Psychedelic-Assisted Therapy: Potential Benefits and Challenges in Mental Health Treatment

Introduction

Psychedelics, as their name suggests (psyche is Greek for soul, and deloun means revealing), are currently, and were in the past, considered “soul-revealing substances”. They can also be called hallucinogens, to emphasize their effect on sensory perception [1]. By definition, psychedelics constitute a class of psychoactive substances that induce characteristic alterations in perception, mood, cognition, and the sense of self (ego), primarily through agonism at serotonin 5-HT2A receptors within the central nervous system. Classical psychedelics include tryptamine derivatives, such as psilocybin and dimethyltryptamine, ergoline derivatives, such as lysergic acid diethylamide (LSD), and phenethylamines, for example, mescaline [2].

A different view divides psychedelics into hallucinogens – tryptamine derivatives, such as psilocybin, ergoline derivatives, such as LSD, and phenethylamine derivatives, such as mescaline; entactogens, or empathogens, commonly exemplified by 3,4-methylenedioxymethamphetamine (MDMA); and dissociatives, such as phencyclidine (PCP) and ketamine [3].

The idea of using drugs to speed up psychotherapy is not new and has been discussed in the literature since the 1940s, when substances from the group of barbiturates, amphetamine derivatives, nitric oxide, LSD, and others were proposed for such purposes [4]. Psychedelics have been used in various cultures in medical and religious contexts for many centuries. The integration of psychedelics into psychotherapy has been considered for decades. The psychedelic effects of LSD were first discovered by Albert Hofmann in the early 1940s [5]. This discovery initiated the first wave of research on these compounds, which continued uninterrupted until the Cultural Revolution of the 1960s. During this period, psychedelics were prohibited, leading to a suspension of all related research in 1966, for over 20 years [6]. In the early 1950s, psychedelics were regarded as a group of compounds that could serve as tools to shorten psychotherapy [7]. Initially, during that decade, psychotherapy with psychedelics followed 2 primary approaches. The “psycholytic” method involved lower doses administered during frequent sessions to enhance the standard therapeutic process. In contrast, the psychedelic method used higher doses during less frequent sessions, aiming to induce mystical experiences and moments of intense catharsis [8].

A meta-analysis of 19 studies conducted between 1949 and 1973 revealed that 79% of patients with mood disorders showed improvement following the use of psychedelics [9]. Although the use of psychedelics in modern treatment remains controversial, and past research methodologies have notable limitations, the hypothesis of their effectiveness in mental disorders should not be entirely dismissed.

Modern research into psychedelics resumed in the 1990s in Germany [10], the United States [11], and Switzerland [12]. Since then, more than a dozen studies have been conducted, including but not limited to investigations into the safety and tolerability of psilocybin in obsessive-compulsive disorder (OCD), the use of psilocybin and LSD to alleviate psychological distress associated with terminal illnesses, psilocybin in tobacco and alcohol addiction, and the effects of ayahuasca and psilocybin in major depressive disorder. A significant drawback of these studies is their failure to meet modern methodological standards, mainly due to limited sample sizes and a lack of conclusive evidence regarding their effectiveness [1].

The purpose of this study is to critically examine and synthesize existing research from the past 10 years regarding the potential use of psychedelics in psychotherapy, with a particular focus on evaluating their therapeutic efficacy, safety profiles, and underlying mechanisms of action. By reviewing clinical and preclinical studies, this work aims to provide a comprehensive understanding of how psychedelics can contribute to the treatment of various psychological disorders, as well as the challenges and opportunities involved in integrating these substances into psychotherapeutic practices.

Methodology

OVERVIEW OF PSYCHEDELIC SUBSTANCES:

Psychedelics, like antidepressants, influence serotonin transmission, among other mechanisms. Serotonin reuptake inhibitors (SSRIs), in addition to their primary action on the serotonin transporter, exert effects on various receptors, including the enhancement of postsynaptic 5-HT1A transmission. This mechanism is thought to reduce stress, impulsivity, aggression, and anxiety, while also enhancing resilience and mitigating emotional shallowness, ultimately leading to improved mood. In contrast, psychedelics achieve mood improvement through agonism at 5-HT2A receptors, which reduces rigidity in thinking and increases sensitivity to environmental stimuli [1].

HALLUCINOGENS: LSD AND PSILOCYBIN:

The prototype of a substance with hallucinogenic properties is psilocybin (4-diphosphoryloxy-N,N-dimethyltryptamine), a compound derived from hallucinogenic mushrooms. Psilocybin functions as both an active ingredient and a prodrug for another hallucinogen, psilocin. A defining characteristic of hallucinogens is their agonism at the 5-HT2A receptor. This concept is further supported by evidence showing that the effects of hallucinogens in humans can be reversed by substances acting as 5-HT2A receptor antagonists, but not by D2 receptor antagonists [3]. The use of hallucinogens is associated with the rapid development of tolerance, a phenomenon known as tachyphylaxis, which results from the downregulation of the 5-HT2A receptor. For instance, daily use of LSD leads to a complete loss of sensitivity to its effects by the fourth day of use [15].

LSD is the most extensively studied of the substances discussed. It was first synthesized in 1938 by Swiss chemist Albert Hofmann in the laboratories of the Sandoz company. Early research focused on its potential use in the treatment of neuroses, alcohol addiction, and psychosomatic disorders [8]. However, this research came to an end in the mid-1960s. In 1965, Sandoz ceased the production of LSD, and in 1966, the use of all hallucinogens was banned in the United States. By 1970, psilocybin and LSD were added to the list of controlled substances [1]. The research was discontinued due to the increasing recreational use of hallucinogens and their political consequences. The use of LSD and marijuana within the hippie subculture, which was protesting the Vietnam War, raised concerns among U.S. federal and state authorities. The anti-war stance and rejection of conventional social norms were viewed as the result of psychoactive substances that altered the minds of young people [14]. The state induced by hallucinogen intoxication is often referred to as a “trip” and is associated with changes in sensory perception. Despite the term, hallucinogens often do not induce true hallucinations but rather illusions – distortions of perceived reality.

Hallucinogens, particularly LSD, are sometimes referred to as psychosis-mimicking substances (psychomimetics), although it is well-established that stimulants induce similar symptoms to a much greater extent. Hallucinogens, on the other hand, in addition to inducing visual illusions, can cause visual metamorphopsia (macropsias and micropsias), mood swings, a subjective sense of time distortion, synesthesia, enhanced auditory perception, and depersonalization and derealization [3]. LSD, in addition to its 5-HT2A receptor agonist effect, shows agonism at the 5-HT2C receptor, while psilocybin acts as an agonist at the 5-HT1A receptor. Both substances are also thought to enhance glutamatergic transmission, although this mechanism is not fully understood [2]. A study discussed the use of LSD in treating anxiety associated with terminal illnesses, but given its receptor profile, this substance could also be used in the treatment of mood disorders [8]. Psilocybin, unlike LSD, is a naturally occurring substance found in mushrooms of the genus Psilocybe [15]. Its use is associated with a lower addictive potential than is ketamine [16]. Research shows that its use results in a diminished ability to suppress or ignore sensory stimuli [17].

One of the proposed effects of hallucinogens on the brain is the disruption of the cortico-striatum-thalamocortical pathway, which plays a key role in conscious activity and the filtering of sensory information reaching the cerebral cortex. Impaired filtering, inhibition, and suppression of exteroceptive and interoceptive stimuli can result in sensory overload and a breakdown of cognitive integrity. This, in turn, leads to perceptual disturbances and alterations in ego functioning [2]. Another unique property of hallucinogens is their ability to induce flashbacks – spontaneous recurrences of experiences from intoxication episodes, lasting from a few seconds to several hours, occurring without subsequent substance use. One hypothesis explaining the occurrence of flashbacks involves emotional conditioning stored in the amygdala. Under the influence of an inert stimulus resembling one present during intoxication, the memory is thought to be reactivated. This mechanism is similar to the reliving of memories observed in post-traumatic stress disorder (PTSD), which has led to contemporary caution regarding the use of hallucinogens or psychedelics in PTSD treatment [3]. Hallucinogens are a group of substances that have long been associated with great therapeutic potential. Some researchers once suggested that they could become to psychiatry what the telescope is to astronomy or the microscope to biology [2]. Future research will determine whether these past predictions hold true and whether the use of hallucinogens in treatment will indeed bring the anticipated revolution or pose a threat.

3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA):

The prototypical empathogen is MDMA. The effects of its use include feelings of connectedness, unity, kinship, and emotional openness, collectively described as empathy. MDMA is a synthetic amphetamine derivative that exhibits greater selectivity for the serotonin transporter than for the dopamine transporter or norepinephrine transporter, than does amphetamine. Within the synapse, MDMA likely acts similarly to hallucinogens, including agonism at the 5-HT2A receptor [3]. Historically, MDMA was first synthesized in 1912 by Merck, with the earliest reports of its use in psychotherapy emerging in the early 1970s [13].

The recreational use of MDMA gained popularity in the early 1980s, particularly within the rave subculture, when participants consumed the substance in the form of “Ecstasy” pills during club events. MDMA is also colloquially referred to as “Molly”, a term likely derived from “molecule”. The use of MDMA at late-night parties, often accompanied by prolonged dancing in enclosed spaces, was associated with dehydration, hyperthermia, and, in some cases, fatalities. These adverse outcomes led to the inclusion of MDMA on the list of banned substances, in 1985 [3].

Despite its similarities to hallucinogens, MDMA is distinguished by its chemical structure and exhibits a more pronounced stimulant-like effect. It produces a “prosocial” effect by reducing reactivity to negative emotional stimuli. Additionally, MDMA use enhances the desire for socialization and closeness with others, an effect that supports both the therapeutic and recreational applications [18]. This prosocial effect is central to MDMA’s most extensively studied application: psychotherapy for PTSD. By fostering emotional openness, MDMA facilitates the exploration of negative emotions and beliefs, such as traumatic memories. Interestingly, other stimulants have demonstrated similar prosocial effects and were historically considered for use in trauma-focused psychotherapy [19]. The current model of PTSD pathophysiology suggests heightened and dysregulated amygdala activity in response to trauma, combined with insufficient inhibition from the ventromedial prefrontal cortex. MDMA appears to counteract these effects by increasing ventromedial prefrontal cortex activity and reducing amygdala activity, potentially addressing some of the neurobiological mechanisms underlying PTSD [20]. In addition, MDMA use increases oxytocin secretion (Wolfson et al), which can contribute to improving the therapeutic alliance in patients undergoing psychotherapy. The direct effects of MDMA include euphoria, reduced general and social anxiety, enhanced emotional perception and expression, increased self-reflection, decreased defensive attitudes, and a reduction in social anxiety. MDMA also promotes prosocial behaviors, such as a willingness to engage in physical touch and hugging, as well as heightened self-esteem and self-acceptance. These effects can lead to a reduction in emotional avoidance, an increased tolerance for processing difficult emotions (the “window of tolerance”), an enhanced ability to recall traumatic events, and facilitation of cognitive restructuring [19]. Beyond its application in PTSD, MDMA has shown potential for treating social anxiety [20] and alcohol addiction [21].

DISSOCIATIVES:

Dissociatives are NMDA receptor antagonists and include ketamine and PCP [3]. These substances were originally developed as anesthetics, as they induce a dissociative state characterized by catalepsy, amnesia, and analgesia. During this state, patients experience perceptual disturbances and a sense of detachment (dissociation) from their surroundings. This dissociative state can also be associated with sensory deprivation, as well as feelings of being in a dreamlike or trance-like condition. At higher doses, both substances cause sedation. Upon awakening, PCP induces a strong psychotomimetic effect, unlike ketamine, which does not produce similar effects [3].

Ketamine has been successfully used as an anesthetic and analgesic, with fewer adverse effects than its parent compound [3]. In low doses, ketamine is sometimes used as a recreational club drug, commonly referred to as “Special K”. In this context, it resembles other hallucinogens; however, unlike classic hallucinogens, it additionally induces dissociative symptoms, including depersonalization and derealization [3].

The first reports on the use of ketamine in psychiatry date back to 1973 (Khorramzadeh and Lofty). The earliest accounts of its potential antidepressant effects appeared in 1974 in Argentina (Fontana). Russian studies later explored its possible role in the treatment of alcohol addiction [22].

Since the late 1990s, researchers have investigated ketamine’s antidepressant properties while attempting to minimize its psychoactive effects, particularly dissociation, which is generally considered an undesirable adverse effect. The most extensively studied patient population consists of individuals with treatment-resistant depression, defined as those who have not responded to at least 2 conventional antidepressants [23]. As a result, the ketamine enantiomer esketamine has become the only psychedelic-like substance currently approved by the FDA for the treatment of treatment-resistant depression [24]. However, its efficacy and long-term safety remain subjects of ongoing debate and research.

Additionally, ketamine has been explored as a potential adjunct in addiction therapy, with some hypotheses suggesting that its effects on prefrontal cortical plasticity can play a role [3]. Nevertheless, the clinical significance of these findings remains uncertain. The use of ketamine in psychotherapy is sometimes associated with transient psychological effects, such as a dose-dependent reduction in negative emotional states. At lower doses, ketamine has been reported to induce a trance-like state that can facilitate communication and reduce the fear associated with recalling difficult memories, potentially leading to a temporary decrease in depressive and obsessive thoughts. At higher doses, however, it can produce a profound dissociative state, characterized by a diminished awareness of one’s body and surroundings, the therapeutic value of which remains controversial [23].

AYAHUASCA AND DIMETHYLTRYPTAMINE:

Ayahuasca, a traditional South American decoction, is commonly prepared from the vine Banisteriopsis caapi, which contains beta-carboline alkaloids, and the shrub Psychotria viridis, which supplies the hallucinogenic compound N,N-dimethyltryptamine (DMT). Historically, it has been used by Amazonian indigenous populations for cultural and healing purposes, particularly in spiritual contexts. Over time, interest in ayahuasca has significantly expanded, not only for religious ceremonies but also for recreational use. The substance itself acts as 5-HT2A receptor agonist [25]. The acute effects of ayahuasca typically begin about 40 minutes after administration and gradually subside over approximately 4 hours. During this time, individuals often report heightened self-confidence, a renewed perspective on personal conflicts, and the ability to confront profound personal truths [26].

Clinical trials investigating ayahuasca have been conducted but remain limited in scope. Several randomized controlled trials have produced promising results, although they necessitate further analysis with larger patient cohorts. A recent systematic review and meta-analysis [27] examined the therapeutic effects of psychedelics, including psilocybin, LSD, and ayahuasca, on depressive symptoms in clinical settings. The meta-analysis, which included 7 studies (n=223), demonstrated significant reductions in depressive symptoms at 1 day, 1 week, and 3 to 5 weeks after treatment. These findings align with the broader conclusions of the systematic review. The results suggest that psychedelics, when combined with psychological support, can offer short- and long-term benefits for patients with depression. However, despite these promising outcomes, important limitations remain. These include small sample sizes, reliance on cross-over study designs for follow-up, and the need for graphical data extraction in certain instances. As a result, the authors emphasize the necessity for further large-scale, rigorously designed randomized controlled trials to confirm these findings and establish definitive conclusions. Moreover, research on ayahuasca has been extended to address a major public health concern – suicide. According to the World Health Organization, more than 720 000 people die by suicide each year, highlighting an urgent need for innovative solutions [28]. A double-blind, parallel-arm, randomized placebo-controlled trial investigated the effects of ayahuasca on suicidality in individuals with treatment-resistant depression. While the results did not reach statistical significance, the study showed a potential trend toward reductions in suicidality, with medium between-group and large within-group effect sizes favoring ayahuasca over placebo across all assessed time points. From a clinical perspective, the findings underscore the importance of exploring novel interventions for suicidality, particularly in treatment-resistant populations. Psychedelics, like ayahuasca, can offer rapid therapeutic effects within psychotherapy or sustained benefits following a single dose. However, it is important to note that suicidal ideation can occur independently of depression, necessitating further research to elucidate the specific impact of ayahuasca on suicidality beyond depressive contexts.

The therapeutic outcomes of ayahuasca are strongly influenced by psychological support and contextual factors during its administration. Structured approaches, such as adherence to dietary protocols and attention to set and setting, are crucial for mitigating risks and enhancing the therapeutic experience. Additionally, there is a pressing need to establish safety measures addressing potential interactions between ayahuasca and prescribed medications, such as SSRIs or dopaminergic stimulants, which can increase the risk of serotonin syndrome. The use of ayahuasca is contraindicated in patients with uncontrolled hypertension, cardiovascular conditions, and liver or gastrointestinal diseases. Furthermore, certain psychiatric conditions, such as bipolar disorder or psychosis, can pose increased risks, including manic episodes or psychotic onset, and thus warrant caution [29]. As with other psychedelics, ayahuasca can occasionally induce dysphoric reactions accompanied by heightened anxiety [30].

Another noteworthy substance is DMT, which, like other psychedelics, acts as a 5-HT2A receptor agonist and, aside from that, activates the 5-HT1A and 5-HT2C receptors [26]. It induces transient disturbances in consciousness, characterized by vivid and complex visual hallucinations, as well as a range of somatosensory, affective, and cognitive effects [31]. Some studies suggest that DMT-induced states share similarities with near-death experiences [32], and in some cases, these experiences can lead to lasting shifts in beliefs about reality and consciousness [33].

When taken orally, DMT is metabolized in the digestive system by monoamine oxidase (MAO), which converts it into an inactive form. As a result, DMT is typically consumed in combination with MAO inhibitors, such as those found in the traditional Amazonian brew, ayahuasca. Ayahuasca contains DMT and β-carboline alkaloids, which inhibit MAO, thereby allowing DMT to remain active and produce lasting effects. In this form, the changes in consciousness typically last between 4 and 6 hours. Alternatively, DMT can be administered through smoking or parenteral routes, including intravenous or intramuscular injections, which produce more immediate effects [29]. To date, a single-blind, placebo-controlled study with a systematic protocol for intravenous DMT administration has been conducted with a group of 11 volunteers [29]. Additionally, a naturalistic, placebo-controlled study was conducted with 30 participants at ayahuasca retreats in the Netherlands, Spain, and Germany, exploring the effects of the substance on symptoms of depression and anxiety [34]. Another double-blind, randomized, placebo-controlled study investigated the effects of ayahuasca in a group of 29 Brazilian patients with drug-resistant depression, showing promising results [35].

Due to the insufficient quantity and methodological limitations of the available research on DMT, and ayahuasca, it is not yet possible to draw definitive conclusions regarding their therapeutic potential. As such, the use of DMT in psychotherapy was not included for further analysis in this study. Table 1 presents the receptor mechanisms underlying the action of the described psychedelics.

Clinical Applications

DEPRESSION THERAPY:

Most studies included in this systematic review on the treatment of depression with psychedelic-assisted psychotherapy focus on psilocybin. In a randomized clinical trial investigating drug-resistant depression in patients with major depressive disorder, bipolar II disorder, and substance use disorders, Rosenblat et al [36] (n=30) found that patients who received psilocybin exhibited a significant reduction in depression severity, compared with a control group. In another study, involving patients with a diagnosis of curable or incurable cancer and co-occurring severe depression, patients who underwent psilocybin-assisted psychotherapy (n=30) demonstrated a marked decrease in depressive symptoms. Notably, this study used group therapy, a form of therapy that is time-efficient and offers the added benefit of being conducted in a group setting, in which participants share similar challenges. This structure can enhance therapeutic outcomes and improve the efficiency and accessibility of treatment [37]. The efficacy of psilocybin-assisted psychotherapy has also been demonstrated in patients with severe depression (n=27) who were not receiving antidepressant treatment and had no history of psychotic disorders, significant suicide attempts, or prior hospitalization. However, a key limitation of this study, which was acknowledged by the authors, was that the psychotherapy sessions were led by practitioners with varying levels of experience and education, including some without formal clinical training [16].

Studies provide some evidence that psilocybin-assisted psychotherapy can have long-term therapeutic effects. An open-label trial conducted by Carhart-Harris et al, which included patients (n=20) with chronic, unipolar, drug-resistant severe depression, demonstrated good treatment tolerability and substantial symptomatic improvement after just 2 sessions of psilocybin treatment, with positive outcomes persisting for 6 months after treatment [38]. Similarly, a randomized trial by Gukasyan et al, involving individuals with moderate to severe unipolar depression (n=27), found that the antidepressant effects of psilocybin-assisted psychotherapy could last for at least 12 months following the therapeutic intervention [39].

Despite the still limited number of studies, ketamine-assisted psychotherapy has attracted significant interest among researchers for the treatment of drug-resistant depression. The only study included in this review, a randomized proof-of-concept trial involving individuals with a diagnosis of drug-resistant depression (n=42), demonstrated the preliminary utility of combining cognitive behavioral therapy (CBT) with ketamine treatment in this patient population [40].

In summary, psilocybin-assisted psychotherapy has shown some promising results in treating depression, particularly in drug-resistant cases, with significant symptom reduction lasting up to 12 months. Studies, including those by Rosenblat et al [36] and Agrawal et al [37], have reported positive outcomes in cancer-related depression and general depression. Psilocybin appears to work by modulating serotonin receptors, disrupting negative neural patterns. Long-term benefits have been confirmed in studies like that by Carhart-Harris et al [36], in which improvements persisted for up to 6 months. Despite encouraging results, limitations such as small sample sizes and variable therapist experience warrant further research to confirm its efficacy.

PTSD THERAPY:

Psychedelic substances currently used in the treatment of PTSD include classic serotonergic psychedelics, such as psilocybin and LSD, and psychoactive compounds, such as MDMA and ketamine. These substances are administered in conjunction with established psychotherapeutic approaches from traditional trauma therapy [41] or alongside therapeutic models specifically designed for psychedelic-assisted treatment [42]. In the treatment of PTSD, strongly recommended psychotherapeutic interventions include CBT, cognitive processing therapy, cognitive therapy, and prolonged exposure. Conditioned recommendations include brief eclectic psychotherapy, eye movement desensitization and reprocessing, exposure narrative therapy, and psychodynamic psychotherapy, as well as interpersonal psychotherapy. Guidelines for the specificity and conduct of MDMA-assisted psychotherapy in the treatment of PTSD include requirements regarding the preparation and competence of the psychotherapist, techniques supporting the therapeutic process, session structure at each stage of treatment, and the conditions under which sessions should take place. It is recommended that psychotherapists possess expertise in trauma-informed therapeutic methods, as well as competence in using breathing exercises, music, mindfulness-based techniques, and somatic interventions [42].

Research on MDMA-assisted psychotherapy for PTSD has garnered considerable interest and offers promising prospects for effectively aiding patients. A randomized trial by Mithoefer et al [43] (n=26) found that patients who received 75 or 125 mg of MDMA, in combination with supportive psychotherapy, exhibited a significant reduction in PTSD symptoms, compared with the group receiving a 30-mg dose [43]. Similarly, the study by Ot’alora et al [44] (n=28), which compared the efficacy of MDMA doses of 100 and 125 mg with a low dose of 40 mg, found that the higher-dose group experienced the greatest reduction in PTSD symptoms, with a significant number of participants maintaining lower symptom levels at 12 months, and 76% of participants no longer meeting the diagnostic criteria for PTSD [44]. A study by van der Kolk et al [45] (n=90) demonstrated that patients receiving MDMA-assisted psychotherapy showed significantly greater improvement in alexithymia than did a control group receiving a placebo. These patients also developed higher levels of self-awareness and self-compassion, which aligns with studies in non-PTSD patients showing that MDMA facilitates openness, interpersonal connection, and enhances positive emotional experiences while reducing negative evaluations of distressing memories [45]. The number of studies on psilocybin-assisted psychotherapy for the treatment of PTSD is limited, with most existing research consisting of single studies. One such study, an open-label trial involving survivors of AIDS, found that psilocybin-assisted psychotherapy helped reduce symptoms of PTSD, attachment anxiety, and demoralization [46]. Also, Khan et al discuss several studies suggesting the effectiveness of this form of treatment in confronting traumatic memories, reducing emotional avoidance, depression, anxiety, pessimism, and social isolation, while simultaneously increasing acceptance, self-compassion, and the capacity to forgive perpetrators of violence [41].

Despite the promising potential of ketamine and LSD in combination with psychotherapy, research in this area remains insufficient. Available studies primarily focus on the effects of these substances alone, without incorporating psychotherapeutic interventions [47].

Psilocybin-assisted psychotherapy has shown potential in treating PTSD, with studies demonstrating its effectiveness in reducing symptoms such as attachment anxiety, demoralization, and emotional avoidance. It has also been linked to improvements in self-compassion, acceptance, and the ability to confront traumatic memories. However, the research in this area is limited, with most studies being individual trials rather than large-scale investigations. While ketamine and LSD also hold promise for PTSD treatment, there is insufficient research on their combined use with psychotherapy, as most studies focus only on the effects of the substances themselves. More comprehensive studies are needed to assess the full therapeutic potential of these substances in treating PTSD.

THERAPY OF ANXIETY DISORDERS:

Research on the treatment of anxiety disorders with psychedelics remains limited. This review includes studies using LSD and MDMA in psychotherapeutic interventions for anxiety disorders. A pilot randomized, double-blind, placebo-controlled study involving patients (n=12) experiencing anxiety related to life-threatening illnesses demonstrated that LSD, when administered in a safe, physician-supervised psychotherapeutic setting, significantly reduced anxiety levels [8]. Another study involving participants (n=39), both with and without terminal illnesses, found that LSD-assisted psychotherapy led to a reduction in neuroticism and an increase in extroversion, with these effects persisting for up to 1 year [48]. In studies investigating MDMA-assisted psychotherapy, a trial involving patients (n=12) with autism spectrum disorder experiencing social anxiety reported significant reductions in anxiety following treatment, suggesting that MDMA can support emotional processing and social engagement [20].

Research on the use of psychedelics for anxiety disorders is still in its early stages but demonstrates promising results. LSD-assisted psychotherapy has shown potential for reducing anxiety and improving personality traits in patients with both a terminal and non-terminal illness, with lasting effects. Similarly, MDMA therapy has proven effective in reducing social anxiety in individuals with autism. However, larger-scale studies are needed to confirm these findings and establish standardized treatment protocols.

ADDICTION THERAPY:

Research on psychedelic-assisted psychotherapy offers promising avenues for the treatment of substance use disorders, although the precise mechanisms underlying its efficacy are not always fully understood. A study on psilocybin-assisted psychotherapy for nicotine dependence in healthy individuals (n=15) highlighted the significance of the mystical experience induced by the psychedelic, rather than the direct pharmacological effects of the substance or the psychotherapeutic process itself. In this trial, 2 or 3 doses of psilocybin combined with CBT led to 80% of participants achieving smoking cessation, with success correlated to higher scores on measures of psilocybin-induced mystical experiences [49].

Ketamine-assisted psychotherapy has also demonstrated efficacy in the context of heroin addiction treatment. In a study involving detoxified patients with heroin dependence (n=59), participants received either a single ketamine-assisted therapy session prior to discharge or additional sessions of ketamine-assisted psychotherapy combined with addiction counseling (n=25). The comparison group (n=27) underwent addiction counseling alone. After 1 year, 50% of participants in the ketamine-assisted group remained abstinent, compared with 22.2% in the counseling-only group [50].

Psychedelic-assisted psychotherapy demonstrates preliminary potential in addressing substance use disorders, but its efficacy and safety require further validation. Psilocybin therapy, while associated with high smoking cessation rates, relies heavily on subjective mystical experiences, raising concerns about reproducibility and the individual variability of such effects. Ketamine-assisted psychotherapy has shown promise in enhancing abstinence rates among individuals with heroin addiction; however, the study sample sizes are small, and long-term safety and generalizability remain uncertain. Importantly, these interventions should be approached cautiously due to potential risks, including the possibility of psychological distress, adverse reactions, or misuse of the substances. Overall, while these initial findings are encouraging, they highlight the need for larger, methodologically rigorous trials to assess both the efficacy and safety of psychedelic-assisted psychotherapy in addiction treatment.

THERAPY OF OCD:

One of the studies we reviewed examined the application of ketamine-assisted psychotherapy in treating OCD. Rodriguez et al [51] investigated the administration of ketamine in combination with a brief course of 10 cognitive-behavioral therapy (CBT) sessions designed to extend the effects of the psychedelic and sustain symptom improvement for up to 2 weeks. The study leveraged ketamine’s potential to enhance neural plasticity and facilitate the extinction of compulsive behaviors. Results from the study group (n=8) demonstrated a rapid reduction in OCD symptoms following ketamine administration and highlighted the supportive role of psychotherapeutic interventions in maintaining these effects. However, the absence of randomization significantly limits the reliability and generalizability of the findings [52].

Preliminary research on ketamine-assisted psychotherapy for OCD suggests promising results, with evidence pointing to rapid symptom reduction and potential enhancement of therapeutic effects when combined with CBT. The findings underscore ketamine’s potential to promote neural plasticity, offering a novel approach to address treatment-resistant OCD. However, the small sample size and lack of randomization in the study raise critical concerns about the robustness and applicability of the results. Safety considerations, including ketamine’s potential for misuse or adverse effects, must also be thoroughly addressed. These findings, while encouraging, remain preliminary and highlight the need for rigorously designed studies to confirm the efficacy and safety of ketamine-assisted psychotherapy in OCD treatment.

Conditions for Conducting the Session

A fundamental element in conducting sessions as part of psychedelic-assisted psychotherapy is the creation of a safe and supportive environment by the therapeutic team. Experimental sessions must occur in settings that minimize external disturbances, such as noise or other distracting stimuli, ensuring an atmosphere conducive to introspection and emotional safety [8]. The provision of basic needs, such as access to water, snacks, and artistic tools for non-verbal expression, is essential for patient comfort and well-being [42]. The environment should be aesthetically pleasing, equipped with comfortable seating or couches, allowing patients to focus on their internal experiences. Additional aids, such as music, headphones, and eye masks, can further facilitate introspection and engagement with emerging mental and physical sensations [16].

From the psychotherapeutic perspective, the therapeutic alliance – defined as the relationship of trust and collaboration between therapist and patient – plays a central role in creating a secure therapeutic context [52]. This bond supports the reduction of anxiety related to challenging memories, enhances self-compassion, and fosters openness to exploring thoughts, feelings, and experiences. Studies indicate that a strong therapeutic alliance significantly contributes to treatment outcomes in psychedelic-assisted psychotherapy. For instance, research on psilocybin-assisted psychotherapy for depression found that a robust therapeutic alliance shortly after treatment predicted sustained improvements in depressive symptoms over follow-up periods of up to 1 year [53]. To foster this alliance, therapists are encouraged to adopt a neutral, mindful, and open stance, approaching the patient’s experiences with curiosity and respect. Such an approach builds trust and safety, which are vital for supporting the patient’s internal processes and fostering the psychological coherence conducive to self-healing [44].

Although early findings underscore the importance of a safe environment and a strong therapeutic alliance in psychedelic-assisted psychotherapy, the method remains experimental. Its therapeutic efficacy, long-term risks, and appropriate safety protocols are not yet fully understood, necessitating further research. Standardized protocols, including clear inclusion criteria and contraindications, are critical to minimize risks and ensure patient safety. Until these gaps are addressed, psychedelic-assisted psychotherapy cannot be regarded as an established treatment method but should be strictly confined to research contexts.

Summary of Current Knowledge on the Course of Psychedelic Psychotherapy

At the initial stage of the therapeutic application of psychedelics in treating mental disorders, psychoanalytic and psychodynamic approaches – focused on unconscious processes and accessing psychic depth – predominated. As Grof noted, “The phenomenology of the psychodynamic experiences in LSD sessions is to a large extent in agreement with the basic concepts of classical psychoanalysis… Observations from LSD psychotherapy could be considered laboratory proof of the basic Freudian premises” [54,55]. However, despite the potential of psychoanalytically derived approaches, their role has diminished over time [56]. This decline coincided with the development of structured psychotherapeutic paradigms grounded in biological sciences, which now attract greater interest from researchers [55].

Regardless of the substance administered, psychedelic-assisted psychotherapy follows 3 core stages: (1) preparation, (2) administration of the psychedelic substance, and (3) integration. The preparatory phase involves gathering patient information, establishing a therapeutic alliance, and preparing participants for the experimental session. During the substance administration phase, the psychotherapist provides support in navigating difficult emotions, processing traumatic memories, and reframing their meaning. This phase is conducted in safe and controlled settings, with the therapist encouraging emotional exploration and reflection. The integration stage, conducted in the following weeks without medication, focuses on helping patients understand and incorporate their psychedelic experiences into daily life. This process aims to foster intrapsychic insight, symptom reduction, and improved functioning [38,42,56,57].

Yaden et al [55] suggest that this structured approach aligns closely with CBT models, including derivatives such as dialectical behavioral therapy (DBT) and acceptance and commitment therapy (ACT). These approaches offer established frameworks for addressing dysfunctional cognitive schemas, regulating emotions, and enhancing psychological flexibility [58,59]. For instance, during preparation, therapists can use psychoeducation, self-monitoring (CBT), pre-treatment strategies, and skills training (DBT). During the substance administration phase, techniques such as mindfulness, distress tolerance (DBT), cognitive restructuring (CBT), and present-moment awareness (ACT) are utilized. Integration can include teaching adaptive behaviors, assigning behavioral experiments (CBT), cultivating a dialectical stance (DBT), and fostering committed action and self-as-context (ACT). These methods aim to enhance therapeutic outcomes while adhering to evidence-based principles [55].

Other psychotherapeutic modalities used in psychedelic treatment include interpersonal psychotherapy, Frankl’s logotherapy, and mindfulness-based cognitive therapy [60]. A growing number of guidelines provide theoretical assumptions, practical recommendations, and clinical examples to assist specialists in safely conducting psychedelic-assisted psychotherapy [42,60,61].

While structured psychotherapeutic models offer promising frameworks for integrating psychedelics into therapy, these approaches remain investigational. The therapeutic context of psychedelic-assisted interventions requires stringent safety protocols, robust inclusion criteria, and a comprehensive understanding of contraindications to protect patients from potential risks. The current evidence is preliminary, and the long-term effects, risks, and critical factors influencing outcomes remain largely unexplored. Consequently, psychedelic-assisted psychotherapy should not yet be regarded as an established therapeutic method and must remain confined to rigorously controlled research settings.

Safety and Ethical Considerations

Psychiatrists remain skeptical of psychedelic-assisted psychotherapy, often expressing caution in offering it to patients [62]. Addressing this skepticism requires further studies designed with rigorous methodology, including multicenter trials with diverse patient populations. One potential advantage of psychedelics in psychiatric treatment is their novel mechanism of action, which can provide solutions in cases in which conventional treatments have failed. Another notable benefit is the rapid onset of therapeutic effects. For example, while SSRIs often require several weeks to show benefits, esketamine can produce improvements within a day [63]. Additionally, due to their probable impact on neuroplasticity, psychedelics often result in long-lasting therapeutic effects.

The use of psychedelics is associated with relatively low risks of physical adverse effects. However, their potential dangers should not be overlooked. These include the risk of addiction, or addictive behaviors, unpredictable psychological effects, and the potential to induce psychosis-like experiences. Case reports also suggest that psychedelics could exacerbate mental health conditions, such as triggering PTSD in some individuals [64]. Given the limited number of randomized, double-blind trials, it remains challenging to definitively assess the safety and efficacy of psychedelics in psychiatry. Further research is needed to balance the potential benefits and risks of these substances. It is crucial to recognize that psychedelics are not standalone treatments but tools that must be integrated into broader therapeutic frameworks.

Psychedelics represent a promising but experimental avenue in psychiatric care. While early findings suggest rapid and sustained benefits in certain mental health conditions, substantial uncertainties about their safety, addiction potential, and psychological risks persist. Establishing rigorous research protocols and exploring their use in combination with established therapies are critical next steps. Psychedelics should currently remain confined to controlled experimental settings, as their benefits and risks are not yet fully understood, and their application in psychiatry demands a cautious and evidence-based approach. The potential clinical applications of the described substances in psychedelic-assisted psychotherapy are summarized in Table 2. It is important to recognize several limitations that can affect the overall findings. First, the variability in study designs across trials must be acknowledged, as differences in methodology, sample characteristics, and intervention protocols can hinder the comparability of results. This variability can contribute to discrepancies in the reported effectiveness of psychedelic substances in treating mental health conditions.

Additionally, potential biases, such as selection bias, reporting bias, and confirmation bias, need to be considered. These biases can significantly influence the validity of study outcomes, skewing the results and potentially leading to overestimation of the therapeutic benefits of psychedelics. For instance, studies with small sample sizes or lack of randomization can be more prone to such biases, affecting the strength and reliability of the conclusions drawn.

Furthermore, the generalizability of the findings remains a critical concern. The applicability of results to diverse populations – especially those with different demographic characteristics, comorbidities, or cultural backgrounds – should be carefully examined. As most trials to date have involved relatively homogenous study groups, it is unclear how these findings would translate to broader, more varied patient populations.

Acknowledging these limitations is essential for a more comprehensive understanding of the state of research on psychedelic-assisted psychotherapy. By doing so, we aim in this review to provide a balanced perspective on both the potential and the challenges of integrating psychedelics into clinical practice.

Key Conclusions on Psychedelic-Assisted Psychotherapy and Navigating the Future of Psychedelic-Assisted Therapy: Research, Ethics, and Clinical Practice

EXPERIMENTAL NATURE OF THE METHOD:

Psychedelic-assisted psychotherapy remains an experimental approach. While preliminary studies suggest potential therapeutic benefits in treating conditions like depression, PTSD, OCD, and substance use disorders, the lack of a sufficient number of randomized, controlled, and multicenter trials makes it difficult to definitively assess its efficacy and safety.

IMPORTANCE OF PATIENT SAFETY:

Ensuring patient safety is paramount in the use of psychedelics. Implementing strict protocols for inclusion and exclusion criteria is necessary, alongside the establishment of comprehensive guidelines to mitigate risks and manage adverse effects.

UNCERTAIN RISK FACTORS:

Key risk factors and long-term consequences of psychedelic-assisted therapy are not yet fully understood. The unpredictable nature of psychedelic experiences and potential adverse effects, such as psychosis-like symptoms or even post-traumatic stress induced by hallucinogens, underscore the need for caution.

INTEGRATION WITH OTHER THERAPIES:

Psychedelics should not be viewed as standalone treatments but rather as tools to be integrated into broader psychotherapeutic frameworks, such as CBT or mindfulness-based approaches, to enhance treatment outcomes.

POTENTIAL FOR UNIQUE MECHANISMS OF ACTION:

The distinctive mechanisms of action of psychedelics, particularly their ability to influence neuroplasticity, suggest they could fill treatment gaps for patients who do not respond to conventional therapies. However, this potential requires further validation through rigorous research.

ETHICAL AND CLINICAL CHALLENGES:

The therapeutic use of psychedelics raises ethical and clinical challenges, including ensuring informed consent, understanding cultural implications, and addressing the stigma associated with these substances.

NEED FOR RIGOROUS RESEARCH:

Future research must prioritize high-quality studies with robust methodologies. This includes randomized, double-blind, placebo-controlled trials on diverse populations to generate reliable and generalizable findings.

THERAPEUTIC ALLIANCE AND SETTING:

The therapeutic alliance and controlled setting are critical components of psychedelic-assisted therapy. Safe and supportive environments, along with a strong therapist-patient relationship, significantly influence the therapeutic process and outcomes.

RAPID AND LONG-LASTING EFFECTS:

Some psychedelics, such as esketamine and psilocybin, have shown rapid therapeutic effects, often within hours or days, compared with conventional treatments like SSRIs. Additionally, their impact on neuroplasticity can contribute to sustained benefits.

CAUTIOUS OPTIMISM FOR FUTURE APPLICATIONS:

While early results are promising and suggest that psychedelics can play a transformative role in psychiatry, their use should be approached with cautious optimism. Comprehensive studies and well-defined clinical protocols are essential to ensure their safe and effective integration into mental health care.