On the Revival of the Use of Hallucinogens in Psychiatry and Addiction Medicine: Part 1

📖 What’s This Paper About?

This paper examines the renaissance of clinical research on classic psychedelic drugs including psilocybin, LSD, DMT, and MDMA in psychiatry and addiction medicine. It reviews the regulatory changes in countries like the USA and Australia where these substances are being legalized for therapeutic use, and explores the principles, requirements, and challenges of conducting psychedelic-assisted psychotherapy research.

Why This Matters

Despite decades of prohibition, psychedelics are showing therapeutic potential for treating various mental health conditions resistant to conventional treatments. This revival represents a paradigm shift in psychiatry, as these substances potentially offer novel mechanisms for addressing depression, PTSD, anxiety disorders, and addictions with just 1-3 therapeutic sessions.

• Psychedelics work differently than traditional psychiatric medications by potentially increasing neuroplasticity and altering default mode network activity
• Clinical research is rapidly accelerating with breakthrough therapy designations by the FDA
• Regulatory frameworks are developing in parallel with scientific evidence, creating unique implementation challenges

Top 5 Takeaways

1. Global Regulatory Landscape Is Rapidly Evolving

Australia became the first country to officially approve therapeutic use of MDMA and psilocybin, while in the USA, states like Oregon are implementing legal frameworks for psychedelic therapy, with projections suggesting most states may legalize psychedelics by 2033-2037.

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The Bigger Picture

The reemergence of psychedelics in psychiatry represents more than just new treatment options – it signals a fundamental rethinking of mental health treatment. Rather than daily medication that manages symptoms, psychedelics potentially offer transformative experiences that can lead to lasting change through altered perspectives and increased neuroplasticity. However, important safety concerns remain, including potential risks for patients with psychotic disorders or cardiovascular conditions, and the need for careful integration of these powerful experiences.

Final Thought

While the early evidence is promising, researchers urge cautious optimism. As one expert notes, only “careful optimization of treatment protocols based on empirical data rather than expert opinion” will determine whether psychedelic therapy fulfills its potential as a revolutionary approach to mental health treatment.

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ON THE REVIVAL OF THE USE OF HALLUCINOGENS IN PSYCHIATRY AND ADDICTION MEDICINE. PART 1

Keywords: hallucinogens, psychedelics, psychedelic therapy, psychotherapy, clinical research, microdosing, psilocybin, methylenedioxymethamphetamine, midomaphetamine, lysergic acid diethylamide, dimethyltryptamine, ayahuasca, mebuphotenine, 5-methoxy-DMT, treatment-resistant depression, post-traumatic stress disorder, generalized anxiety disorder

INTRODUCTION

Hallucinogens (psychodysleptics, psychotomimetics) represent a class of psychoactive substances whose main effect is the induction of psychotically altered states of consciousness. They constitute a diverse class of psychoactive substances that can induce altered states of consciousness characterized by serious disturbances in thinking, mood, and perception. Based on their clinical effects, most hallucinogens can be classified as psychedelics, dissociatives, and deliriants.

Deliriants typically include tropane alkaloids with pronounced anticholinergic activity (blocking muscarinic acetylcholine receptors). These include atropine, hyoscyamine, and scopolamine – alkaloids of belladonna, henbane, and datura. The clinical effect produced by these compounds corresponds to the presentation of cholinolytic delirium.

Dissociative hallucinogens include, in particular, synthetic compounds – dissociative anesthetics phencyclidine and ketamine, whose common property is the blockade of excitatory glutamate NMDA receptors in the central nervous system (CNS). In subanesthetic doses, ketamine induces a dissociative state characterized by “out-of-body experience,” depersonalization, derealization, and altered perception of space and time. At higher doses, users may experience dreamlike clouding of consciousness with visual and auditory scenario-like hallucinations of fantastic or mystical content (near-death experience).

Dissociatives also include kappa-opioid receptor agonists (stimulators) such as salvinorin A, the active substance in Salvia divinorum. Considering ibogaine’s affinity for kappa-opioid and NMDA receptors, as well as its dream-like effect, this hallucinogen most likely also produces dissociative symptoms. The effects of muscimol, an alkaloid from red and panther fly agaric mushrooms, can partly be considered dissociative as it acts as a stimulator of the special inhibitory GABA-C receptor in the CNS.

Classic psychedelics typically include 5-HT2A serotonin receptor stimulators. Although psychedelics may have varying affinity for other serotonin and non-serotonin receptors, their hallucinogenic potential is determined specifically by 5-HT2A receptors. These compounds will be the focus of the discussion below.

In the past decade, psychedelics have again become the object of scientific attention. Preliminary results of clinical studies show that psychedelics may have therapeutic potential in treating certain non-psychotic disorders that are resistant to conventional therapies. Current research is focused on treating post-traumatic stress disorder, depression, addictions, generalized anxiety disorder, and anxiety/demoralization associated with approaching end of life in terminal illnesses. Despite the pharmacological nature of the intervention, psychedelic therapy cannot be viewed exclusively from the perspective of psychopharmacotherapy, as it is more a form of psychotherapy (psychedelic-assisted psychotherapy). In modern studies, one to three psychedelic sessions are conducted, separated by weeks or even months of psychotherapy aimed at integrating the psychedelic experience. The first session is also preceded by several weeks of psychotherapeutic preparation of the patient. At the same time, research on the use of psychedelics in microdosing regimens (approximately 20% of the standard hallucinogenic dose) is also emerging.

Plant-derived psychedelics such as mescaline (from cacti of the genus Lophophora), psilocybin (from mushrooms of the genus Psilocybe), and dimethyltryptamine (from Psychotria viridis and Diplopterys cabrerana plants) have been used for millennia in cultures around the world. The earliest evidence of mescaline use was discovered by archaeologists in Texas and dated to 5700 years ago through radiocarbon analysis. Cave paintings in Spain depicting psilocybin mushrooms date from 6000 to 8000 years ago. Thus, humanity has had close connections with psychedelics throughout its history. Psychedelics affect all spheres of mental activity: perception, emotions, thinking, self-awareness, and sense of time.

The era of medical research on hallucinogens began with the discovery of the hallucinogenic properties of lysergic acid diethylamide (LSD) in 1943 by Albert Hofmann at the Sandoz pharmaceutical company as a synthetic derivative of ergot alkaloids. After his famous descriptions of his first accidental LSD ingestion, he convinced Sandoz to make LSD available and free to researchers worldwide who were interested in studying its properties.

By the mid-20th century, more than 1000 articles had been published describing the treatment of 40,000 patients with mental disorders, including addiction, using classical psychedelics such as LSD. In the 1950s-1960s, medical research on LSD flourished. At that time, it seemed that this altered state of consciousness provided access to repressed memories and emotions and thus could help people who were failing in psychotherapy. The U.S. government, through the National Institutes of Health, had funded more than 130 grants to study LSD before it was banned in 1967.

The effects of mescaline, psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), ayahuasca (N,N-dimethyltryptamine), and LSD are very similar and related to the ability of these compounds to selectively stimulate 5-HT2A serotonin receptors. For the purposes of this review, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy; midomaphetamine) is considered a psychedelic. In terms of mechanism of action, MDMA stimulates 5-HT2A receptors significantly less than psychedelics; however, it is a powerful stimulator of serotonin release, which determines its unique empathogenic effect used in the treatment of post-traumatic stress disorder.

The information about psychedelic drugs presented in this article is intended for medical and pharmaceutical professionals, is meant for distribution in a specialized medical scientific publication, and does not aim to promote or illegally advertise narcotic drugs, psychotropic substances or their precursors, plants containing narcotic drugs or psychotropic substances or their precursors, or parts thereof containing narcotic drugs or psychotropic substances or their precursors, as well as new potentially dangerous psychoactive substances.

LEGAL REGULATION OF PSYCHEDELIC SUBSTANCES IN THE RUSSIAN FEDERATION

Russian legislation regulating the turnover of psychedelics is based on the provisions of international law. The United Nations has adopted three international conventions: the Single Convention on Narcotic Drugs of 1961, the Convention on Psychotropic Substances of 1971, and the Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988, which define the list of narcotic drugs, psychotropic substances, and their precursors, as well as measures to combat such offenses. A significant portion of psychedelics is included in Schedule I of the Single Convention on Narcotic Drugs of 1961. Schedule I drugs are defined as having no recognized medical use but with significant potential for harm and dependence.

The primary regulatory legal act governing the circulation of narcotics, including psychedelics, in the Russian Federation is Federal Law No. 3-FZ of January 8, 1998, “On Narcotic Drugs and Psychotropic Substances.” In accordance with this law, the Government of the Russian Federation issued Decree No. 681 of June 30, 1998, which approved the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation (hereinafter referred to as the List). This List is supplemented with new substances as needed. All classical psychedelics discussed in this article are included in the List, and criminal and administrative liability is established for violating the rules of their circulation. In particular, Schedule I of the List includes lysergic acid and its derivatives, specifically LSD (lysergic acid diethylamide), MDA (3,4-methylenedioxyamphetamine or tenamphetamine); MDMA (3,4-methylenedioxymethamphetamine or midomaphetamine), mescaline (3,4,5-trimethoxyphenylethylamine) and its derivatives, DMT (N,N-dimethyltryptamine), including its derivatives psilocin (4-hydroxy-DMT), psilocybin (dihydrophosphate of psilocin) and mebuphotenine (5-methoxy-DMT), as well as a number of other hallucinogens. The inclusion of these psychedelics in Schedule I of the List means that the circulation of these substances in the Russian Federation is prohibited, they should not be used in medical practice, and their use is limited exclusively to scientific, expert, educational, and operational-investigative activities.

LEGISLATIVE REFORM REGARDING PSYCHEDELICS IN THE USA

The Controlled Substances Act of 1970 (CSA) established federal control over the storage, distribution, and production of drugs in the United States. Shortly thereafter, the Drug Enforcement Agency (DEA) was created to enforce the CSA, which classified psychedelics, MDMA, and cannabis as Schedule I substances.

Results from numerous studies, including large multicenter clinical trials of psilocybin for treatment-resistant depression (COMPASS, 2021) and MDMA for post-traumatic stress disorder, have preliminarily confirmed acceptable safety and psychotherapeutic usefulness of these compounds, leading to increased medical interest in them in recent years.

In May 2019, Denver, Colorado, became the first U.S. city to decriminalize psilocybin. By the end of 2019, many cities were considering initiatives to decriminalize psychedelics. This recognized the need to train emergency response personnel, educate and share messages in the areas of public order and health, collect data, and provide ongoing reporting on psilocybin safety.

In late 2020, Oregon became the first U.S. state to both decriminalize possession of psilocybin and legalize it for therapeutic use. An advisory board was created that presented recommendations for training professionals and informing clients about the risks and benefits of psilocybin therapy. According to current Oregon state laws, psilocybin use is restricted to licensed facilities with trained counselors.

Oregon Ballot Measure 109 outlined extensive recommendations (to be monitored by the Oregon Health Authority) regarding the licensing of psilocybin production and testing its purity. The testing laboratories themselves must be accredited by the Environmental Laboratory Accreditation Program. Additionally, requirements for qualification, training, and licensing of professionals providing psychedelic therapy services were defined.

In recent years, the active development in this area has led to the creation of academic centers for psychedelic science in the United States, including at Johns Hopkins University, as well as at the Universities of California, Texas, and Washington. In 2022, the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse and Alcoholism (NIDAA) began offering educational programs to support researchers interested in working with psychedelic drugs. Support for research by the National Institutes of Health (NIH) provides greater funding and scientific rigor.

In 2021, private companies invested more than $730 million in the development of psychedelic drugs. Private investment in psychedelic development has increased sharply since 2018, facilitated by the U.S. Food and Drug Administration (FDA) granting “breakthrough therapy designation” to clinical studies of psilocybin for depression, MDMA for post-traumatic stress disorder (PTSD), and LSD for generalized anxiety disorder. This status defines an accelerated procedure for drug registration in case of successful clinical trials. It is expected that in 2024, the FDA will make a decision on the authorization of MDMA for the treatment of PTSD. It remains unclear how the healthcare system will implement psychedelic treatment, as it represents a dramatic departure from currently accepted medical approaches and requires solving unique challenges.

It is rare for a pharmaceutical product to be made available through legislative reform rather than approval by regulatory bodies such as the FDA. Cannabis has been legalized through legislative reform in most U.S. states, despite maintaining DEA Schedule I status and lack of FDA approval. In July 2022, the American Psychiatric Association published a position statement concluding that clinical use should be determined by scientific evidence in accordance with applicable regulatory standards, not by ballot initiatives or public opinion. Based on data from cannabis legalization, J.S. Siegel et al. predict that most U.S. states will adopt laws legalizing psychedelics by 2033-2037.

Perhaps most important are the issues on which current U.S. legislation on hallucinogen legalization remains silent: 1) there is no exact mechanism for verifying the chemical composition of products acquired outside medical facilities; 2) there is little discussion about training, licensing, and monitoring for providers of psychotherapeutic services; 3) clinical infrastructure for providing psychedelic psychotherapy has not yet been developed; 4) there is still no clinical data on pharmacological interactions with concomitant medications and potential contraindications to treatment (e.g., psychotic disorders or cardiovascular diseases).

Despite the readiness with which some jurisdictions have begun to use psychedelics as a legal treatment method, critical questions about the mechanism of action, dosage and frequency of administration, duration of response to repeated courses of treatment, drug interactions, and the role of psychotherapy in therapeutic effectiveness remain unanswered. The last point, which is of enormous importance from a safety perspective, is the suggestibility and vulnerability of a patient under the influence of a hallucinogen. Thus, training and clinical supervision are necessary to ensure safety, as well as the therapeutic effectiveness of this heterogeneous class of treatment methods. Some efforts in this direction are being made in the United States and Canada.

The Multidisciplinary Association for Psychedelic Studies (MAPS) – a public organization developing psychedelic methods for treating mental disorders – announced in December 2023 the submission of a new drug application (NDA) to the FDA for MDMA (3,4-methylenedioxymethamphetamine, midomaphetamine) used in combination with psychotherapeutic intervention for post-traumatic stress disorder.

The data presented above show that after decades of strict legal restrictions, the United States is rapidly moving toward expanding access to psychedelics. Integrating psychedelic treatment into clinical practice will require removing many levels of legal prohibitions, FDA approval of developing pharmaceutical psychedelic preparations, clarification of prescription guidelines, and development of treatment models that will guide drug manufacturers, physicians, and patients.

Without a final FDA decision, the American Psychiatric Association has yet to give its approval, and scientists generally agree – both in the United States and Australia – that more research on the efficacy and safety of psychedelics is needed.

APPROVAL OF PSILOCYBIN AND MDMA IN AUSTRALIA

As of July 1, 2023, psychiatrists in Australia can prescribe MDMA and psilocybin for controlled clinical use.

According to WHO, of the 280 million people worldwide suffering from depression, one-third live with treatment-resistant depression, where symptoms do not improve with either the first or second antidepressant. One-third of patients with PTSD are also resistant to medication and psychotherapeutic treatment.

After an almost three-year process and extensive consultations with experts, both drugs were added to the list approved by the Therapeutic Goods Administration of Australia (TGA). MDMA was approved for the treatment of PTSD, and psilocybin for the treatment of treatment-resistant depression. These two drugs were transferred from Australia’s most strictly controlled category, Schedule 9 (prohibited substances), to Schedule 8 (controlled substances). While Canada and Israel permit individual use of psychedelics for compassionate reasons or as part of clinical trials, Australia has become the first country to approve the use of hallucinogenic drugs as medications to be prescribed by licensed psychiatrists. Psychiatrists will need to provide justification for why they believe these drugs are suitable for specific patients, as well as a proposed treatment protocol similar to clinical trial protocols.

The therapeutic effect will require a small number of psilocybin administrations – likely from one to three all-day sessions with pre- and post-psychotherapeutic support. Clinical studies have used a model of a therapist dyad (called guides or observers), meaning two therapists per client. One of the therapists was required to have medical education and was usually a psychiatrist. Patients undergoing treatment plan to spend the day in session and receive a dose of the drug in the morning. After 6-8 hours, the patient should return to normal consciousness. When the therapy team determines that the patient is ready to go home, they are picked up by a support person who remains with them for the next 24 hours.

In his interview with The Guardian, Daniel Perkins, executive director of the non-profit psychedelic medicine research center Psychae Institute (Melbourne, Australia), said that “There are also concerns that the transition to clinical application is premature and that incompetent or poorly equipped doctors may flood the space.” He also warned that the trial data demonstrating the efficacy of psilocybin and MDMA are preliminary and remain limited.

DRAFT GUIDANCE FROM THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) ON CLINICAL TRIALS OF PSYCHEDELIC DRUGS

In 2023, the FDA issued the first draft guidance for clinical trials of psychedelic drugs. This guidance provides general recommendations for developers of psychedelic drugs. For the purposes of this guidance, the term “psychedelic” is used to refer to classical psychedelics, understood as 5-HT2A serotonin receptor agonists, such as psilocybin and lysergic acid diethylamide (LSD), as well as entactogens/empathogens, such as MDMA.

Psychedelic drug development programs are subject to the same rules and the same standards of evidence as programs for developing other drugs. However, designing clinical studies of these compounds presents a number of unique difficulties. Psychedelic drugs cause severe perceptual disturbances and alterations in consciousness, which makes the use of classical placebo meaningless. Some psychedelic development programs also include psychological intervention. Psychedelics are thought to have equally rapid and long-lasting effects after just one or a few doses. These and other unusual characteristics should be considered when planning clinical studies so that their results can be interpreted. Since this is a completely new area, experience in developing research programs is very limited. Instead of providing specific recommendations for research design, the FDA draft guidance presents fundamental constructs that all sponsors, including academic institutions, should consider.

Many considerations are expressed regarding the safety assessment of psychedelics. In particular, it is suggested to pay special attention to the cardiological safety of hallucinogens due to the ability of many of them to stimulate 5-HT2B serotonin receptors. It is known that long-term exposure to 5-HT2B receptor agonists can cause thickening and deformation of heart valves. Currently, the FDA recommends excluding subjects with existing valvulopathy or pulmonary hypertension from studies of multiple administrations of drugs with this mechanism of action until this risk is better characterized. Investigation of addictive potential is conducted as a component of safety assessment of any drug affecting the CNS in accordance with separate FDA guidelines.

In terms of demonstrating efficacy, the following considerations may be unique to psychedelic drugs. In the context of hallucinogen development, using traditional placebo as a control may be problematic. Subjects receiving the active drug experience functional unblinding due to strong perceptual changes. Those who receive placebo in this context may experience a nocebo effect – worsening of symptoms as a result of realizing they did not receive the active substance and knowing they received placebo. However, placebo allows for better study of the safety of the investigational drug. The FDA also suggests considering alternatives to inert placebo – for example, subperceptive doses of the same psychedelic drug or other substances that cause some subjective effects (e.g., niacin – skin hyperemia, or diphenhydramine – drowsiness). One measure to minimize bias could be the use of blinded raters who do not know which drug the subject received. Raters are expected to use special blind questionnaires to evaluate subjects. It is suggested to use different and complementary designs in phase 2 and 3 clinical trials that will help solve various problems. For example, a study using low, medium, and high doses of a hallucinogen without placebo can be complemented by a placebo-controlled study. The study without placebo can provide information on the dose dependence of efficacy without the risk of nocebo reactions. Meanwhile, a placebo-controlled study, despite functional unblinding, would better characterize tolerability and safety.

Many psychedelic drug development programs include providing psychotherapy either during the dosing session or during subsequent sessions. This additional variable complicates the assessment of efficacy and presents a problem for developing instructions for medical use. At the time of publication of the draft FDA recommendations, the contribution of the psychotherapeutic component to the effectiveness of hallucinogens had not been characterized. Psychotherapeutic interventions can potentially increase result distortion. Therefore, developers should provide justification for including a psychotherapeutic component and describe elements of the study design aimed at reducing systematic error or quantifying the contribution of psychotherapy to the overall treatment effect. A therapist observing a session will be able to tell which drug the subject received by observing their behavior. Therefore, it is preferable that the session observer not participate in subsequent psychotherapy, according to the draft Recommendations.

The FDA recommendations also point to the need to characterize the duration of the therapeutic effect, the recommended interval between doses to maintain the effect, as well as the safety and efficacy of repeated administration. For treating chronic conditions such as PTSD and major depressive disorder, developers should additionally evaluate the effectiveness of the treatment at 12 weeks. Developers should monitor subjects for a year after the final assessment at week 12 to track symptom recurrence and the need for repeated dosing of the psychedelic.

MECHANISM OF ACTION OF PSYCHEDELICS

It has been demonstrated that 5-HT2A receptor agonists induce hallucinatory experiences, while blockers of these receptors nullify their hallucinogenic effect. 5-HT2A receptors are widely represented in brain areas involved in perception, emotional processing, memory, executive functions, self-analysis, and awareness, including the prefrontal cortex, anterior cingulate gyrus, and amygdala. Additionally, 5-HT2A receptors activate a cascade that triggers the production of brain-derived neurotrophic factor (BDNF), which ultimately increases neuroplasticity.

At the network level, studies have revealed modulation of default mode network (DMN) activity. This network is currently the main focus of neuroimaging of psychedelic effects. Key nodes of the DMN are the prefrontal cortex, cingulate gyrus, lateral temporal cortex, inferior parietal lobe, and hippocampus. The activity and functional connectivity of these structures are responsible for the recall of autobiographical memories and the process of self-referential thinking (perceiving oneself). In this state, a person is aware of their own thoughts, feelings, absorbed in reflections or memories about themselves, and does not pay attention to what is happening around them. DMN activity increases during introspective rest and decreases during focus on external objects. This is similar to the practice of meditation, which is also associated with decreased synchronized activity in the DMN.

Using functional MRI, it was shown that under the influence of psychedelics, activity and functional connectivity within the DMN decreases, while its connection with other brain areas strengthens, which correlates with the subjective experience of “ego dissolution,” when people report losing their sense of self, and the boundaries between the “self” and the surrounding world become blurred. Such experiences, often described as mystical, may be central to the therapeutic effect of psychedelics.

New studies also use MRI technologies to understand the influence of psychedelics on neural pathways in the resting state. In his 2019 interview, Dr. Griffiths, a leading psilocybin researcher at Johns Hopkins University, said: “Neuroimaging studies have shown that during the action of psilocybin, many neural connections are activated between areas of the brain that usually don’t interact with each other. This has led to the hypothesis that the action of psychedelics may open a window of neuroplasticity, during which neuronal restructuring occurs.” This striking difference in the mechanism of action of psychedelics from currently used therapeutic agents suggests that it is precisely the experience of an altered state of consciousness that leads to sustainable improvement after one or several sessions.

In addition to material changes registered using molecular, electrophysiological, and neuroimaging methods, important theories have been proposed to identify the psychological mechanisms underlying the antidepressant effects of psychedelic psychotherapy. The idea that psychedelics can be a catalyst for achieving insight and emotional breakthrough in psychotherapy was initially central to the theory of their mechanism of action. Another possible mechanism is that psychedelics affect inflexible and maladaptive thinking patterns and, by providing access to negative attitudes, allow beliefs to be changed.

Furthermore, it has been shown that spiritual or mystical experiences correlate with sustained psychological improvement, suggesting that these experiences may play a key role in the development of the antidepressant effect of psychedelics. Studies show that higher levels of mystical experiences are associated with better therapy outcomes. This supports the suggestion that psychedelics may change patients’ worldview.

In a recent study published in the journal Psychopharmacology, experts from the Center for the Study of Psychedelics and Consciousness at Johns Hopkins University investigated belief changes associated with psychedelic experiences. They found that a single experience with psychedelics increases the diversity of non-materialistic beliefs, particularly beliefs about the separation of consciousness, meaning, and purpose of life. For the study, researchers analyzed data collected from August 2020 to July 2021 from 2,374 people who had a psychedelic experience that led to a change in beliefs. During the survey, participants expressed their opinions regarding 45 statements before and after the psychedelic experience. Beliefs were conditionally classified into five groups:

1) dualism – belief that consciousness and body are separate from each other;

2) paranormal/spirituality – this group included a wide range of beliefs, including belief in the existence of consciousness after death of the physical body, the possibility of communicating with the deceased, reincarnation, and that some people can predict the future;

3) consciousness of non-mammals – relates to the question of whether inanimate objects (e.g., trees) have consciousness;

4) consciousness of mammals – a group of beliefs related to aspects of consciousness in animals;

5) superstitions – superstitious beliefs prevailing in a particular culture, such as avoiding the number “13” or black cats.

The results showed an increase in the prevalence of beliefs in the first four groups. In contrast, changes in beliefs about superstitions were insignificant. The percentage of participants identifying themselves as believers (e.g., in God) increased from 29% to 59% after the psychedelic experience. Higher scores of mystical experience were associated with more significant changes in beliefs. Acquired beliefs, assessed on average eight years after the psychedelic experience, generally remained unchanged.

Sandeep Nayak, MD, lead researcher and assistant professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine, said: “Until now, we haven’t paid enough attention to belief changes caused by psychedelics. Protective measures against certain belief changes in clinical practice are important, but it’s not yet clear how much such non-materialistic beliefs can be therapeutic.”

CONNECTION BETWEEN EFFECTIVENESS AND PSYCHOTHERAPY

Psilocybin and other psychoactive substances currently being studied require more than just administering a capsule and waiting for a positive effect. This often includes several weeks of psychotherapy preceding the first dose of the psychedelic, and then immediately afterward. In an article describing the goals and objectives of psychedelic therapists, J. Phelps identifies three main stages of treatment: preparation for the session using a psychedelic, the treatment (dosing) session itself, and integration of the psychological material that emerges during it.

Another important aspect that needs to be controlled is “set” and “settings.” “Set” refers to the goals of the patient and therapist for the session, which are discussed in detail during the preceding psychotherapy. Set includes motivational factors, intentions, and expectations. Additionally, it includes the specific type of guidance that the therapist will use throughout the psychedelic experience. “Settings” refers to the state of the physical, psychological, and emotional environment of the patient before and during the psychedelic session. Proper settings include a quiet room where the patient lies with a blindfold; it’s recommended to select music for accompaniment in advance. Optimization of these auxiliary procedures will become an important part of the treatment methodology, and demand for trained therapists will grow.

All published studies of psilocybin include psychotherapy as an integral part of the intervention. Psychotherapeutic support has been associated with a high probability of mystical experiences and has been generally accepted as an integral part of psychedelic treatment. However, published studies provide only brief descriptions of the psychotherapy itself. A systematic review of common components of psychedelic therapy identified the following elements. In preparatory sessions, the focus is on building therapeutic alliance and trust, understanding the patient’s needs, defining intentions, and providing information about what to expect from the dosing session and subsequent treatment. Dosing sessions involve two service providers who are non-directive, with emphasis on the patient focusing inward rather than actively interacting with external therapists. The role of guides (psychotherapists) is primarily described as necessary for ensuring safety and psychological support, not as active or directive in the patient’s psychedelic “journey.” All studies also used a pre-selected music playlist, most often consisting of classical music without words. The use of music is described as an important aspect of dosing sessions. Integration sessions are necessary to connect the experience gained with the initial intentions outlined in the preparatory sessions.

It has been suggested that psilocybin may promote personality changes in patients with treatment-resistant depression. In a small study, participants with moderate to severe treatment-resistant depression were given doses of psilocybin 10 and 25 mg with a 1-week interval. Using the NEO Personality Inventory (NEO-PI-R), baseline personality was assessed before treatment and reassessed 3 months after treatment. In assessing the five personality traits, it was found that there was a significant increase in openness and extraversion scores with a significant decrease in neuroticism scores. Positive personality changes correlated with the degree of the patient’s insight during the psychedelic experience.

CLINICAL EFFECTS AND SAFETY CONCERNS OF PSYCHEDELICS

When using moderate and high doses of psychedelic substances, acute psychotomimetic effects can be expected in almost 100% of patients. Acute psychoactive effects generally include changes in five spheres: cognition, perception, emotions, mystical experience, and social connections. Drawing a line between therapeutic and side effects is difficult, since both positive and negative emotional-psychological effects can have therapeutic effects. Subjective assessment of an effect as a side effect or therapeutic may influence which side effects researchers report at different research centers. Additionally, side effects and safety concerns may be more common in real clinical circumstances, including more complex patients.

Cognitive changes associated with psychedelic exposure range from increased thinking flexibility and creativity to distractibility and even complete disorganization. Perceptual disturbances may be illusory/hallucinatory (primarily visual) or dissociative (derealization, depersonalization, and time distortion). Negative emotions include anxiety, irritability, agitation, paranoia, and mood lability. These negative emotions can cause significant distress in patients and a desire to stop the drug’s effect, so careful monitoring is necessary. Mystical/spiritual experience is described as transcendence (experience of the “otherworldly”), ego dissolution (blurring of “subject-object” boundaries), ineffability (inaccessibility of the experienced to expression through human language), unity with the world, encounters with deities, etc. Spiritual and mystical experiences when taking psychedelics correlate with clinical improvement.

The main danger associated with taking psychedelics is the risk of harming oneself or others in an altered state of consciousness. Media coverage has highlighted cases of recreational use of psychedelics with tragic consequences of physical harm to others and oneself (including fatal outcomes). Clinical studies conducted to date show that these are rare events that can be prevented through proper participant screening, session monitoring, and safety protocols.

Given concerns about potentially possible serious side effects, contraindications for clinical use of psychedelics are related to the risk of exacerbating pre-existing disorders. In particular, a criterion for exclusion in all clinical studies is a history of psychosis, mania, or violence toward others. A common exclusion criterion is also the presence of first or second-degree relatives with psychosis or bipolarity. However, these exclusion criteria are based on the theoretical risk of psychosis exacerbation. Given the high prevalence of treatment resistance in bipolar depression, it is important to determine whether psychedelics can be used safely and effectively in this group of patients.

Acute somatotropic effects of psychedelics include increased blood pressure, nausea, and headaches, which may persist for several days after ingestion. Studies assessing blood pressure during dosing sessions found relatively mild and transient elevations.

Although no cases have been recorded during short-term clinical studies, there are theoretical concerns about the development of hallucinogen use disorders. Expert opinion suggests a low risk of developing physical or psychological dependence with clinical use of psychedelics. Another potential long-term risk of concern is the development of hallucinogen persisting perception disorder (HPPD). This is an unusual side effect observed in people who regularly use psychedelics. However, no cases of HPPD have been reported in published studies. A probable explanation for this is that personal and family history of psychosis is an exclusion criterion. However, concerns remain about patients who may need repeated doses to maintain the therapeutic effect. The threshold of use that may be associated with the risk of HPPD remains unclear.

CURRENT CLINICAL STUDIES OF PSYCHEDELICS

Below is data presented on the official website of the U.S. government’s clinical trial registry, ClinicalTrials.gov. Numbers in the format NCT – clinical trial numbers in this database, are presented for the possibility of more detailed familiarization.

At the time of writing this review, more than 20 clinical studies of psilocybin for major depressive disorder are active. Of these, 2 large Phase 3 studies are being conducted by the British biotechnology company COMPASS Pathways. In the Phase 3 study NCT05711940, 568 participants with treatment-resistant depression will be randomized in a ratio of 2:1:1 to use psilocybin at doses of 25, 10, or 1 mg. The study includes a screening period of 3 to 10 weeks and 16-week follow-up after psilocybin administration. The purpose of this study is to evaluate the efficacy of psilocybin administered with psychological support. The second Phase 3 study NCT05624268 is an international multicenter double-blind, placebo-controlled randomized study of psilocybin for treatment-resistant depression in parallel groups with a fixed dose of psilocybin 25 mg. 255 participants will be randomized in a ratio of 2:1 to the psilocybin or placebo group. The study consists of three parts (A, B, and C) and will last approximately 62 weeks. Part A will include a 6-week observation after the initial administration of psilocybin. The duration of effect and long-term safety, as well as the efficacy and safety of repeated dosing will be evaluated during a 20-week period after double-blind repeated administration of psilocybin (part B) and a 26-week open-label follow-up period (part C).

There are also a number of Phase 2 clinical studies of psilocybin for alcohol use disorder being conducted in the United States, Canada, Denmark, and Finland, by both university institutions and private biotechnology companies. One of the large studies, NCT05995769, is being conducted by the University of Calgary in collaboration with Johns Hopkins University, the University of Maryland, and the Canadian Institutes of Health Research (CIHR) and will include 128 people. The main objective of this study is to determine whether taking psilocybin in combination with standardized psychotherapeutic intervention (motivational counseling) can reduce the frequency of alcohol consumption in patients with alcohol use disorder (AUD). Patients with AUD will be randomly assigned to a high-dose group (25 mg – active drug) or low-dose group (1 mg – active control) of psilocybin. All participants will receive 5 weekly sessions of motivational counseling starting the day after taking the investigational drug dose. The severity of alcohol use will be assessed by the percentage of heavy drinking days using the Time Line Follow Back (TLFB) method before and at 1, 4, and 12 weeks after taking the psilocybin dose. Also in 2023, a study NCT01943994 of psilocybin for nicotine dependence with 95 participants was completed but not yet published.

The largest study of psilocybin for PTSD, NCT06141876, includes 160 patients. This is a randomized double-blind placebo-controlled study to assess the safety, tolerability, and efficacy of psilocybin-assisted psychotherapy in treating severe depression among adults with post-traumatic stress disorder. It is being conducted by the biotechnology company Apex Labs Ltd and is planned to be completed by the end of 2025.

The U.S. National Cancer Institute’s Phase 3 study NCT05398484 with 300 patients with mood disorders at the end of life continues. This is a randomized double-blind placebo-controlled multicenter study of the effect of psilocybin-assisted psychotherapy on anxiety, depression, demoralization, and fear of death, as well as quality of life in outpatients with advanced cancer. The study assesses the magnitude and duration of the therapeutic effect. It compares a single “high” dose of psilocybin 25 mg with a single dose of niacin 100 mg (active placebo) in combination with a psychotherapeutic platform.

Most LSD studies are conducted in Switzerland and the Netherlands. Most of these are Phase 1 studies on healthy volunteers, studying the mechanism of action and clinical pharmacology of LSD. Nevertheless, there are separate Phase 2 studies for depression at the end of life, alcohol dependence, and anxiety. Also interesting is the Phase 2 study NCT05200936 of multiple microdosing of LSD for ADHD in adults, conducted by Mind Medicine Inc. This is a multicenter randomized double-blind placebo-controlled Phase 2a study to evaluate the efficacy of a low dose of LSD (MM-120) compared to placebo, taken for 6 weeks (twice a week). The low dose (microdosing) of MM-120 (20 µg) is approximately 20% of the standard hallucinogenic dose of LSD.

There are also 2 Phase 2 clinical studies of LSD for cluster headache. The aim of the study NCT05477459, sponsored by the Radboud University Medical Center in the Netherlands, is to investigate the efficacy and safety of taking microdoses (25 µg) of LSD every 3 days for 3 weeks compared to placebo. The treatment period is followed by a 5-week follow-up period.

The clinical pharmacology and effects of mebufotenine on healthy volunteers are being studied in three Phase 1 studies. GH Research Ireland Limited is conducting several small pilot studies of this metabolically stable derivative of DMT for the treatment of depression. DMT itself is metabolically unstable and is rapidly destroyed by the enzyme monoamine oxidase in the human body. For this reason, the Amazonian hallucinogenic drink ayahuasca, in addition to the source of DMT (the plant Psychotria viridis), contains plant MAO inhibitors harmine and harmaline obtained from vines of the species Banisteriopsis caapi. The AIMS Institute is conducting a small study of the range of safe doses of SM-001 on healthy volunteers. SM-001 is a standardized aqueous extract of two types of Peruvian plants, Banisteriopsis caapi and Psychotria viridis. This study is also being conducted to assess the plasma levels of four active components of ayahuasca: dimethyltryptamine, harmine, tetrahydroharmine, and harmaline depending on the dose of the preparation.

Many clinical studies of MDMA (midomaphetamine) are also conducted on healthy volunteers to study the mechanisms of its prosocial effects and clinical pharmacology. At the time of writing this article, more than 10 Phase 2 clinical studies on the efficacy and safety of MDMA for PTSD are active. The largest of these (120 participants) is being conducted by the University of Sydney in patients with comorbid post-traumatic stress disorder complicated by alcohol use disorder (NCT05709353). Clinically significant improvement with the use of integrated trauma-focused therapy methods (COPE) is observed in only 49% of patients. It is assumed that MDMA may increase the response to COPE in PTSD. This study aims to assess the clinical efficacy and tolerability of MDMA in combination with COPE compared to COPE in combination with active control, in this case – niacin. Researchers hypothesize that patients who received MDMA will experience a reduction in the severity of PTSD symptoms, as well as a decrease in the number of heavy drinking days. 14 weeks of psychotherapy will include 2 sessions of MDMA (80-160 mg) or placebo control (niacin 250 mg).

CONCLUSION

Despite a long history of prohibiting hallucinogens, recent research shows some potential for these substances in treating various mental disorders such as depression, post-traumatic stress disorder, generalized anxiety disorder, and addictions.

Despite preliminary positive results, research continues to more fully understand the mechanism of action and optimal protocols for using psychedelics. It is also important to consider ethical and legal issues associated with the use of psychedelics for medical purposes.

Conducting rigorous scientific research on psychedelics is associated with many problems. First of all, there is a problem of effective blinding of the study drugs. In the studies conducted, most patients and coordinators were able to recognize which drug the subject received, thanks to the consciousness-altering nature of the effect of hallucinogens. Expectations of what will happen during the dosing session can affect the effectiveness of the therapy being studied. In some studies, systematic errors are likely to arise due to the relatively small sample size, as well as due to selection bias when using participants willing to take a Schedule I drug.

Given current legislation and the lack of high-quality evidence confirming the effectiveness and safety of psychedelic therapy, the working group of the Canadian Network for Mood and Anxiety Treatments (CANMAT) on psychedelics reached a consensus that psychedelics can be considered only as experimental treatment for now. Optimization of treatment protocols (e.g., dosage, number of psychedelic sessions, role of repeated doses, type of psychotherapy, choice of music, follow-up care, monitoring requirements, etc.) to improve efficacy and safety is a priority research area, as current protocols are based on expert opinion rather than experimental data. According to CANMAT, only cautious optimism is justified regarding the fact that psychotherapy using psychedelics will be able to provide a new class of interventions different from currently available treatment methods.

This is informational, not medical advice.

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