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The Ultimate Guide to Psilocybin Therapy

February 7, 2022

Unlike antidepressants, which require daily use, a variety of studies show that psilocybin therapy quickly and sustainably reduces depression and anxiety. These findings are stimulating paradigm shifts in psychiatric care. Instead of daily prescriptions, psilocybin and other psychedelics suggest a different approach; namely, one focusing on therapeutic experiences whose reverberations can last weeks, months, or years. 

Yet making psilocybin therapy accessible–either in non-medical, state-directed service centers or within medicine–will be a tightrope walk on many levels. Psilocybin-assisted therapy can induce profoundly useful psychological insights. Yet this same compound, if not stewarded with high levels of care and finesse, can just as easily traumatize people. The wrong approach could also derail the growing research into psilocybin’s role in treating conditions as historically perplexing as Alzheimer’s disease. 

Covering its history, key therapeutic strategies, and the current understanding of psilocybin’s mechanisms of action, this guide is for clinicians, therapists, researchers, and others interested in the tensions that linger as psilocybin therapy inches closer to widespread availability. 

Psychedelics Catalyze New Understandings of the Mind

Beginning with LSD, interest in the therapeutic potential of psilocybin began after R. Gordon Wasson published a vivid account of his experience taking mushrooms within a divinatory ritual in Mexico. Already intrigued with the molecular structure of psychedelic-like compounds, Dr. Albert Hofmann, the “Father of LSD,” read Wasson’s article and soon received an invitation from French mycologist Professor Roger Heim, who accompanied Wasson on his journey, to study the chemical composition of psilocybin. 

In 1958, Hofmann became the first to introduce Western science to psilocybin. Hofmann isolated its active compounds from the mushroom P. mexicana, incorporating psilocybin into psychedelic research as “Indocybin.” As favorable evidence mounted, psilocybin and other psychedelics brought forth a new conceptual model: psychiatrists recognized that if a traumatic event could shape a life, a therapeutic experience could reshape it. As clinical reports about their therapeutic viability grew into the thousands, researchers saw psychedelics as opportunities to give patients more than what was possible with the current tools of psychiatry–long-term medication or asylum stays. 

The period from1950 into the 70s drove major discoveries into psychedelics’ biochemical and neurological promise. Because psychedelics stimulated more research into the underlying biology of mental health conditions, this period led to the rise of psychopharmaceuticals. It also unlocked information about the serotonin system and its interactions with psychedelics, marking the beginnings of what many call the “pharmacology of consciousness.” 

Shifting Public Perceptions of Psychedelics

However, as psychedelics became more prominent in the academic, psychiatric, and intelligence communities, they filtered into the wider culture, both through literature and first-person experiences. Books such as Aldous Huxley’s The Doors of Perception combined with the distribution of psychedelics into the population accelerated the already growing disenchantment with the status quo. 

As psychedelics became synonymous with the counterculture movement, government agencies and special interest groups launched propaganda campaigns emphasizing the potential dangers of psychedelics. In 1968, the Drug Enforcement Agency (DEA) placed psilocybin, LSD, and mescaline alongside heroin and cannabis as Schedule 1 substances, having “no medical use and a high abuse potential.”

Although they remained illegal, private organizations and universities continued to study the mechanisms and biomedical uses of psychedelics. Evidence of their role in treating obsessive disorder, anxiety, and addiction kept a steady, though quieter, momentum. In the late 90s, public enthusiasm about psychedelics grew as they became more prominent fixtures in raves and festivals around the world. 

According to a white paper by the Usona Institute, this period also saw the growth of the “cyberdelic” movement, which likened the newly immersive internet to a psychedelic experience with profound consequences for the future of the species. Ethnobotanist and philosopher Terence Mckenna’s claim, “the only difference between computers and drugs is that computers are too big to swallow,” captures the era’s growing intrigue with virtual reality and “smart drugs.” The resurgence of interest in psychedelics was also related to the rise of micro-dosing in Silicon Valley, which inspired more people to view psychedelics as tools for personal growth. 

What Mystical Experiences Taught Psychiatry

Public excitement, along with technological improvements, caused this enthusiasm to bleed into the scientific community. In 1994, Dr. Rick Strassman published the first study about the effects of DMT since the 1970s. This study was unique for its vivid accounts of the minute details of the participants’ experiences on DMT. It became the first of many to explore the purposes and functions of hallucinogenic states.

Interest in the promise of psychedelics escalated when Dr. Roland Griffiths and colleagues published a study in Psychopharmacology showing the effects of psilocybin among “spiritually inclined” people. At a two-month follow-up, the subjects reported spiritually affecting, mystical-type experiences that improved their quality of life. Interestingly, their reduced scores on anxiety and depression inventories correlated with the extent to which their insights were mystical in nature. 

This study answered questions left open by 1957’s classic “Good Friday” experiment, which first sparked scientific curiosity (and skepticism) about the psychological consequences of mystical experience. By improving the blinding and controls of the earlier experiment, the 2006 study reaffirmed the importance of understanding the brain mechanisms governing mystical experience, their causes, and their reverberations on mental health.  

According to research in the Journal of Contextual Behavioral Science, this study also pointed to a common thread among many investigations–the clear link between certain acute psychedelic effects, such as psychological insights or mystical experiences, and psilocybin’s benefits.

Griffiths et al. and other research groups next took psilocybin research in the direction of anxiety and depression related to terminal illness. In 2016, authors in the Journal of Psychopharmacology provided a single, moderate dose of psilocybin therapy to 29 people with cancer-related anxiety and depression. 

In those who received an active dose, the experience brought new healing understandings about the purpose of their lives and the meaning of their illnesses. At a 6.5 month follow-up, 60 to 80 percent of participants maintained higher degrees of acceptance about the possibility of death and were less depressed and anxious by clinically significant degrees. Since previous meta-analyses showed that SSRIs didn’t perform better than the placebo for cancer-related depression or anxiety, this and related studies not only intensified interest in psilocybin but filled a gap in cancer care. 

In 2020, research published in JAMA Psychiatry made clear that psilocybin therapy could be useful for a much wider population. With two doses of psilocybin along with psychotherapy, individuals with major depression recorded rapid, substantial reductions in depression, with half of the participants remaining in remission after four weeks. As described in this case study, the antidepressant effects seen in this investigation were approximately four times larger than those in studies of traditional antidepressants. 

At the time of writing, two organizations are close to receiving FDA approval for psilocybin therapy. Beginning in 2018, research performed by Compass Pathways and the Usona Institute earned breakthrough therapy designations for treatment-resistant depression (TRD) and major depressive disorder (MDD). By November 2021, Compass Pathways announced positive results for the largest randomized, controlled double-blind psilocybin therapy study for TRD. In their Phase IIb trial, researchers showed that one large 25 mg dose of COMP360 (their synthetic psilocybin product), along with “psychological support,” led to reductions in depression in as little as one day that lasted for up to three weeks. The goal of this study was to identify the appropriate dose for a larger, more pivotal phase III trial underway in 2022. Similarly, the non-profit Usona Institute is currently conducting double-blind, placebo-controlled, clinical trials of single-dose psilocybin for MDD, which is a much broader classification than TRD. 

The magnitude of these results has led to a proliferation of investor and scientific interest in psilocybin and other psychedelic-assisted therapies. Yet the very fact that psilocybin therapy earned a breakthrough therapy designation is in itself a good sign. According to New Atlas, as of 2019, approximately one in three drugs that earned breakthrough therapy designations went on to receive FDA approval. 

At this time, various organizations are creating libraries of psychedelic compounds that could also become widely available. As scientists illuminate more about its underlying mechanisms of action, animal models also speak to psilocybin’s therapeutic potential in conditions such as Alzheimer’s disease, autism spectrum disorder, and anorexia nervosa.

How Does Psilocybin Work? 

The FDA’s designation of psilocybin as a breakthrough therapy came at the same time that research in the Journal of Contextual and Behavioral Science described psychological flexibility as a likely mediator of psilocybin’s antidepressant effects. “Psychological flexibility” refers to the ability to react resourcefully to changing contextual demands, adjust to new circumstances, and live according to values. Dr. Griffiths has even compared psilocybin’s effects to a “narrative inflection point” encouraging a rethinking and potential disidentification with long-held beliefs and behaviors.

Studies into the default mode network (DMN) also lend viability to these descriptions. Research in Human Brain Mapping suggested that psilocybin’s ability to untether people from ingrained modes of thinking could be a product of a “release and reset” mechanism it exerts on the brain. Across several studies, the influence of psilocybin causes a “release” in the DMN that manifests as reduced connectivity. Since numerous studies describe the DMN as home to the “narrative self,” or the hub of recursive, self-directed thinking, this could explain the experience of ego dissolution. 

Interestingly, although DMN activity diminishes under psilocybin’s influence, afterward it undergoes a kind of “reset,” with connectivity appearing stronger in weeks after the experience. Citing correlations between reductions in depression scores and the way in which the DMN appears to reset, Scientific Reports pointed to this phenomenon as a key element of psilocybin’s transformative effects.

It’s also worth noting that psilocybin study participants often report changes in their emotional comportment to their lives. These findings have inspired research into psilocybin’s effects on emotional processing, particularly for people with TRD. A 2020 paper in the Journal of Psychopharmacology traced changes in the functional connectivity of the amygdala before and after psilocybin treatment on participant responses to happy, fearful, or neutral faces. After psilocybin therapy, participants had greater amygdala connectivity during facial processing that correlated with lower levels of rumination and depression. 

The authors described psilocybin as having “reviving” effects on emotional responsiveness. These emotional modulations could be the reason people report easier access to their emotions during psilocybin-assisted psychotherapy.

A Window of Opportunity: The Philosophy Behind Psilocybin Therapy

Since the early days of psychedelic research, investigators have explored whether certain therapeutic approaches could extend the benefits of psilocybin more effectively than others. The birth of psychedelic-assisted therapy (PAP) as a framework happened shortly after the synthesis of LSD. 

Psychoanalysts interested in concepts like the ego and the inner self conceptualized psychedelics as “catalysts” for insight-based therapies, emphasizing the processing of unconscious material as a way of overcoming psychological distress. Believing that healing is primarily a matter of inner work, PAP also encourages people to “surrender” and “open” to difficult emotions. By accepting, rather than fighting, difficult or otherwise heavy material, emotional breakthroughs naturally occur. A major goal on the part of practitioners is therefore to support individuals’ ability to translate those breakthroughs into lifestyle and belief changes that improve their lives. 

Many of the key features of the PAP protocol are traceable to Dr. Stanislav Grof’s LSD Psychotherapy, which combined extensive fieldwork in LSD psychotherapy with a map of human consciousness. Although it’s not the first or only reference text, it’s cited in nearly all modern PAP studies, including clinical studies of ketamine, psilocybin, and MDMA. The protocols in that text account in large part for the standard elements of psychedelic therapy. 

Although the details can vary, considerations like set and setting and the three-part preparation, administration, and integration process form the basis of PAP. Beyond these commonalities, psychedelic therapy generally comes in two forms: psycholytic or psychedelic psychotherapy. 

Clinical trials tend to follow a psychedelic psychotherapy model. These studies bookend the experience with preparation and integration processes but focus on maximizing the therapeutic consequences of high doses of psychedelics. On the other hand, psycholytic therapy aims to complement or enhance a long-term therapeutic relationship using low doses of psychedelics over many sessions. Proponents of psycholytic therapy believe lower doses amplify transference dynamics between the client and individual. Since transference dynamics are thought to reveal details about pivotal early-life relational wounds, psychedelics can unravel insights about subtle, far-reaching inner conflicts at a faster rate than talk therapy alone. 

Unlike the conventional allopathic model, where from the patient’s perspective, a clinician’s degrees and board certifications are the core negotiators of trust, the therapeutic relationship assumes a prime level of importance. According to the Journal of Psychopharmacology, because of the particular way psychedelics antagonize the 5-HT2A receptor, an experience’s context, or its “set and setting” could be fundamental to psychedelics’ therapeutic effect. 

As a result, a clinical environment, with visible medical equipment or staff in white coats, could increase the likelihood of anxious responses. Researchers counteract this by bringing PAP environments to living room level comfort: soft couches, contemplative statues, eye masks, and soothing music. On the other hand, setting, or a person’s beliefs about the experience, centers on the space between individual and therapist. The therapist and client build an alliance based on shared intentions or interpretative frameworks for the experience. 

A wide array of therapeutic modalities complement PAP, including those more conventional, such as cognitive behavioral therapy, or those inspired by depth psychology or trauma-informed therapy models. Things like shadow work prompts or trauma release exercises, to name just two examples, can be extremely useful for helping people prepare for and integrate their experiences. Recent studies have also pointed to the benefits of psychedelics in the context of group therapy. 

Therapeutic modalities with goals that directly mirror a compound’s effects can be especially potent for two reasons: they not only provide interpretive maps that bring clarity during the therapeutic experience, but they offer a terminology people can use to revisit the meaning of their experiences later on. 

Below is an incomplete list of therapeutic frameworks that work especially well with psilocybin. 

Acceptance and Commitment (ACT) therapy

Created in 1982 by Stephen C. Hayes, acceptance and commitment therapy (ACT) is a type of contextual-behavioral therapy that encourages the growth of psychological flexibility to reduce depression and anxiety. 

Psilocybin puts people in direct contact with many of ACT’s core therapeutic goals. As explained in the Yale Manual of Psilocybin-Assisted Therapy for Depression, psilocybin and other psychedelics stimulate a feeling of union with all things, and in some cases, complete ego dissolution. In this state, a person glimpses reality beyond their limited self-identity. With the first-hand experience of unity afforded by psilocybin, they can more automatically de-identify from self-critical narratives. 

As a result, they feel encouraged by direct insights into their fluidity or their status as a hub of ever-changing feelings and perceptions. In ACT terminology, they view the “self as context” rather than the “self as content,” or the self as identical with the interpretations they collect about their lives. Framing the psilocybin experience on ACT terms can help a person revive or re-stimulate these perspective shifts long after therapy. 

Internal Family Systems (IFS)

In addition to ACT therapy training, many practitioners receive Internal Family Systems training within education programs conducted by MAPS and other organizations. Developed by Dr. Richard Swartz in the 1980s, IFS describes the psyche as a conglomeration of sub-personalities or inner “parts” that act in contradicting ways. These parts represent early traumas, defend against pain, or lock emotions out of conscious awareness.

However, beneath these parts, all psyches have a core internal resource called the Self, which is fundamentally curious and wise enough to direct healing for the entire psyche. To instigate a healing process, IFS first aims to make people aware of their conflicting parts. With this awareness, they tap into traits of the Self, such as the capacity to hear, understand, and remain present with all their parts without identifying with or becoming dominated by them.

Intriguingly, Stan Grof’s concept of the perinatal matrices anticipates presuppositions running through IFS as well as PAP. With stages of bliss, confinement, and eventual emergence, the perinatal matrices map the unconscious dynamics of the birthing process. 

Though at times seemingly hostile or limiting, emotions (or parts) serve critical functions. As in birth as in the psychedelic experience, understanding and growth demand presence and release, not war. With its focus on gentle inquiry into charged emotions, IFS can help a person identify underlying emotional conflicts from a place of warm yet detached curiosity, rather than from fear, shame, or guilt.

The Hakomi Method

Created by experimental psychologist Ron Kurtz, this body-centered approach combines elements of Taoism, mindfulness, and somatic awareness to conjure a doorway to the vast space beneath the thinking mind. The Hakomi Method of Mindfulness-Centered Somatic Psychotherapy conceptualizes bodily sensations, gestures, facial expressions, postures, and other features as windows into a person’s conscious and unconscious beliefs, memories, emotions. 

Bringing unconscious patterns into view, a person can plunge beyond rigid identifications and explore deeper, more receptive, or intuitive states. Unlike other therapies, which use mindfulness in support of therapy, Hakomi therapy is conducted within a state of mindfulness, amplifying feelings of safety and groundedness. This outlook removes defensiveness and provokes key unconscious material to rise to the surface. 

One technique involves using “probes” to uncover hidden beliefs. A therapist might say, “You are a powerful person,” then invite you to mindfully witness the memories, emotions, and sensations this thought triggers. Reactions speak to unconscious dynamics, beliefs, and conflicts that lie beneath the surface-level personality. With ordinarily subterranean conflicts available for conscious processing, therapists help clients reconfigure painful or confusing sensations and stories until they no longer subtly influence their behavior. 

As mentioned, psilocybin stimulates an unusual sense of present moment grounding due to its reductions in the functional connectivity in the DMN. Accordingly, Hakomi’s focus on the intricacies of a person’s immediate experience can support new understandings about the nature of consciousness. These insights can alter a person’s inner orientation, possibly leading to new, healing approaches to their suffering.

The Legalities of Psilocybin Therapy

At the federal level, psilocybin remains a Schedule 1 drug, alongside heroin, MDMA, LSD, mescaline, and others. However, multiple cities have chosen to decriminalize psilocybin possession and use. Denver was the first city to decriminalize personal use and possession of psilocybin-containing mushrooms, along with Oakland, Santa Cruz, Washington, DC, Somerville, Ann Arbor, and Cambridge. 

Although decriminalization isn’t synonymous with legalization, decriminalization lowers the severity of psilocybin possession as a crime. In addition, Oregon passed Measure 110, or the Drug Addiction Treatment and Recovery Act. As of February 1, 2021, this act replaces criminal prosecution with a health-directed approach, punishing low-level possession with one of three options: getting a health assessment, treatment and recovery services, or paying a $100 fine.

Since psilocybin therapy itself isn’t yet legal or decriminalized, practitioners risk their license if they administer psilocybin. However, at the time of writing, therapists can legally give psychedelic integration therapy services, which involve preparation and support for before or after a person’s independent psychedelic healing process. 

Fortunately, the opportunities for psilocybin-assisted therapy are expanding thanks to the Psilocybin Program Initiative, or Oregon Measure 109. This program allows the Oregon Health Authority (OHA) to develop the first-state run psilocybin therapy service program. This permits individuals 21 and older to receive psilocybin-producing mushrooms and fungi products after a preparation session with a trained facilitator. Investigators are currently undertaking a two-year development period, from January 2021 to December 31, 2022, creating regulations, shaping best practices, and determining training and educational protocols for facilitators. As the first of its kind, this program will lay a foundation for future state-led psilocybin services. 

Since psilocybin therapy received a breakthrough therapy designation, it’s currently on the “fast track” to approval, meaning that the FDA is working to accelerate the development and review process so that patients can access it as soon as possible. In the meantime, it’s possible to use psilocybin legally in the context of a clinical trial or to visit a psilocybin retreat center in Mexico, Jamaica, or the Netherlands.

The Future of Psilocybin Therapy

Although psilocybin can be state-regulated and medicalized simultaneously, many see a tension between the two. Proponents of legalization consider it a desirable, freer alternative to medicalization. The state-directed legal model lets people without diagnosed conditions receive psilocybin services. 

In other words, people who want to take psilocybin for personal growth reasons, not because they’re clinically depressed, can do so. Guided by their preferences, people will also have the freedom to prepare for sessions with their facilitator outside of the service center. Although under Measure 109, psilocybin must be administered under supervision, integration therapy can also occur at a location of the individuals’ choice. They also can decide against having an integration session altogether. 

To supporters, this level of autonomy honors the fact that psychedelics do more than aid with depression, anxiety, or rumination. They also invite people to blaze new trails or unclench long-held stories about themselves. The level of individual autonomy legalization provides also honors humans’ long history with psilocybin, a compound likely at the root of the formation of religion as we know it. Since medicalization restricts the use of psilocybin to a narrow catalog of diagnoses, proponents of legalization worry that a few powerful companies will control and limit psychedelic medicine’s direction and availability. These worries solidified in 2019, as for-profit psychedelic companies sought patents on unique formulations of psilocybin (and even certain aspects of the therapeutic process). As a result, many in the psychedelic therapy community began viewing medicalization as hostile to the goal of bringing these compounds to as many people as possible. 

On the other side, medicalizers believe that psilocybin and other psychedelics should be approached like psychiatric drugs, staying in the hands of doctors and researchers rather than lawmakers. Proponents of medicalization view the FDA approval model as the safest way to ensure consistency and quality in dosing and care protocols. 

As described in Motherboard, there’s also a need to anticipate and respond to individual reactions to psychedelics. Importantly, because some individuals will view psychedelics as a “last resort,” or a final stop in a long trajectory of failed treatments, anxious or even minor reactions could be profoundly disappointing or destabilizing. Clinicians would need carefully coordinated, evidence-based ways of responding to each individual’s situation. Of course, optimizing patient safety is a core goal of both approaches. Systematizing best practices and equipping facilitators to support individuals across a variety of situations are two urgent questions being answered in the development period currently underway in Oregon. What remains to be seen, though, is whether one of these options may prove more up to the challenge than the other. 

Arguably, these opposing schools of thought speak to differences in the worldview beneath the biomedical and biopsychosocial treatment models. After all, psychiatry lists certain manifestations of grief within the DSM-5, making personal responses to loss pathological once they last beyond a certain point or push against a certain threshold. Those who favor state-led centers to medicalization may, among many things, be wary of psychiatry’s tendency to reduce kaleidoscopic human experiences to qualifying labels or psychometric rating scales. From a biopsychosocial perspective, depression isn’t necessarily a mental illness. It’s an understandable reaction to problems spanning from loss of community, more screen time than exercise, and other imbalances of modern life. 

For this reason, limiting psychedelics only to people in certain types of distress overlooks that their unique effects–especially their ability to disrupt rigid ways of thinking and behaving–could be key to healing many of the societal ills at the root of the mental health crisis, not only their overt manifestation in anxiety, depression, and the like. 

As psychedelic therapy becomes available, questions regarding the model in which it belongs, if either, will be easier to answer. Its future may depend on a balancing act: the process of combining tools from both the biopsychosocial and biomedical models without letting one overshadow the other. 


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