Mind-expanding substances as new possibilities for therapy

Affective disorders and stress-related illnesses are an increasing global health care challenge with rising socioeconomic costs. A considerable proportion of patients do not respond or respond only temporarily to the treatment strategy with conventional psychotropic drugs. For some years now, the clinical-experimental use of psychoactive substances has been increasingly investigated again.

Affective disorders and stress-related illnesses represent an increasing global challenge to health care and impose rising socioeconomic costs due to their epidemic prevalence [1]. The treatment strategy with conventional psychotropic drugs is essentially substition-oriented; for example, the mode of action of antidepressants is mainly based on increasing cerebral serotonin or noradrenaline concentrations. Apart from the delayed onset of action and significant side effects, a considerable proportion of patients do not respond or respond only transiently to this pharmacological substitution [2].

In focus: Rapidly acting serotonergic and glutamatergic psychoactive substances

Therefore, new innovative therapeutic approaches using glutamatergic and serotonergic psychoactive substances such as ketamine, psilocybin, MDMA, LSD, and ayahuasca are increasingly being explored in experimental neuropsychopharmacology, showing a more rapid onset of action and more sustained effects in the context of only a few administrations [3–5]. Over the past decade, for example, the dissociative anesthetic ketamine has been shown in several randomized controlled trials to have a rapid-onset antidepressant effect lasting several days in unipolar, bipolar, and treatment-resistant depression after a single intravenous administration [6]. Initial pilot clinical studies show that psilocybin, the active ingredient of hallucinogenic mushrooms, also exhibits rapid and sustained antidepressant effects [7] and, as an adjuvant, can support nicotine or alcohol cessation [8,9]. In the area of “palliative care”, existential anxiety and depression in life-threatening physical illness can be alleviated with LSD or psilocybin-assisted psychotherapy [10–12]. Furthermore, the predominantly empathogenic serotonergic substance MDMA shows sustained relief of PTSD symptoms after only 2-3 treatments [13]. The Multidisciplinary Association for Psychedelic Studies (MAPS) is currently launching Phase III studies to investigate the efficacy and prospective FDA approval of MDMA for the treatment of PTSD [14]. In Switzerland, too, from 1988 to 1993, therapists of the Swiss Medical Society for Psycholytic Therapy (SÄPT) were granted an exemption by the Swiss Federal Office of Public Health (BAG) to perform psycholytic therapies with the substances MDMA and LSD in their practices. During these five years, approximately 170 patients were treated, undergoing a total of slightly more than one thousand full-day sessions with mostly positive therapeutic results [15].

Ayahuasca: From indigenous medicine to clinical trial drug

In addition to LSD, MDMA, ketamine, and psilocybin, there is also growing interest worldwide in ayahuasca, a traditional Amazonian plant preparation that has been used ritually in indigenous medicine for centuries and is increasingly being taken outside indigenous contexts for personal development and health prevention. In addition to numerous anecdotal reports, an increasing number of studies on ayahuasca have been published in recent months suggesting clinically relevant positive effects in the treatment of anxiety disorders, depression, addiction disorders, and stress and trauma sequelae. [16]. Due to the increased mental clarity, cognitive flexibility, and deepened emotional introspection capacity compared to everyday consciousness, ayahuasca may also prove useful in the future as a phytotherapeutic adjuvant for process-oriented psychotherapy support [17].

Ayahuasca contains the psychotropic agents dimethyltryptamine (DMT) and β-carbolines (MAO inhibitors), which exhibit rapid-acting effects on the serotonin system and promote neuroplasticity [16]. DMT could also be detected endogenously in the human body as a structural analog of serotonin, but its physiological role has not yet been adequately clarified.

Preclinical findings indicate that DMT, as a neuroprotective and immunomodulatory “adaptogen,” counteracts the negative effects of chronic stress on the immune and nervous systems, and thus, as a component of ayahuasca taken, could improve stress resilience [16]. Serotonergic psychedelics such as LSD, psilocybin, or DMT act predominantly as 5-HT2A receptor agonists on glutamatergic pyramidal neurons and increase excitability of the prefrontal cortex.

Interestingly, ketamine also increases glutamatergic neurotransmission via stimulation of NMDA receptors, thereby also promoting synaptic plasticity associated with antidepressant efficacy [3]. Increased global brain connectivity under the influence of psychedelics enables greater global integration of neural information processing, leading to acceleration of phase transitions and transformation processes [4].

Paradigm shift from substitution-based to transformation-based therapy.

Because of their unique modes of action, psychotropic substances such as ketamine, psilocybin, MDMA, LSD, and DMT/ayahuasca can be grouped into a new class of glutamatergic and serotonergic psychotropic drugs with rapid antidepressant and potentially sustained psychointegrative properties. The therapeutic approach is based less on a prolonged pharmacological substitution of neurotransmitters than on a rapid and sustained change in dysfunctional neuronal control circuits. The goal of this transformation-based therapy is to move the patient from a suboptimal state of consciousness to a more adaptive state that can be further stabilized through concurrent psychotherapy. The psychotropic properties of these substances do not represent a side effect, but can be used specifically for therapeutic purposes. For example, it has been shown that the intensity of positively experienced self-delimitation (so-called “peak experience”) modulates therapeutic effects under the influence of psilocybin [4]. Such transformative experiences can be achieved through various consciousness techniques such as ergotropic arousal (e.g., ecstasy, psychedelics) or trophotropic calming (e.g., trance, meditation). In this context, pharmacologically-induced states (e.g., ketamine, psilocybin, or ayahuasca) exhibit the same neural biosignature as non-pharmacological methods (e.g., meditation): Connectivity and activity in brain areas mediating self-referential information processing decreases as a consequence of the expanded state of consciousness, opening new windows of plasticity for psychotherapeutic transformation [4]. Through the experience of expanded states of consciousness, patients regain a piece of consciousness competence, namely to free themselves from dysfunctional spaces of consciousness through increased cognitive flexibility. The method resembles a radical exposure therapy: Only those who face the totality of their states of consciousness learn to move within them again with increased confidence and without fear through corrective experiences.

Many psychiatric symptoms result from early childhood trauma and attachment disorders that limit later relationship skills and increase vulnerability to mental disorders through reduced stress resilience. Especially when the early traumas are in the preverbal domain, they often remain difficult to access through cognitive-behavioral conversational psychotherapy, and therapeutic approaches to symptom relief tend to be palliative in nature. For this group of patients in particular, transformational psychotherapy involving altered states of consciousness could improve emotional-cognitive integration to the extent that these patients learn to rebuild increased self-acceptance and self-care, not only through cognitive restructuring, but on the basis of pharmacologically supported emotion-focused and corrective consciousness experiences, in order to break autodestructive behavior patterns. Serotonergic psychoactive substances are thought to increase empathic connectedness to oneself, to others, and to the environment, thus contributing to a general improvement in relational homeostasis [18].

Benefits, risks, and limitations of substance-assisted psychotherapy.

In previous clinical trials, serotonergic and glutamatergic psychoactive substances showed good efficacy with relatively good tolerability. Due to the highly context-sensitive effect of these substances, it is essential to ensure a suitable set (internal state) and setting (environment). Individual or small group psychotherapeutic settings have proven effective, with the majority of patients focusing on the inner experience while receiving supportive guidance. During the integration phase, the experience can be worked through psychotherapeutically at intervals in order to further stabilize corrective experiences of consciousness. Low-risk use of psychotropic substances can thus be ensured in a controlled setting. As with any medical intervention, careful education, risk-benefit analysis, and informed consent must be obtained beforehand. Pharmacologically induced altered states of consciousness can also acutely trigger anxiety, panic, or feelings of loss of control and reality due to their unusual intensity if the patient is predisposed to them. Therefore, treatments should always be performed under medical-psychotherapeutic supervision and after careful screening of patients.

Substance-assisted therapy is contraindicated in cases of acute suicidality, emotional instability, or psychosis proneness. Because serotonergic and glutamatergic psychoactive substances can transiently increase blood pressure and heart rate, prior cardiac screening and regular monitoring of vital signs during the session is recommended. Likewise, attention should be paid to relevant interactions with existing medications: Antiglutamatergic and GABAergic drugs (e.g., antiepileptics, benzodiazepines), opioids, and SSRIs usually attenuate the effects of serotonergic psychedelics, whereas MAO inhibitors contribute to unpredictable effect enhancement and are therefore contraindicated because of the risk of serotonin syndrome. Toxicologically, glutamatergic and serotonergic psychoactive substances are considered sufficiently safe at doses and treatment frequencies commonly used in therapy.

Most serotonergic psychedelics are classified as non-marketable narcotics, their clinical use is subject to approval by the cantonal ethics committees for research projects and the Federal Office of Public Health (FOPH) for experimental individual healing trials, and for the time being is only possible under special permits. Ketamine can be prescribed as an off-label therapy for the treatment of treatment-resistant depression under close medical supervision due to its approval status and scientific evidence. Unlike commonly prescribed narcotics such as benzodiazepines and opiates, serotonergic psychoactive substances have no risk of developing dependence. Contrary to earlier assumptions, it could not be confirmed that the lifetime prevalence of psychedelic drug use is associated with an increased risk for the occurrence of psychiatric syndromes; on the contrary, a significantly reduced incidence of suicidal thoughts and attempts was shown in people who regularly use psychedelics [19]. The risk of long-term side effects is also reduced by the irregular and limited number of treatments, which also has health economic advantages. However, since most active ingredients and preparations are not patentable, the incentives for industrial research and pharmaceutical development in the field of serotonergic psychotropic substances are decreasing.

Conclusion

In summary, serotonergic and glutamatergic psychotropic substances may prove to be an innovative therapeutic option as an adjuvant to psychotherapy in a more transformational treatment strategy for affective disorders, addiction, trauma, and stress-related disorders. However, further randomized-controlled trials in representative samples are needed to demonstrate the safety, tolerability, and therapeutic efficacy as well as the biomechanisms of these experimental treatment approaches in patient populations suitable for them.

Take-Home Messages

The clinical-experimental use of psychoactive substances has been the subject of increased scientific research in recent years.
Dependence disorders, stress and trauma sequelae disorders, and anxiety disorders and depression in the presence of life-threatening physical illness currently represent the best evaluated indications for substance-assisted psychotherapy with serotonergic psychoactive substances.
The treatment approach with psychoactive substances is not based on a prolonged pharmacological substitution of neurotransmitters, but aims as a transformation-oriented paradigm at the rapid change of dysfunctional neuronal control circuits.
Psychoactive substances show a relatively good safety profile and tolerability in a controlled clinical experimental or scientific setting.
Experimental treatment with non-marketable substances is subject to approval by the cantonal ethics committees and the FOPH and is initially only possible in scientifically supervised contexts within the framework of special permits.

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