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Psilocybin for treatment of anxiety disorder

Psilocybin for treatment of anxiety disorder



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Has psilocybin been used for treatment of anxiety disorder? I've mostly found it used in the treatment of depression in patients diagnosed with cancer (Nichols et al. 2017) and patients not diagnosed with anything at all (Griffiths et al. 2006). Alternatively, how legitimate is it to generalize the results of the cancer patients to a chronic anxiety disorder patient?

Nichols, D. E., Johnson, M. W., & Nichols, C. D. (2017). Psychedelics as medicines: an emerging new paradigm. Clinical Pharmacology & Therapeutics, 101(2), 209-219.

Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268-283.


There has been some preliminary research in the 1960's. From "The neurobiology of psychedelic drugs: implications for the treatment of mood disorders" by Vollenweider and Kometer:

Psycholytic therapy was introduced by Ronald Sandison and applied in Europe at 18 treatment centres. In psycholytic therapy, low to moderate doses of LSD (50-100 μg), psilocybin (10-15 mg) or, sporadically, ketamine were used repeatedly as an adjunct in psychoanalytically oriented psychotherapy to accelerate the therapeutic process by facilitating regression and the recollection and release of emotionally loaded repressed memories, and by increasing the transference reaction. A review of 42 studies reported impressive improvement rates in (mostly treatment-resistant) patients with anxiety disorders (improvement in 70% of patients), depression (in 62% of patients), personality disorders (in 53-61% of patients), sexual dysfunction (in 50% of patients) and obsessive-compulsive disorders (in 42% of patients).

Unfortunately, the majority of these studies had serious methodological flaws by contemporary standards. In particular, with the absence of adequate control groups and follow-up measurements and with vague criteria for therapeutic outcome, the studies did not clearly establish whether it was the drug or the therapeutic engagement that produced the reported beneficial effect. It was also difficult to draw firm conclusions regarding potential long-term efficacy. Nevertheless, the studies provide a conceptual framework for the application of psychedelics, with the data suggesting that the most promising indication for psychedelic use might be found in the treatment of depression and anxiety disorders.


Psilocybin-Assisted Psychotherapy

Psilocybin is a naturally occurring psychedelic compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms, colloquially called "magic mushrooms" or "shrooms". These mushrooms have been used since ancient times for medicinal and spiritual purposes. In current times, psilocybin has been found to be effective for people with a number of mental health concerns. Psilocybin has been shown to accelerate the healing process in many people for distressing emotional symptoms, such as depression, OCD, and anxiety. Psilocybin-assisted psychotherapy combines the therapeutic effects of psilocybin with the support of an experienced and trusted therapist. The psychotherapy component of psilocybin treatment allows the client to process what is gained through the psilocybin experience with the therapist, supporting integration of these insights for lasting symptom relief.

How does psilocybin-assisted psychotherapy work?

Our past and current life experiences and the meaning we make from them can give rise to negative and overwhelming psychological, emotional, and physical symptoms. Factors such trauma, loss, discrimination, poverty, and other negative life experiences can shape our perception of ourselves and the world, including how we react and respond to life's challenges and our ability to navigate our emotions. These perceptions can become habitual patterns and cycles that contribute to suffering. Individuals who seek psilocybin-assisted psychotherapy often struggle with life-long or treatment-resistant depression and anxiety. They have tried other forms of therapy and are still in need of relief from their debilitating symptoms. Psilocybin can help clients break out of self-destructive patterns and reconnect with a sense of purpose, passion, and creativity in life.

How can I get psilocybin-assisted psychotherapy?

Our psychiatrist, Dr. Jordan Sloshower, is one of the leading experts in psilocybin-assisted psychotherapy. He is currently offering this as a treatment for depression through a study he is conducting at Yale University. Details of this opportunity are listed below. Therapists at BWC provide other types of psychedelic-assisted psychotherapies as well.

Therapists at BWC are available to assist people through the therapeutic use of psilocybin and non-ordinary states of consciousness.

Psilocybin-Induced Neuroplasticity in the Treatment of Major Depression

Purpose: This study will investigate neurobiological and psychological effects of psilocybin-assisted therapy in people with major depressive disorder. The primary hypothesis is that psilocybin administered in a therapeutic context will result in neuroplastic changes that parallel improvement in symptoms of depression.

  • Patients with current moderate to severe major depressive disorder despite one adequate antidepressant trial
  • Engaged in treatment with a mental health provider
  • To participate, patients will need to be off psychiatric medications (e.g.,SSRIs) that may alter the effects of psilocybin (providers can discuss this with study physicians).

Major exclusions include: Uncontrolled medical and neurological conditions, history of psychotic disorders or bipolar disorders in participant or first degree relatives, active substance abuse disorder.

  • Approximately16 weeks of study participation
  • Two experimental sessions approximately four weeks apart during which participants will receive two of the following three interventions: 1) placebo, 2) low dose psilocybin, and 3) medium-high dose psilocybin
  • Experimental sessions will be embedded within a psychotherapeutic framework consisting of eight preparatory, debriefing, and follow-up sessions with trained psychotherapists.
  • Electroencephalographic (EEG) data will be collected at four time points to assess changes in neuroplasticity.

Compensation: Subjects can receive up to $350 for participating in this study


Treatment Resistant Depression

Treatment resistant depression is diagnosed when someone continues to suffer from depression, despite having been on treatment. Doctors might prescribe rounds after rounds of antidepressants along with ongoing psychotherapy, but the person’s symptoms just do not seem to improve substantially enough. The drop-out rates of traditional treatments for depression vary. However, a meta-analysis found that the average drop-out rate is around 17.5%. Interestingly, the highest drop-out rate was found for cognitive behavioural therapy (CBT), which is why it should be emphasized that psilocybin could be used in conjunction with this therapy for improved results.

The Need for Alternative Treatments

These drop-out rates, and the ever-rising rates of depression are two very important factors that emphasize the need for alternative treatments. It has been established that 6.7% (16.2 million) of adults in the United States experienced an episode of depression at some point last year. These rates of depression have become progressively worse and antidepressant usage has increased tremendously (by about 65%). Depression, and the associated risk of suicide, is certainly on the rise with no sign of remittance. Additionally, there are not many new depression medications in the pipeline. This clearly shows how important the need is for alternative treatments.


How to Find Psychedelic Treatment for your Psychological Disorder

Mental health disorders are the elephant in the room of modern day society. An estimated 8.3 million Americans suffer from chronic stress, anxiety, depression, PTSD, and related psychological conditions, and those numbers are on the rise. In addition to that, nearly 24 million Americans are addicted to alcohol or drugs, and even with the best of intentions they face a long struggle and steep odds to get clean and address the underlying issues at the heart of their destructive patterns. The good news is that thanks to a resurgence in the study of psychedelic-assisted therapy, we are on the verge of adopting a whole new set of incredibly powerful medicines that seem to be tailor-made to deal with this epidemic of mental illness and addiction. Psychedelic treatment and psychedelic-assisted therapy are proving to be some of the most potent and successful treatments for addiction and psychological distress that we have ever seen.

How to Find Treatment

Psychedelic therapy is still illegal in the US, but thanks to the efforts of organizations like the Multidisciplinary Association for Psychedelic Studies (MAPS), psychedelics like MDMA are on track to become a FDA-approved prescription medicine within a few years, and others such as psilocybin may not be far behind. There are some psychedelic-assisted clinical trials happening at prominent hospitals and universities, but the number of participants admitted to these studies are quite low.

Generally speaking, if you want to find psychedelic treatment in the the near future, you will have to travel outside of the US to places like Mexico, Brazil, and Costa Rica. A simple Google search will uncover dozens of psychedelic healing centers around the world, but we strongly recommend speaking with the facilitators and people who have been there to properly investigate and “gut-check” any center. Almost everyone in this field will recommend that you use a combination of due diligence investigation and your intuition when choosing a location. We have featured a few of these retreat centers in previous articles, which you can find here:

It’s also important to know that not all psychological disorders lend themselves well to psychedelic treatment. While there is no scientific basis for the propaganda that psychedelics can “make you crazy,” it has been suggested that those with latent schizophrenia could have their condition triggered early by a strong psychedelic experience. Keep in mind this is still a new frontier of research, and people with certain medical conditions or on certain medications should absolutely not take certain psychedelics. Any properly run treatment clinic will have a full physical and mental health screening before treatment, and walk you through any contraindications that may be revealed. We do not endorse any illegal behavior, but from a harm reduction perspective, anyone who chooses underground treatment should exercise extreme levels of research, discernment, and safety precautions throughout the process.

Finding Integration Support

Beyond the psychedelic journey itself, integration of the experience after the fact plays a critical role in ensuring that the insights, progress, inspiration gained are translated into daily life in a sustainable way. Whether you are fresh out of an underground ayahuasca ceremony that helped you deal with childhood trauma, or a recent outpatient of an iboga center that helped you detox from an opiate addiction a few weeks or months of integration support from someone who understands psychedelic treatment is immensely beneficial in securing your new goals, perspectives and commitments. While this is still a budding field in the US, we have featured three of these such programs: Holistic House Vegas– a brick and mortar healing center which specializes in addiction rehab after ibogaine treatment, Being True to You– a service that offers premium remote coaching and support all over the US and even certification programs in integration coaching, and Innerspace Integration– an integration program closely aligned with the Aware Project.

Releasing the Stigma

One of the most insidious aspects of mental illnesses is the stigma that surrounds them. Despite the statistics that show how common these disorders are, our culture still often adopts a “toughen up and go it alone” approach, leading many to isolate themselves and be fearful of speaking up about their condition, much less seek help. Psychotherapy, prescription medications, and conventional rehab centers do help many people stabilize their lives, but sometimes these routes are not enough to fully eradicate the pain, trauma, and stress that lay at the core of the disorder, leading people to simply numb their symptoms without seeking true healing.

Radical shifts in behavior, self-image, and wellbeing are something that psychedelics excel at when used appropriately, but not everyone is able to travel abroad for psychedelic treatment or willing to find underground options. The single most important thing that anyone suffering from an addiction or mental disorder can do is to speak up about it to their loved ones and seek help. Shame and stigma surrounding these issues should be forever discarded, as these conditions are an integral part of the human condition, and everyone faces stress, challenges, and addictive habits in their own way. This point was beautifully summarized in a recent conversation we had with comedian and podcaster Duncan Trussell:

“In the field of mental health, I think we would see a kind of renaissance… and perhaps we would see some reduction in certain types of mental illness. Not just because psychedelics are great for treating depression, but also because another thing that’s great for treating depression is not hiding the fact that you’re depressed. If we we’re not afraid to go outside to the park with big, beautiful, black dilated eyes and stare up into the sky holding hands with strangers and laughing for a few hours, then maybe we won’t be afraid to tell people that we love that we’re not feeling okay, that something seems to be different. From the moment you start announcing you’re in a bad place, you are on the pathway to healing.” -Duncan Trussell


Psilocybin and the Treatment of Anxiety and Depression

Over the last several years, a number of academic institutions have been researching the impact that the psilocybin molecule has on treating a variety of mental health conditions, including anxiety and depression. Psilocybin is the active psychedelic compound that naturally occurs in over 200 species of fungi. When humans ingest psilocybin, the body quickly converts it to psilocin, and this results in mind-altering effects such as euphoria, visual hallucinations, and distortions of space and time that are commonly reported by those who ingest these fungi or so-called &ldquomagic mushrooms.&rdquo

As it happens, the mind-altering effects caused by the ingestion of psilocybin may serve to be extremely useful in treating symptoms in those that suffer from anxiety and depression. This article will discuss some of the research that has been done on the treatment of depression and anxiety with psilocybin and why it is becoming increasingly important to find safe and effective treatments for these mental health conditions.

In 2016 at Imperial College London, Robin Carhart-Harris and his research team carried out an experiment to research the effects of psilocybin in patients with moderate to severe treatment-resistant depression. In the experiment, 12 patients (six men and six women) were given two doses of psilocybin (10mg and 25mg, 7 days apart). Before, during, and after each psilocybin treatment, patients were provided with psychological support. Treatments also took place in a comfortable, living room like setting. Patients&rsquo depressive symptoms were then evaluated 1 week and 3 months following treatment. The researchers found that depressive symptoms were significantly reduced both 1 week and 3 months after treatment. Furthermore, none of the patients experienced serious adverse effects during their treatment with psilocybin.

This study highlights the fact that it does not take many doses of psilocybin (2 in this case) to allow for patients to experience sustained decreases in depressive symptoms. This study also highlights the importance of set (one&rsquos mindset before using psilocybin) and setting (one&rsquos physical environment while using psilocybin) as patients were supported psychologically and were in a comfortable setting throughout their entire treatment with psilocybin. This could be a significant reason as to why this experiment was as successful as it was. In fact, Carhart-Harris and 2 of his colleagues conducted an experiment in 2018 specifically to investigate how the quality of experience of a psilocybin treatment influences the beneficial impacts associated with the treatment. In that study, the authors found that the quality of experience (or set and setting) had a significant impact on whether the patients experienced reductions in depressive and anxious symptoms after their treatments.

Meanwhile at the Center for Psychedelic and Consciousness Research at Johns Hopkins University, Roland Griffiths and his research team were also conducting studies on psilocybin and its potential for the treatment of mental health conditions. In 2016, this team carried out a study to investigate the effects of psilocybin on patients with life-threatening cancer and depression/anxiety. The 51 patients that took part in the study were divided into 2 groups. One group took a very small dose of psilocybin (1mg or 3mg per 70kg of body weight, 5 weeks apart) and one group took a higher dose (22mg or 30mg per 70kg of body weight, 5 weeks apart). The researchers found that the patients that had received a higher dose of psilocybin experienced decreases in clinician and self-rated depressive and anxious symptoms. Furthermore, when the researchers followed up with the patients 6 months later, 80% of the patients in the high-dose group continued to display sustained significant decreases in their depressive and anxious symptoms.

A similar 2010 study by Charles Grob and colleagues at the UCLA School of Medicine gave moderate doses of psilocybin (0.2mg per kilogram of body weight) to 12 patients with advanced-stage cancer and anxiety. When the researchers followed up with patients 1 and 3 months after treatment, they found that the patients had experienced significant reductions in their anxiety symptoms. In both this study and Griffiths&rsquo 2016 study, none of the patients who participated in the studies experienced adverse negative psychological impacts during or after their treatments with psilocybin. These studies highlight that psilocybin can be both safe and effective in reducing anxiety symptoms - even in a population (cancer-patients) that typically develops severe and significant depressive and anxious symptoms.

The reason why psilocybin is so successful at treating symptoms of depression and anxiety is not entirely known, but the answer might have something to do with the interaction between psilocybin and the &ldquoDefault Mode Network&rdquo (DMN). The DMN consists of an interacting group of brain regions that correlate with one another. These brain regions include the Posterior cingulate cortex which is responsible for our &ldquoperception of self&rdquo or ego, the Medial prefrontal cortex which is responsible for the processing of personal information, the Angular gyrus which is responsible for spatial awareness and perception, the Dorsal medial subsystem which allows us to determine or infer the actions of others, and the Medial temporal subsystem which is responsible for the perception of time. An overactive DMN is associated with behaviours such as excessive self-criticism, negative filtering (when one only focuses on negative aspects of a situation), catastrophizing, and mind reading (when one assumes to know what others are thinking). Since many people with anxiety and depression are also prone to these types of behaviours, it has been hypothesized that an overactive DMN is highly common in people with these conditions. However, when one takes a dose of psilocybin the DMN is dampened. This dampening of the DMN may help individuals to break their negative thought patterns and thus reduce their anxious and depressive symptoms.

So why is this relevant? Well, anxiety disorders are the most common psychological disorders in the US, and their rates have been skyrocketing over the last decade. Nearly 1 in 5 US adults have an anxiety disorder, and nearly ⅓ of US adults will have an anxiety disorder at some point in their lives. Rates of major depression are on the rise as well, both in the US and worldwide. It is estimated that nearly 7% of US adults experience at least one significant episode of depression in any given year. What is causing this rise in anxiety and depression in the US and in other western countries? The answer to that question is likely a complex set of factors and each individual person who suffers from these disorders is likely influenced by some factors, and not others. Regardless of the cause for an individual&rsquos anxiety or depression, treatment with psilocybin may be able to significantly reduce symptoms associated with these conditions and provide relief for many.

In conclusion, while anxiety disorders and depression are becoming more common, especially in the US and in other western countries, psilocybin might be able to help. The aforementioned studies described in this article showed promising results when patients with significant depressive and anxious symptoms were treated with a dose of psilocybin. Even minimal doses of psilocybin were shown to have lasting psychological benefits in these patients. Moreover, not a single patient in any of these studies experienced lasting adverse negative psychological effects as a result of their treatments with psilocybin. It is clear that psilocybin has the potential to be a safe and effective way to treat anxiety and depression and it would be wise to continue to study the beneficial impacts of psilocybin on those that suffer from these psychological disorders, with the hope that this treatment method may soon become more widely available.

I am a mycologist living in British Columbia, Canada. I have perfected a method of mushroom cultivation that works excellently for several Agaricus Genus mushroom species. In my spare time I love to write about psychology, fungi, and the psychedelic experience.


The Potential for Abuse

All the drugs reviewed here, except ketamine, are currently classified by the DEA as Schedule I controlled substances under the Controlled Substances Act. As noted earlier, this classification was created by the U.S. Congress in 1970 to diminish the availability of drugs of abuse: “Substances in this schedule have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse” (139). Other drugs under this classification include heroin, marijuana, methaqualone, and mescaline. Psychedelic drugs have remained Schedule I drugs for almost 50 years. Ketamine is classified as a Schedule III substance, which is for drugs with an accepted medical use (e.g., anesthesia) and a potential for abuse.

In 2010, the United Kingdom’s Independent Scientific Committee on Drugs published a study that directly addressed the prevalence and severity of adverse effects of potential drugs of abuse on a nine-category matrix of harm (140). They derived scores estimating the magnitude of overall harm to users (and to others) for each drug and substance of abuse. At the top of the list was alcohol, with a harm score of 72, followed by heroin, with a score of 55, then crack cocaine, with a score of 54. Benzodiazepines and ketamine both had a harm score of 15, and methadone’s score was 13. Ecstasy, LSD, and psilocybin were at the bottom of the list with harm scores of 9, 7, and 5, respectively. This publication was extremely controversial, although not without support, and eventually led to the dismissal of the lead author, David Nutt, from Britain’s Advisory Council on the Misuse of Drugs. In response to this criticism, Nutt and his colleagues refined their methodology and used a multicriteria decision analysis to again evaluate the harmfulness of drugs, both to the individual and to society (140). The results were similar, with alcohol, heroin, and crack cocaine having the highest overall harm scores and Ecstasy, LSD, and psilocybin ranking at the bottom of the list. Given that the societal harm scores were influenced by data from economic costs, health records, police records, and an expert group approach, their generalizability is limited by availability of the analyzed substances in specific countries.

A National Institute on Drug Abuse (NIDA) “DrugFacts” brochure states that certain hallucinogens (e.g., PCP) are potentially addictive and can produce drug cravings and tolerance over time (141). However, hallucinogens are not associated with uncontrollable drug-seeking behavior (141) and animals cannot be trained to self-administer hallucinogens (142). Other hallucinogens (e.g., DMT in the form of ayahuasca tea) do not lead to addiction or tolerance (141). Medical administration of hallucinogens should include careful consideration of the appropriate dosage, patient screening, and appropriate preparation of the patient, including preparation and follow-up of psychedelic-assisted psychotherapy sessions in accordance with an approved procedure based on research evidence (143).

Another NIDA DrugFacts brochure acknowledges research evidence of the abuse potential of MDMA in animals, albeit to a lesser degree than cocaine (144). While MDMA self-administration models in animals suggest patterns of episodic use at irregular intervals, the observed potential for abuse seems to be less than that for amphetamine and methamphetamine (145). The prospective long-term follow-up study of individuals with PTSD who received MDMA (N=19 described above [116]) reported that no study participants developed a substance abuse problem (with any illicit drug) during the follow-up period of 7–17 months, suggesting that, at least in research settings, MDMA can be administered with minimal risk that patients will subsequently seek out and self-administer “street Ecstasy.” However, further evaluation of MDMA’s long-term risks is needed (116).

Researchers at Johns Hopkins University recently evaluated the abuse potential of medically administered psilocybin (143) and determined that, if approved as a medication, psilocybin would be appropriate for Schedule IV classification. Other substances currently classified as Schedule IV include benzodiazepines and hypnotics with a relatively low potential for abuse and dependence.

The available evidence supports a plan for further research into the abuse potential of psychedelic compounds, with consideration of both their therapeutic potential and their risk of abuse or misuse. Future research on psychedelic compounds should include measures of drug-seeking behavior over time, urine drug screens to monitor illicit drug use, and efforts to determine which patient populations may be vulnerable to developing new (or to experiencing relapse of preexisting) substance use disorders.


Psilocybin-assisted psychotherapy produces large, rapid, and sustained antidepressant effects

Combining the psychedelic drug psilocybin with supportive psychotherapy results in substantial rapid and enduring antidepressant effects among patients with major depressive disorder, according to a new randomized clinical trial. The findings have been published in JAMA Psychiatry.

The new study provides more evidence that psilocybin, a compound found in so-called magic mushrooms, can be a helpful tool in the treatment of psychiatric conditions.

“Prior studies in cancer patients and in an uncontrolled clinical trial in depressed patients using psilocybin-assisted therapy showed promising results. Because there had not been a control group those prior studies were limited,” said study author Alan K Davis, an assistant professor at Ohio State University and adjunct assistant professor at Johns Hopkins University.

“We were interested in testing whether psilocybin-assisted therapy would be helpful for people with depression because depression is one of the most prevalent and debilitating conditions in the world.”

In the study, which was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, 27 people with a long-term documented history of depression were randomly assigned to either begin treatment immediately or after an 8-week delay.

The treatment consisted of 18 sessions. During two of these sessions, psilocybin doses were administered by two clinical monitors who provided guidance and reassurance. The doses were given two weeks apart and each psilocybin session lasted approximately five hours, with the participant lying on a couch wearing eyeshades and headphones that played music, in the presence of the monitors.

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The participants completed a measure of depression and other psychological assessments upon enrollment, and at one and four weeks following completion of their treatment. Most participants showed a substantial decrease in their depression symptoms following the treatment, and almost half were in remission from depression at the follow-up. Those in the delayed group didn’t show decreases in their symptoms before receiving the psilocybin treatment.

“Depressed participants completed therapy and 2 psilocybin sessions. Participants in the immediate treatment group had a large decrease in depression following treatment compared to those in the waitlist control group,” Davis told PsyPost.

“After both groups had received treatment, 71% of participants had a clinically significant response to the treatment (greater than 50% decrease in depression scores) at 4-weeks post-intervention and 54% were in remission from depression at 4-weeks post-intervention. This represents a large effect of this treatment among people with major depressive disorder, approximately 4 times larger effect compared to studies of antidepressant drugs.”

However, the participants reported some challenging experiences during the psilocybin sessions, the most common being “I felt like crying”, “Sadness”, “Emotional and/or physical suffering”, “Feeling my heart beating”, and “Feeling my body shake/tremble.” Many also experienced mild-to-moderate headache.

One participant dropped out of the study because of anxiety about their first psilocybin session. Another participant dropped out of the study after their first psilocybin session because of sleeping issues — but “it was not clear whether sleep difficulties were exacerbated by the intervention,” the researchers said. A third participant chose not to undergo a second psilocybin session after showing a reduction in depression symptoms immediately following their first session.

“Although this study is an important step in this line of research, the lack of placebo control and a short term follow-up (1 month) limits our understanding of how well this treatment works. We are currently working on analyzing long-term follow-up data from this study where we followed participants up to 1 year after their treatment. Current studies are testing psilocybin therapy against placebo in a large multi-site trial in the U.S. and Europe,” Davis said.

He also noted that the drug is not a miracle cure.

“Psychotherapy is substantial. We provide approximately 11 hours of therapy to each person in addition to the two full-day psilocybin therapy sessions. It is likely the combination of psychotherapy and psilocybin that makes this treatment efficacious. This treatment will always have a psychotherapy component and will not be approved by the FDA as a stand-alone medication,” Davis explained.

The study, “Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial“, was authored by Alan K. Davis, Frederick S. Barrett, Darrick G. May, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson, Patrick H. Finan, and Roland R. Griffiths.


Psilocybin for Psychological and Existential Distress in Palliative Care


Condition or disease Intervention/treatment Phase
Depression, Anxiety Distress, Emotional Drug: Psilocybin Phase 1 Phase 2

Patients with advanced illness report feeling a sense of hopelessness, loss of autonomy and relationships, and a lack of purpose in life. These feelings of psychological suffering have been described as "existential distress" and are associated with poor outcomes, including decreased medication adherence and quality of life, increased desire for hastened death and rates of suicide, and has been identified as a primary reason why individuals pursue medical assistance in dying (MAiD).

Current treatments for psychological and existential suffering have low efficacy and are challenging to use in a palliative context. Pharmacological approaches for treating psychological suffering may reduce symptoms of depression and anxiety, but evidence to support their efficacy in palliative care (PC) is underwhelming. Antidepressant and anxiolytic medications also take time to work and can cause serious side effects such as falls and confusion, which can be substantial deterrents for patients. Similarly, results from randomized controlled trials (RCTs) and meta-analyses have demonstrated psychotherapeutic interventions show limited benefit in a PC population. Further, psychotherapy can be time consuming and slow to work, which is not ideal for patients with limited life expectancy. Given the burden of psychological and existential distress among patients followed by PC providers, there is a need to develop scalable, brief, and rapidly effective therapeutic approaches to reduce this distress.

Psychedelic medications offer an innovative, safe, complementary approach to address psychological and existential suffering in patients receiving PC. Studies from the 1950's showed serotonergic hallucinogens ("psychedelics") improved depression and anxiety symptoms in cancer patients. However, legislative changes restricted the use of these medications in clinical care and research. Interest in psychedelic medications has been rekindled by two recently published RCTs that studied the use of psilocybin (a mushroom-derived 5HT2A agonist) during a single psychotherapeutic session in cancer patients with anxiety and/or depression. These trials demonstrated rapid, clinically meaningful, and long-lasting reductions in depressed mood and/or anxiety symptoms and improvements in quality of life and death acceptance. There is also evidence suggesting psilocybin microdosing - taking sub-hallucinogenic doses continuously over longer time periods, rather than a one-time hallucinogenic dose - can improve mood and anxiety. The effects of microdosing, however, have not been rigorously evaluated, particularly in patients with life limiting illness.

Results from recent trials are encouraging but knowledge gaps remain. First, studies to date primarily enrolled patients with localized disease who experience different distress than that of patients with advanced disease who are near the end of life. Second, it is unclear if Canadians would find psilocybin an attractive option in the context of MAiD legalization, which provides an alternative option for patients with severe psychological suffering. Third, there is no empirical research on the therapeutic effects of psilocybin microdosing, as most studies have followed macrodosing protocols. While preliminary efficacy of macrodosing has been demonstrated, there are important barriers to administering this therapy in a PC context. Previous trials had slow recruitment rates, suggesting there may be barriers related to the acceptability of psilocybin macrodosing from the perspectives of patients and families. Macrodosing requires the patient to dedicate an entire day to participating in a guided hallucinogenic experience and remain in an acute care setting where they can be closely monitored. It also requires patients to engage in preparatory sessions with monitors and a post-therapy session. In a PC context, this time commitment may not be acceptable or feasible for patients who are nearing the end of life. Additionally, macrodosing requires at least two trained moderators to guide the patient through their psychedelic experience and facilitate the pre- and post-dosing sessions. In most PC settings, it is not feasible to have clinicians dedicate two days to a single patient, thus limiting the scalability of this intervention.

Psilocybin microdosing has the potential to overcome barriers to the feasibility and acceptability of macrodosing. By removing the requirement for trained moderators, minimizing the time commitment required of patients, eliminating the hallucinogenic effects of the therapy, and allowing patients to receive treatment either as an inpatient or in the community, microdosing may be a more acceptable option to patients and families and allow psychedelic therapy to be scalable across various PC settings. Psilocybin microdosing is a novel, complementary therapy that, while still unproven for patients near the end of life, has the potential to fundamentally change the way psychological and existential distress is responded to in PC, improving the lives of the 30% of patients who experience this suffering at the end of life.

To determine if psilocybin microdosing is a safe, feasible, and efficacious treatment for psychological distress among patients nearing the end of life followed by palliative care providers. All participants will receive a 4-week psilocybin microdosing intervention.

As this is a feasibility study, no formal sample size calculation was performed to determine the number of patients required to reach a level of precision on any study endpoint. Rather, the goal of this study is to provide estimates, along with their margins of error, of the recruitment rate and efficacy outcomes which will inform a subsequent two-arm randomized controlled trial. Participating sites see approximately 5,300 patients per year. It is anticipated that 30% will have psychological distress. Assuming a minimum of 1 in 6 patients are eligible and 15% of eligible patients will enroll, the goal is to enroll a sample of 40 participants over a 1-year period.

Analyses will adopt an intent-to-treat approach. Because the goal of this trial is to demonstrate feasibility and preliminary measures of efficacy, the main analyses will include calculation of feasibility outcomes using descriptive statistics and 95% confidence intervals (CIs), as well as effect sizes with 95% CIs for primary and secondary efficacy measures, comparing patients' 4-week follow-up assessments to baseline assessments. Participants will also be stratified based on demographic and clinical characteristics to assess trends in outcomes. Notably, there is some evidence that selective serotonin reuptake inhibitors (SSRIs) in particular may attenuate the effects of psilocybin. As such, sub-analyses will evaluate outcomes in participants taking an SSRI medication versus those who are not. A sub-group analysis by setting of care (inpatient vs outpatient/community) will also be conducted.

Analyses of safety data will include the mean and standard deviation of the peak effect observed (i.e. highest observed blood pressure, heart rate) and proportion of participants experiencing adverse mood and behaviour events. The incidence of delirium and serotonin syndrome will also be recorded.

Details of Eligibility, Intervention Protocol, and Outcome Measures are provided elsewhere.

Layout table for study information
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: The study is a multi-site, open-label, single-arm phase 1/2 proof-of-concept dose-finding, feasibility and preliminary efficacy clinical trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Psilocybin for Psychological and Existential Distress in Palliative Care: A Multi-site, Open-label, Single Arm Phase 1/2 Proof-of-concept, Dose-finding, and Feasibility Clinical Trial
Estimated Study Start Date : August 2021
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine

Phase 1 (week 1): all enrolled participants will take a single 1mg oral dose of psilocybin once per day on Monday and Thursday. If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 2 for week 2.

Phase 2: The participant will take a single 1mg oral dose of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 3 for week 3.

Phase 3: The participant will take two 1mg oral doses (2mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday). If no adverse events are reported at any point during the week (Mon-Fri), the participant will continue to Phase 4 for week 4.

Phase 4 (maximum allowable dose): The participant will take three 1mg oral doses (3mg total) of psilocybin once per day for 5 consecutive days (Monday to Friday).


Discussion

All studies included in this review have suggested that psilocybin has a favorable safety profile, being well tolerated in general (see Table ​ Table2). 2 ). The most common adverse events reported were transient hypertension, anxiety and nausea, and headaches that were limited to the experimental sessions in the majority of cases. These events go in accordance with previous reports. 13,42,54,55 The occurrence of adverse events was more often reported with higher doses of psilocybin 27 however, out of all studies, there were no reports of serious adverse events and all adverse events were readily managed by the staff without the need of pharmacological intervention. The safety of psilocybin use is conditioned mainly by the individual's expectations and the surrounding environment, which explains the wide amplitude of subjective effects 4 and the concern about the conditions under which drug sessions were conducted in many of the studies cited.

Regarding results, on depression and anxiety symptomatology, 4 studies 16,21,27,32 consistently showed immediate and enduring anti-depressant and anxiolytic effects. Notably, results have shown BDI score reductions lasting as long as 6 months 16 and reaching as high as 83% anti-depressant response and 85% remission rates (defined by BDI scores), 7 weeks following a single dose of psilocybin. 21 Significant reductions were also reported on other depression measures such as QIDS, GRID-HAMD-17 or MADRS. Furthermore, significant evidence for anxiety symptom reduction was also observed on scales such as STAI and HAM-A, with reports of 76% and 52% of response and remission rates, respectively 27 (defined by HAM-A scores). Regarding OCD, 1 open-label study has found symptomatic relief and significant reductions on YBOCS scores. 39,56� On tobacco addiction, 2 open-label studies regarding the same experiment have showed abstinence on 80% of the subjects after 3 months and on 67% after 9 months from the final dose session. In addition, 60% were biologically verified as abstinent roughly 27 months after the last dose session. Nevertheless, these 2 studies did not differentiate the effects of moderate and high doses. In regard to alcohol abuse, the open-label study reported significant reductions on the percent of heavy drinking days and percent of drinking days to up to 28 weeks. However, it was not able to differentiate the effects of the 2 doses used. Although the level and quality of evidence for psilocybin on substance use disorder are low, the preliminary results published so far are promising and have motivated researchers to conduct larger controlled trials: a 50-participant study on psilocybin-facilitated smoking cessation treatment ( <"type":"clinical-trial","attrs":<"text":"NCT01943994","term_id":"NCT01943994">> NCT01943994), a 180-participant study on psilocybin-assisted treatment of alcohol dependence ( <"type":"clinical-trial","attrs":<"text":"NCT02061293","term_id":"NCT02061293">> NCT02061293), the first study on psilocybin-facilitated treatment for cocaine use ( <"type":"clinical-trial","attrs":<"text":"NCT02037126","term_id":"NCT02037126">> NCT02037126) and multiple studies on depression ( <"type":"clinical-trial","attrs":<"text":"NCT03775200","term_id":"NCT03775200">> NCT03775200, <"type":"clinical-trial","attrs":<"text":"NCT03429075","term_id":"NCT03429075">> NCT03429075, <"type":"clinical-trial","attrs":<"text":"NCT03715127","term_id":"NCT03715127">> NCT03715127, <"type":"clinical-trial","attrs":<"text":"NCT03181529","term_id":"NCT03181529">> NCT03181529, <"type":"clinical-trial","attrs":<"text":"NCT03380442","term_id":"NCT03380442">> NCT03380442, <"type":"clinical-trial","attrs":<"text":"NCT03554174","term_id":"NCT03554174">> NCT03554174, <"type":"clinical-trial","attrs":<"text":"NCT03866174","term_id":"NCT03866174">> NCT03866174) and OCD ( <"type":"clinical-trial","attrs":<"text":"NCT03356483","term_id":"NCT03356483">> NCT03356483, <"type":"clinical-trial","attrs":<"text":"NCT03300947","term_id":"NCT03300947">> NCT03300947). Overall the results obtained across studies are impressive, given that few administrations show long lasting effects, well beyond the time-course of the acute drug effects. Moreover, the studies on different disorders have coherently shown a significant therapeutic effect.

The mechanisms underlying the effects measured are, however, yet to be confirmed and several explanations have been proposed. Given that the agonism of psilocybin on the 5-HT2A receptor is well-established, there is evidence supporting that it plays a role on the therapeutic effects reported, especially on depression. Some authors 59 propose that one of the mechanisms through which psilocybin improves depression symptoms is by blocking the activity of inflammatory cytokines, namely TNF-α, whose levels have been found to be significantly higher in depressed patients. 60 Research with fMRI in healthy volunteers after psilocybin administration has shown reduced activity in the medial Pre-Frontal Cortex (PFC) and decreased connectivity within the default mode network (DMN). 61,62 This becomes more relevant given that depressive symptoms have been associated with increased activity in the medial PFC 63,64 and that activity normalization of medial PFC has been shown with anti-depressant treatment. 65� In the last paper regarding fMRI studies in patients with treatment-resistant depression under psilocybin treatment, 68 increased DMN connectivity was observed 1 day after psilocybin administration. The authors proposed that, after psilocybin administration, DMN connectivity is reduced acutely and normalized afterwards with mood improvements, in a sort of “reset” mechanism. In the same study, 68 a significant relationship was observed between reductions in amygdala cerebral blood flow (CBF) and reductions in depression symptomatology after psilocybin administration. Moreover, psycho-spiritual mechanisms have been proposed and explored before, 51,69 as well as on several studies 21,27,41,53 included in this review. Significant correlations have been found between mystical-type experiences and the outcomes. These mystical-type experiences are defined by feelings of positive mood, sacredness, a noetic quality, transcendence of time and space and ineffability. 42 In one of the trials 27 the correlations were still significant when the overall psilocybin effects’ intensity was controlled in a partial correlation analysis, suggesting that mystical-type experiences per se play an important role, independent from the overall intensity of psilocybin effects. A mediation analysis also suggested that mystical-type experiences mediated the therapeutic effects of psilocybin.

Regarding limitations, generalizability is limited since it includes 6 open-label studies. When it comes to OCD, the single open-label study's results 39 should be analyzed carefully. Because even the lowest dose of psilocybin produced significant symptom reduction, this means that either there is a placebo effect present that cannot be measured for lack of a true placebo, or that psilocybin can be effective in such a low dose. Thus, further research on the effects of psilocybin in this disorder should try to clarify this by comparing it with a true placebo or a non-psychedelic active comparator. Furthermore, authors could not find a clear dose-response relationship to the change in YBOCS score nor correlation between YBOCS score reduction and the perceived psychedelic intensity. Additionally, the dose escalation protocol, which was also conducted on the tobacco addiction study, may have contributed to expectancy bias in both subjects and staff. Moreover, the need for staying at the hospital overnight may have introduced bias by selecting patients that could tolerate hospitalization. On alcohol dependence 41 study, the lack of biological verification of alcohol use would decrease the bias risk of self-reported-only measures if conducted. Another limitation refers to the significant number of subjects across studies that reported previous psychedelic use, which contributes to expectancy bias. On the other hand, because psilocybin produces highly discriminable effects, blinding becomes a challenge, thus increasing the bias risk. The best option seems to be the use of an inactive low dose of psilocybin, as it showed some protection against monitor expectancy and it assures the benefit of the instruction that psilocybin is going to be administered on each session. 27 Additionally, because psilocybin administration was associated with psychological support on most studies, it is not possible to make strong inferences regarding the extent of the effects. Nevertheless, the possibility of a synergistic interaction between the psilocybin administration and the psychological support is likely and should be explored.

Further trials with larger samples should be sought to confirm the results found so far, including research on the mechanisms underlying the effects reported. Altogether, the results from the studies reviewed in this paper suggest a very promising therapeutic potential from psilocybin. The results obtained so far, alongside the need for more effective psychiatric treatment, justify a call for further research.


Psilocybin Effective for Treating Major Depressive Disorder, Research Suggests

Sean is a fact checker and researcher with experience in sociology and field research.

Key Takeaways

  • Psilocybin is a psychedelic substance found in "magic mushrooms."
  • A small study of adults with major depression found that psilocybin led to significant improvements in participant's mental health.
  • No serious adverse effects from psilocybin were reported, but safety concerns for certain patients, lack of insurance coverage, and the time-consuming nature of the treatment pose challenges.

An estimated 17.3 million adults in the United States had at least one major depressive episode in 2017, according to data from the National Survey on Drug Use and Health (NSDUH).   Standard depression treatment options include a variety of anti-depressant medications, but in the future, there could be another way to treat the illness – the psychedelic substance psilocybin.

A small study of adults with major depression, led by Johns Hopkins Medicine researchers and published in JAMA Psychiatry found that two doses of psilocybin, in conjunction with supportive psychotherapy, led to “large, rapid, and sustained antidepressant effects.”   Over a four-week period, most participants showed improvement in their depressive symptoms and half of them achieved remission.