional experience, and consciousness (17). Pharmacologically, they share a high binding affinity and (partial) agonistic effect on serotonin 5-HT2A receptors, which is responsible for their specific psychedelic effects such as increased sensory perception, ego-dissolution, and intense emotions, also known as “psychedelic experience” (18). Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) is the main psychoactive ingredient in hallucinogenic mushrooms, especially in those of the liberty cap species (psilocybin) which occurs naturally worldwide. Natural psychedelic substances have been used by indigenous cultures in psychospiritual and medical rituals for millennia. They are still used today as intoxicants for recreational consumption (17).

Classic psychedelics, and above all psilocybin, are currently being investigated for the treatment of various psychiatric disorders where they have produced some promising results. Although methodological weaknesses, such as the absence of effective blinding and still moderate case numbers to date, diminish the validity of the evidence so far, this still could be one of the most promising developments in the field of psychiatric therapy over the past decades.

In several indications, the quality and intensity of the acute subjective experience under psychedelics has been observed to be associated with therapeutic response (19). Given their context sensitivity (20), psychedelics are always administered in current clinical trials in a supportive, psychotherapeutic setting and under therapeutic supervision. The extent to which the psychotherapeutic integration of drug administration and the psychedelic experience that is regularly associated with it is essential for its efficacy is currently the subject of intense debate. It is also uncertain which quality of the acute experience is beneficial and what are the medium and long-term neurobiological effects of the psychedelic experience. Initial preclinical data show that after administering psilocybin to mice the critical learning period essential for the development of social skills, for example, is reopened (21). Cognitive and emotional mechanisms learned at an early age can be “relearned” in this respect. It is reasonable to assume that after administration of the drug a therapeutic window is opened in a similar way in humans, in whom a type of metaplasticity is enhanced as with animals. Metaplasticity describes how easy or how difficult it is for a synapsis to become neuroplastic, depending on prior experience and activity. In humans, there are also initial signs that psilocybin has a fundamentally different neurobiological effect as compared with SSRIs (22, 23). Although SSRIs also exert neuroplastic effects (24), they appear to be significantly less pronounced preclinically than those seen after psilocybin (25, 26). Even though the underlying key factors of the majority of mental disorders are still largely unknown, this could be the neurobiological basis of a distinct, transdiagnostic effect of psilocybin which ultimately leads to disease modification. However, it has to be recognized that even classic psychotropic drugs (such as antidepressants, antipsychotics) probably have transdiagnostic effects based on their diverse pharmacological actions, i.e., they have a positive impact on the same disease dimensions in various disorders. This selective literature review will present the available studies on psilocybin for the treatment of mental diseases.

Methods

The search was carried out in September 2024 in the PubMed and ScienceDirect databases employing the keywords (“psilocybin”) AND (“long-term effects”) AND (“mental disorders”). The choice of studies for inclusion focused on clinical controlled trials to ensure relevance for clinical practice. Inclusion and exclusion criteria are listed in the eBox. Extraction and selection of the data were undertaken independently by two of the authors (MS and LM).

eBox

Literature review for the selection of Table 1

eTable

Search aspects/search strings*

Results

Of the 161 articles originally identified, 12 were included after reviewing the title, abstract, and full text (Table 1). The most evidence currently available on psilocybin involves the treatment of unipolar depressive disorders, including treatment-resistant depression (TRD) (Table 1). Further evidence of efficacy was found in randomized, placebo-controlled trials on substance use disorders and anxiety accompanying life-threatening illnesses. Here, there was also a corresponding improvement in depressive symptoms and vice versa. Initial explorative open trials also demonstrated significant improvement after psilocybin for other indications (Table 2).

Table 1

Randomized controlled clinical trials involving psilocybin

Table 2

Additional smaller clinical studies on psilocybin for other indications

After only one or two single doses, psilocybin led to long-term improvement in depression for at least six weeks after starting treatment. The only six-week comparative study to date comparing psilocybin with the classic antidepressant escitalopram showed no significant difference in depressive symptoms between two separate doses of psilocybin and daily escitalopram (27). The study showed that therapy with psilocybin was superior to treatment with escitalopram after six weeks with regard to relevant secondary outcome parameters. These included scales for measuring anhedonia, well-being, mental performance, and functionality. Other studies have also confirmed significant positive effects of psilocybin on these disease dimensions (28).

Apart from the evidence of a rapid onset of its antidepressant effect (29), initial long-term observations also show lasting effects after treatment with psilocybin, in some cases even many months after treatment – unlike, for example, ketamine/esketamine for which various studies have increasingly demonstrated a need for maintenance therapy (30, 31). The three follow-up studies that report effect strengths also refer to comparable effect strengths after up to 54 months in comparison with the primary study (Table 1).

From this we conclude the following hypothesis:

Given the potential for transdiagnostic factors, the long-lasting efficacy in many cases after only a few single doses, without the need for long-term medication, and the positive effect on parameters of mental health and functionality that are not limited to psychopathology, it can be assumed that psilocybin does not have a disorder-specific and symptom-based mechanism of action, but rather a disease-modifying and salutogenic one.

Discussion

We shall now proceed to discuss the role of psychotherapy, context, and risks of treatment in light of our own hypothesis.

In most current clinical trials, psychedelics are administered as part of a psychotherapeutic setting. Historically, this is based on the therapeutic approaches of psycholytic (multiple substance doses of low to moderate amounts together with psychotherapeutic interventions under the influence of the medication, embedded in long-term, psychodynamically oriented psychotherapy) and psychedelic therapy (high to very high doses in a single dose or only a few applications with the aim of achieving a “mystical” or “peak” experience) (20). In modern clinical studies, this psychological support usually comprises a number of therapeutic sessions in order to prepare the patient for the psychedelic experience, support during the acute psychedelic experience, and psychotherapeutic follow-up measures (32).

Psychotherapy may generally be defined as a conscious and planned interactional process to influence behavioral disorders and states of suffering using psychological means towards a defined goal using scientifically evaluated techniques (33). Psychotherapy produces and accompanies a process of change and learning in order to alleviate in the long term an existing mental disorder. Likewise, psychotherapy could be said to have disease-modifying qualities even without medication, as underlined by the more sustained effectiveness of psychotherapy as compared with pharmacotherapy in some indications (34).

Pharmacotherapy is also always provided within a psychosocial setting and in many cases includes a psychotherapeutic approach. According to the undirected susceptibility to change model, antidepressants – and serotonergic antidepressants in particular – do not affect mood as such (35). Instead, they make the individual more sensitive to the effects of the environment by increasing neuronal plasticity. This model suggests that an increase in serotonergic neurotransmission can not only increase the likelihood of recovery from depression, but – under adverse conditions – also the risk of developing a psychopathology. This enhanced context sensitivity in both directions probably applies in particular to therapy with psychedelics (20). In comparison with usual combination therapy, the biological substance effects appear here to enable and enhance psychotherapeutic and psychological mechanisms of action (20). Apart from an increase in neuroplasticity, biological effects also include in particular an acute reduction in thalamic filter function and increased connectivity of otherwise functionally separate brain regions, as well as a reduction in the activity of the so-called default mode network (DMN), which is thought to be overactive during depression in the sense of constant self-centered, dysfunctional obsessional thoughts and rumination (22). Psychological mechanisms of action of psychedelics are, for example, confrontation with biographical experiences in the form of exposure, an increase in psychological flexibility (36), improved understanding of emotions leading to emotional breakthroughs (for example the resolution of an emotional conflict), or the adoption of a benevolent and accepting attitude towards one’s own self (37). When treating with psychedelics, therefore, biology and psychology presumably work together inseparably and synergistically to create corrective learning experiences.

This presumably increased plasticity also explains why psychedelics such as psilocybin also undoubtedly involve risks. On the whole, serotonergic psychedelics are well tolerated in terms of their somatic effects. Side effects such as headaches or increase in blood pressure are usually moderate and transient in nature and do not require intervention (38). Psychedelic substances can bring about psychotic disorders, although this was not encountered during the selected studies. Recent studies on twins indicate that the risk has so far been overestimated (39). Less common, but potentially long-term, psychological changes are of greater concern and include complications such as derealization syndromes or hallucinogen persisting perception disorder (HPPD) which are as yet still poorly studied (40). Investigations are still needed into when treatment with psilocybin is useful and when it is considered a risk in the course of the disease. Further questions that the current data situation is still unable to answer adequately include which patients benefit from the treatment, whether multiple doses offer advantages over a single dose, and what impact psilocybin has on suicidality.

Conclusions

There is promising evidence supporting the efficacy of psilocybin in the treatment of various mental disorders. Most of the evidence available is on the treatment of depressive disorders. Its potentially transdiagnostic, rapid, and sustainable efficacy as well as its positive effect on further dimensions of mental health beyond the patient’s symptoms and psychopathology imply that it may have disease-modifying and salutogenic mechanisms of action. Psilocybin, especially in combination with psychotherapy, could be a form of treatment that targets disease causes (psychological and biological) and for this reason could have a more lasting, and indeed curative, effect. This hypothesis will require testing in larger cohorts and in long-term studies (for example by measuring its long-term impact on mortality and hospitalizations). The concept of disease modification should not lead to the conclusion that psilocybin will benefit all patients. It will also most likely be contraindicated in some diseases (e.g., psychotic disorders).

Psychedelic-assisted psychotherapy could possibly penetrate traditional psychiatric care structures in order to transform them. One of the central aims of a treatment model that follows the concept of pharmacologically extended salutogenesis is to move away from long-term drug treatment of illnesses (with the aim of avoiding recurrences) towards a focus on the creation and promotion of health resources and resilience.

Funding

This review article was funded by the Federal Ministry of Education and Research (BMBF; funding code 01EN2006 A/B).

Conflict of interest statement

MS is a member of the German Society for Psychedelic Research and herapy (DGPFT) and has received lecturer fees from the MIND Foundation.

LJM is a member of the DGPFT (board of directors) and the MIND Foundation.

AJ is co-founder and partner of OVID Health Systems, the OVID Clinic Berlin, OVID Investment Company, the OVID Day Care Center, and the MIND Foundation (Berlin, Deutschland).

HJ is co-founder and partner of the MIND Foundation, OVID Health Systems, and the OVID Day Care Center (all in Berlin, Germany).

For the past three years, GG has been working as advisor for AbbVie (Chicago, USA), Boehringer Ingelheim (Ingelheim, Germany), the Institute for Quality and Efficiency in Health Care (IQWiG, Cologne, Deutschland), Johnson & Johnson (New Brunswick, USA), Lundbeck (Copenhagen, Denmark), MindMed (New York, USA), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Roche (Basel, Switzerland), and ROVI (Madrid, Spain). He worked as a consultant for Gedeon Richter (Budapest, Hungary), Johnson & Johnson, Lundbeck, Otsuka, and Recordati. He has received research funding from Beckley Psytech (London, UK) and Boehringer Ingelheim. He is co-founder and/or partner of the Mind and Brain Institute (Zornheim, Germany), OVID Health Systems, the OVID Clinic Berlin, OVID Investment Company, the OVID Day Care Center (all in Berlin, Germany, and the MIND Foundation (Berlin, Deutschland). He is Deputy Chairperson of the German Society for Psychedelic Research and Therapy (DGPFT).

LVF declares that he has no conflict of interests.

Manuscript received on 19 May 2024, revised version accepted on 14 October 2024.

Translated from the original German by Dr. Grahame Larkin

Corresponding author
Prof. Dr. med. Gerhard Gründer

Department for Molecular Neuroimaging

Central Institute of Mental Health

J5, 68159 Mannheim

Cite this as:
Spangemacher M, Mertens LJ, Färber LV, Jungaberle A, Jungaberle H, Gründer G: Psilocybin as a disease-modifying drug—a salutogenic approach in psychiatry. Dtsch Arztebl Int 2024; 121: 868–74. DOI: 10.3238/arztebl.m2024.0224

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