Psychedelics as Reemerging Treatments for Anxiety Disorders: Possibilities and Challenges in a Nascent Field

Early uses of psychedelics were modeled on contemporary, psychoanalytically based understanding of psychiatric illness and focused on the perceived ability of psychedelic compounds to reduce ego defenses during psychotherapy (7). This model, known as psycholytic therapy, used repeated, low to moderate doses of psychedelics, usually lysergic acid diethylamide (LSD), during therapy sessions and sought to use the drug experience to enhance a psychodynamic understanding of patients’ symptoms (8). By the early 1960s, a radically different model began to be increasingly used, with a vastly different structure, approach, and conceptualization. Dubbed psychedelic therapy, or psychedelic-assisted psychotherapy, it drew heavily from the school of transpersonal psychology and was often deepened by drawing on quasi-religious or spiritual traditions (9, 10).

Psychedelic-assisted psychotherapy relied on a high degree of preparation with extensive therapy sessions leading up to a single, high-dose drug session, which was then followed by a series of integration therapy sessions in which the patient was encouraged to interpret what transpired during the psychedelic experience. The psychedelic session, presided over by a therapist at all times but with emphasis on the patient’s internal experience (nondirective), was augmented by the use of ensuring a calm environment and décor, often with the accompaniment of music and eyeshades to accentuate an internally focused experience (11). Special attention was paid to set (the mindset or expectations brought by the patient to the session) and setting (a comfortable, nonclinical environment) (11). This model has been largely retained today, and it has been utilized in some degree by nearly all clinical studies in the contemporary era. Although some protocols may embed psychedelic-assisted therapy sessions into preexisting structured psychological programs, such as programs based on cognitive-behavioral therapy or motivational therapy (12, 13), the drug-administering sessions usually retain this nondirective, psychedelic psychotherapy model.

The primary pharmacologic mechanism of all psychedelics is by way of agonist activity at the serotonin (5-HT) 2A receptor, and significant advancements have been made in the past decade in uncovering potential effects of this action. One of the most well-established and increasingly researched effects of psychedelics on the brain is in modulation of the default mode network (14), a network of the brain that normally becomes activated during mental time travel (15), self-reflection (16), and theory of mind (17). The default mode network is implicated in the pathogenesis of rumination in depression (18), and abnormal default mode network activity has been described in numerous psychiatric conditions, including substance use disorders (19), posttraumatic stress disorder (PTSD) (20), and various anxiety disorders; for a review, see Sylvester et al. (21). The acute effects of a psychedelic experience, particularly when conducted in a therapeutic setting, have also been shown in a variety of studies with 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca. These effects appear to be associated with durable alterations in personality characteristics, with decreases in neuroticism (22, 23), increases in openness to experience (22–25), and increases in extraversion (22). These findings, in addition to shining light on psychological mechanisms of change following psychedelic-assisted psychotherapy, are provocative because they suggest that contemporary conceptions of the stability of adult personality characteristics may be less durable than currently thought (26).

Among the psychedelics, MDMA is somewhat unique and deserves specific mention. MDMA acts primarily via release of the monoamines serotonin, norepinephrine, and dopamine; it also stimulates release of central neurohormones, including oxytocin and prolactin (27). MDMA produces positive affective and prosocial states (28) and has been found to modulate neural circuitry involved in emotion regulation and memory, including the amygdala and hippocampus (29). These findings have led to the suggestion that MDMA may exert its effects via altered trauma-related memory reconsolidation and fear extinction (30), thus making it perhaps uniquely suited for treatment of anxiety and stress-related disorders.

Although numerous psychedelic compounds are known to exert similar effects on the human brain, only a few have been researched in human studies in any significant fashion. Moreover, even fewer agents have been tested for potential clinical application, including MDMA, psilocybin, LSD, and dimethyltryptamine (DMT).

Taken together, evidence is accumulating to suggest that psychedelics, when provided in a structured setting, either as psychedelic-assisted psychotherapy or in a more traditional setting, such as an ayahuasca ceremony, hold vast potential for fundamentally shifting symptoms in a variety of anxiety disorders. Despite the current promising findings, nearly all studies conducted to date have focused largely on either PTSD or depression. Further research is clearly needed.

However, psychedelic research and medicine currently faces several issues concerning barriers to research, education of clinicians and other stakeholders, scalability, and cultural equity and social justice. First, psychedelics have a unique history that affects contemporary research efforts directly, via an anachronistic legal legacy, and indirectly, via associated attitudes and biases toward the substances among those in the medical community. Despite a thriving research scene and growing evidence to suggest the efficacy of psychedelics in the treatment of a variety of mental conditions, progress in psychedelic research was abruptly curtailed in the early 1970s when the federal government, due not to science but to a cultural backlash and moral panic, criminalized the agents as having no medical potential. This move plunged psychedelic research into 3 decades of quiescence and prohibition out of which the field is only beginning to recover.

The current wave of research on psychedelics, dubbed by some a “psychedelic renaissance” (74), may face similar issues of conscious and unconscious bias and stigma because of the past notoriety of these drugs, which is reinforced by their categorization by the DEA as schedule I compounds (i.e., having no possibility of therapeutic potential). In addition to perpetuating stigma against psychedelics, this designation also results in practical barriers to conducting clinical research with these agents that may be prohibitive (75, 76); these barriers stifle research endeavors at a time when novel therapeutics for anxiety disorders are critically needed. Although rigorously designed studies must be conducted before these treatments can judiciously be approved for widespread use, the medical and psychiatric community can and should do more to advocate for more sensible drug policy because it shapes and hamstrings efforts at carrying out this research in the first place.

Evidence suggests that this stigma may also perpetuate negative bias against psychedelics by psychiatrists and related clinicians themselves. Despite the increasing likelihood of approval of both psilocybin- and MDMA-assisted psychotherapy in the next 2–3 years by the FDA (5, 6), psychiatrists have reported a lack of education and knowledge about psychedelics’ potential clinical applications; moreover, surveys have revealed a dearth of didactic time in psychiatric training programs focused on this growing area (77). Similarly, psychiatrists and other medical specialists have reported concerns about potential hazards of psychedelics but overall have reported optimism in their potential uses for the future (77, 78).

Psychiatry training programs and psychiatry departments should implement curricula and programs to educate trainees and faculty alike on the current evidence base for psychedelics so that misinformation and stigma do not dominate perceptions of a treatment that will likely be legal and widely available in the coming years. Given the significant media attention, it is also likely that patients will be seeking these treatments before approval; thus, they will be using psychedelics in nonmedical settings with the goal of relieving psychiatric symptoms, including anxiety disorders. Psychiatrists should be prepared to answer questions from patients planning such quests; if not able to support the plan itself, they should nonetheless be willing and able to provide accurate information and harm reduction whenever possible.

Second, current models of psychedelic-assisted psychotherapy require extensive training of therapists (e.g., the only current certification for psychedelic therapy training in the United States, offered by the California Institute of Integral Studies [CIIS], requires 150 hours of training) (79); in addition, the therapeutic process itself includes multiple hours of therapy sessions, including preparatory and integration sessions before and after therapy, as well as long (≥8 hours) psychedelic therapy sessions themselves. Evidence certainly supports the need for adequate training of therapists who will work with these substances: psychedelics produce a complex, and often unpredictable, experience that can raise unique challenges for both the patient and the therapist (80). Because of putative concerns over adverse events occurring in the drug treatment sessions, many studies utilize protocols that allow only practitioners with advanced degrees (i.e., M.D. or Ph.D.) to act as psychedelic therapists. Thus, the current model requires substantial resources, many training hours, as well as specialized and costly personnel; these requirements may limit the scalability of such treatments after FDA approval occurs.

A similar issue is the lack of current training programs for psychedelic therapists; currently, only one fully operational training program (CIIS) exists in the United States outside of training for clinical trials (79). This lack of programs indicates that if and when FDA approval occurs, the field may be facing an inadequate supply of trained therapists available to meet the demand of these novel treatments, despite the increasing interest expressed by psychiatrists for specialized training in this area (B. Barnett et al., submitted manuscript, 2020). Furthermore, although the current model of psychedelic-assisted psychotherapy has been shown to be effective, it should not prevent future investigations into alternative therapeutic models. Further explorations have begun to assess whether psychedelic-assisted psychotherapy may enhance preexisting therapy programs, such as programs based on cognitive-behavioral therapy (39); however, more work is needed. For example, consideration of group therapy models, as practiced in both traditional settings and in some semistructured Western models (51), could lead to a significant reduction in cost and wider accessibility. Indeed, some steps have already been taken toward successful integration of group therapy with integrated psychedelic sessions (81) and even group psychedelic therapy (51).

Third, psychedelics have been utilized by indigenous peoples for thousands of years across every continent; in nearly all cases, the prohibition of these natural medicines was originally a central component of the cultural suppression imposed by European-Western colonialist conquests (82). Current drug approval is proceeding under a Western medical model that emphasizes these treatments as nothing more than medical interventions operating under a doctor-patient contract, devoid of further spiritual or community implications. Although this model is certainly in line with the mechanism for which drugs must be approved as medicines to treat specific illnesses, well-established, traditional uses of these compounds have strongly emphasized the importance of community, culture, and spirituality as critical pieces of the partaker’s recovery. As paradigm shifting as psychedelic-assisted psychotherapy may be, future work can and should consider the broader cultural and anthropological history of these agents; indeed, evidence from both waves of psychedelic research has strongly supported the fact that context is critical for maximal optimization of the impact of these compounds (11).

In similar fashion, numerous indigenous groups continue to practice healing using psychedelics (such as Santo Daime in Brazil and the Native American Church in the United States). As psychedelic compounds make their way through the U.S. medical regulatory system, the field must also consider the rights of other indigenous healers whose work with psychedelics may currently be jeopardized by persecution and criminalization. It can well be argued that the continued criminalization of these treatments by people who have thousands of years of experience using them as medicines is only the continued legacy of colonial and Western-centric suppression (82). Respecting the role of traditional healers and the history of cultural appropriation may also reduce the ongoing racial disparity in the field of psychedelic studies, in which the vast majority of participants and therapists have not been from racial-ethnic minority groups (83). As part of a broader cultural and political focus on inclusivity in medicine, psychedelic research, as a nascent arena, has an opportunity to establish itself as an inclusive and forward-thinking field from its (re)inception in the current wave of research. This foundation might have broader implications in addressing the disparities that continue to exist in clinical psychiatry and research (84, 85).

Pschedelics thus present unique opportunities in the study and treatment of anxiety disorders, and mental illness more broadly, at a time when existing treatment options are failing many patients and psychopharmacological research has otherwise slowed. As a time-limited treatment that produces significant and durable results, psychedelic-assisted psychotherapy would represent a paradigm shift in conventional treatment models within psychiatry. This fact alone inherently suggests that the field of psychiatry has a great deal of work ahead. Efforts to reform psychedelic drug policy at the federal level must be supported insofar as current policy acts as a major barrier to much-needed research. Educational programs to prepare psychiatrists and psychiatric trainees about these uniquely acting compounds must also be developed, including guidelines for treatment and therapist training.

Finally, as agents that have been used in traditional healing practices across the world for thousands of years, psychedelics have a unique history that sets them apart from any currently existing psychiatric treatment; this narrative shines more light on implications for Western-dominated conceptions of treatment versus healing, illness and disease, and inclusion versus exclusion. For the field to realize its maximum potential, psychiatrists and other medical specialists would do well to consider these possibilities now.