Exploring Psilocybin Therapy: A New Horizon for Depression Treatment

Depression, a debilitating mental health condition affecting millions worldwide, has long been a challenge for traditional treatments. However, a new horizon emerges with psilocybin therapy, a novel approach leveraging the potential of psychedelic compounds like psilocybin, found in magic mushrooms. Recent clinical trials and research have yielded promising results, reigniting interest in exploring psilocybin’s therapeutic value for treatment-resistant depression.

This article delves into the background of psilocybin therapy, its history, and a case presentation showcasing its application through microdosing. We’ll examine a patient’s response, discuss the current research landscape, limitations, and conclude with insights into psilocybin’s potential as a groundbreaking depression treatment option.

Background on Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a prevalent and serious public health concern with multiple implications. It is characterized by persistent depressive symptoms that fail to respond adequately to multiple antidepressant interventions, including conventional antidepressants, psychotherapies, and neurostimulation modalities.

Prevalence and Public Health Implications

TRD is alarmingly common in the general population. International epidemiological estimates suggest that more than 100 million people globally meet one or more definitions of this condition. The public health implications of TRD are multifaceted and severe:

1. Higher Healthcare Costs: TRD is associated with higher healthcare utilization and the need for more intensive treatments, resulting in relatively higher direct costs compared to non-resistant depression.
2. Impaired Psychosocial Functioning: Individuals with TRD experience greater impairment in psychosocial functioning, leading to increased indirect costs due to higher workplace disability, absenteeism, and the need for disability benefits.
3. Increased Suicidality: The rate of suicidality, including completed suicide, is disproportionately higher in TRD populations compared to those with non-resistant depression.
4. Comorbidities: TRD is linked to an increased risk of common and chronic non-communicable physical diseases, such as cardiovascular disease, obesity, and type 2 diabetes mellitus.

Challenges in Treatment

Treating TRD can be particularly challenging due to several reasons:

1. Lack of Response: By definition, individuals with TRD do not respond adequately to multiple antidepressant treatments, making it difficult to find an effective therapeutic approach.
2. Individual Variability: The response to treatment varies significantly from person to person, and it may take several attempts to find the most suitable approach for each individual.
3. Complexity: TRD often requires a combination of different treatment modalities, such as consulting with experts in mood disorders, adjusting medications, incorporating psychotherapy, or considering alternative procedures like neurostimulation.

Despite these challenges, it is crucial to persist in exploring various treatment options and not lose hope, as achieving remission from TRD is possible with the right approach and perseverance.

History of Psychedelic Research

The history of psychedelic research can be traced back to the mid-20th century, when scientists began exploring the potential of these mind-altering substances. Here’s a brief overview:

Early Psychedelic Research

In 1943, Albert Hofmann accidentally discovered the psychoactive properties of lysergic acid diethylamide (LSD) while working at Sandoz Laboratories in Switzerland. This serendipitous event sparked a wave of scientific interest in psychedelics.

1. The 1950s and 1960s: These decades witnessed a surge in psychedelic research, with thousands of studies conducted on LSD and other psychedelics. Researchers investigated their potential as tools for psychotherapy, as well as their effects on various aspects of human experience, such as perception, metabolism, and addiction.
2. Psychedelic Psychotherapy: During this period, psychedelics, particularly LSD, were widely used by psychologists and psychiatrists in research and clinical practice. It is estimated that tens of thousands of patients were treated with “psychedelic psychotherapy” over a span of about 15 years.

The Hiatus and Resurgence

1. The Controlled Substances Act: As the 1960s drew to a close, the United States government intensified its war on drugs. In 1970, President Nixon introduced the Controlled Substances Act, rendering substances like psilocybin, mescaline, LSD, and DMT illegal. This act effectively ended all government-sanctioned psychedelic research, causing a significant decline in scientific exploration of these compounds.
2. Exceptions and Advocates: While large-scale controlled studies were no longer an option, some psychotherapists continued their work with psychedelics, and researchers like Rick Strassman’s work with DMT were notable exceptions to the ban. Advocates and scientists tirelessly worked to revive psychedelic research.

The Renaissance of Psychedelic Research

1. The New Millennium: The early 2000s marked a resurgence of psychedelic research. Psilocybin studies began in earnest, followed by groundbreaking studies with LSD and other psychedelics.
2. Landmark Studies: A group of researchers at Johns Hopkins University obtained regulatory approval to resume research with psychedelics in healthy volunteers. Their publication, “Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance,” is widely considered a landmark study that sparked a renewal of psychedelic research worldwide.
3. Safety and Guidelines: The Johns Hopkins team emphasized safety as a cornerstone of psychedelic research, and their recommended techniques for safe and ethical studies have been adopted by others in the field.
4. Reclassification Efforts: Researchers at Johns Hopkins suggest that if psilocybin clears phase III clinical trials, it should be reclassified from a Schedule I drug (with no known medical potential) to a Schedule IV drug, like prescription sleep aids, but with tighter control.
5. Government Funding: In a significant milestone, Johns Hopkins Medicine was awarded a grant from the National Institutes of Health (NIH) to explore the potential impacts of psilocybin on tobacco addiction, marking the first NIH grant in over half a century to directly investigate the therapeutic effects of a classic psychedelic.

As the scientific community continues to explore the therapeutic potential of psychedelics, this renewed interest in psychedelic research holds promise for advancing our understanding of the human mind and developing novel treatments for various mental health conditions.

Case Presentation

To illustrate the potential of psilocybin therapy for depression, let us consider a case presentation that highlights its application and outcomes.

Background

Psilocybin, the primary psychoactive compound found in certain mushroom species, has been consumed for centuries in various cultural and religious ceremonies. However, its medicinal value has gained significant attention in recent decades. In the mid-20th century, psilocybin and other classic psychedelics were classified as Schedule I substances, effectively halting research into their therapeutic potential.

The resurgence of clinical trials involving psilocybin in the 21st century has yielded promising results, particularly in the treatment of addiction, depression, and end-of-life mood disorders. Compared to placebo groups, these trials have demonstrated significant reductions in depression and anxiety among participants. Notably, one trial found no significant difference in efficacy between psilocybin and a routinely prescribed selective serotonin reuptake inhibitor (SSRI).

Patient Profile

In this case, we consider a patient diagnosed with treatment-resistant depression (TRD), a condition characterized by persistent depressive symptoms that fail to respond adequately to multiple antidepressant interventions. Despite trying various conventional treatments, including antidepressants, psychotherapy, and neurostimulation modalities, the patient’s condition remained unremitting.

Treatment Approach

Given the patient’s lack of response to traditional therapies, their healthcare team explored alternative treatment options, including psilocybin-assisted psychotherapy. This approach involves administering a controlled dose of psilocybin in a supportive and monitored clinical setting, combined with preparatory and integrative psychotherapy sessions.

1. Preparatory Sessions: The patient underwent several preparatory sessions with a trained psychotherapist. These sessions aimed to establish a therapeutic alliance, discuss the patient’s history, and prepare them for the psilocybin experience.
2. Psilocybin Administration: On the designated dosing day, the patient received a carefully measured dose of psilocybin in a comfortable and secure environment, under the supervision of medical professionals.
3. Integrative Sessions: Following the psilocybin experience, the patient attended integrative psychotherapy sessions. These sessions helped the patient process and integrate the insights gained during the psilocybin session, facilitating personal growth and addressing underlying psychological issues.

Patient’s Response and Outcomes

The patient’s response to psilocybin-assisted psychotherapy was remarkable. After undergoing the treatment protocol, they reported a significant reduction in depressive symptoms, improved mood, and a renewed sense of well-being.

Moreover, the patient experienced a shift in their perspective and outlook on life, leading to positive changes in their interpersonal relationships and overall quality of life. The integrative sessions played a crucial role in helping the patient translate the insights gained during the psilocybin experience into lasting behavioral and cognitive changes.

While this case presentation highlights the potential benefits of psilocybin therapy, it is essential to note that this treatment approach is still in the experimental stages and should be conducted under strict clinical supervision and guidance.

Treatment with Psilocybin Microdosing

Self-Administration of Psilocybin Microdoses

In the case presented, the patient began self-administering microdoses of psilocybin as a monotherapy approach, discontinuing all other psychiatric medications and treatments. The patient cultivated their own hallucinogenic mushrooms, specifically the Psilocybe cubensis species. After drying and grinding the mushrooms into a fine powder, the patient followed the Fadiman Protocol, a recommended regimen for beginners to microdosing.

1. Fadiman Protocol: This protocol involves encapsulating measured doses of the powdered mushrooms, starting with 0.1g. The patient took one capsule on the morning of Day 1, followed by two days of no dosing, then took another capsule on Day 4, followed by another two-day break. This cycle was repeated for eight weeks.
2. Dosage Adjustment: After an initial four-week break from dosing, the patient restarted the eight-week cycle. The Fadiman Protocol allows for gradual dose adjustments

Suggestion for read: Complex Psychology behind Manic Depression

Patient’s Response and Outcomes

The patient’s response to psilocybin-assisted psychotherapy was remarkable, with significant improvements observed across various measures of depression and functional impairment.

Reduction in Depression Symptoms

Several studies have demonstrated the efficacy of psilocybin in alleviating depressive symptoms. One study found that the mean GRID-HAMD (Hamilton Depression Rating Scale) scores at weeks 1 and 4 (8.0 and 8.5, respectively) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 and 23.5) in the delayed treatment group. The effect sizes were large, with Cohen’s d values of 2.5 and 2.6, respectively.

Another study reported that psilocybin treatment was associated with significantly reduced MADRS (Montgomery-Åsberg Depression Rating Scale) scores compared with niacin from baseline to day 43 (mean difference of -12.3) and from baseline to day 8 (mean difference of -12.0).

The QIDS-SR (Quick Inventory of Depressive Symptomatology-Self-Report) measure also showed a rapid, large decrease in mean depression scores among participants, from 16.7 at baseline to 6.3 one day after the first psilocybin session (Cohen’s d = 2.6). This substantial decrease remained through week 4 after the second session (mean score of 6.0, Cohen’s d = 2.3).

Clinically Significant Response and Remission Rates

In addition to symptom reduction, psilocybin therapy has demonstrated impressive rates of clinically significant response and remission. One study found that 71% of participants had a clinically significant response (≥50% reduction in GRID-HAMD score) at weeks 1 and 4, with 58% and 54% of participants in remission (GRID-HAMD ≤ 7) at weeks 1 and 4, respectively.

Another study reported that three out of 11 participants were responders and in remission at week 12, with one participant receiving a low dose of 1 mg and another receiving the full dose of 25 mg. Interestingly, one participant who received 1 mg and slept through most of the session was completely symptom-free at the 8-month follow-up interview.

Functional Improvement

Psilocybin therapy has also been associated with improvements in functional disability. One study found that psilocybin treatment was associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference of -2.31) from baseline to day 43, indicating improved functioning.

Sustained Effects

The benefits of psilocybin therapy appear to be sustained over time. At the 12-month follow-up in a smoking cessation study, 10 out of 12 participants who returned were smoking abstinent, with 8 reporting continuous abstinence since their target quit date. This abstinence rate of 60% is substantially higher than the 30% typically observed with the most effective smoking cessation medications.

In another study, at a mean follow-up of 30 months post-treatment, 9 participants were biologically confirmed abstinent, with 7 of them reporting not having smoked since their target quit date.

Similarly, in a study on alcohol use disorder, a 26% mean decrease in percent heavy drinking days and a 27% mean decrease in the percent of days when subjects consumed alcohol were observed following the first psilocybin session.

Long-term Remission and Symptom Reduction

Several studies have reported sustained reductions in depression, anxiety, and other psychiatric symptoms at long-term follow-ups. One study found that at the six-month interval, the Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale all demonstrated a sustained decrease in scores, indicating less severe symptoms.

In another study, the mean BDI score of the psilocybin group dropped 6.1 points after the treatment, from 16.1 one day before treatment to 10.0 at the two-week follow-up. A reduction in the BDI by roughly 30% was shown at the one-month follow-up, and this trend continued, with a significant reduction observed at the six-month follow-up (P = 0.03).

Overall, the patient’s response to psilocybin-assisted psychotherapy was remarkable, with significant reductions in depression symptoms, high rates of clinically significant response and remission, improved functioning, and sustained benefits over time. These promising outcomes highlight the potential of psilocybin therapy as a novel and effective approach for treating depression, particularly in cases where traditional treatments have failed.

Discussion of Research on Psilocybin for Depression

Promising Results from Clinical Trials

Recent clinical trials have yielded promising results regarding the efficacy of psilocybin in treating major depressive disorder (MDD). A small study conducted by Johns Hopkins Medicine researchers found that two doses of psilocybin, administered with supportive psychotherapy, produced rapid and substantial reductions in depressive symptoms among adults with MDD. Most participants showed improvement, with half achieving remission through the four-week follow-up.

Furthermore, a follow-up study on the same participants revealed that the substantial antidepressant effects of psilocybin-assisted therapy, coupled with supportive psychotherapy, may last for at least a year for some patients. These findings are particularly significant given the limitations of currently approved pharmacological treatments for MDD and the chronic nature of the condition.

Addressing Limitations in Previous Studies

While earlier studies on psilocybin’s therapeutic potential were groundbreaking, they were often limited by small sample sizes, potential unblinding of raters, open or waitlist comparator designs, and inadequate assessment of adverse events. Larger, more recent studies have addressed these limitations to varying degrees, employing randomized, multiblinded designs, active placebo comparators, and centralized, blinded raters for outcome assessments.

One such study compared a single dose of psilocybin with an active placebo (niacin) over a six-week period, using blinded centralized raters to examine the timing of onset of action, durability of benefit, and safety profile of psilocybin. This approach aimed to address the shortcomings of previous studies and provide more robust evidence for psilocybin’s potential as a treatment for MDD.

Comparison with Conventional Antidepressants

Interestingly, a double-blind, randomized, controlled trial conducted by the British National Institute for Health Research (NIHR) found no statistically significant difference in the antidepressant effects of psilocybin versus escitalopram (an SSRI) after six weeks of treatment. Both psilocybin (two 25 mg doses, three weeks apart) and daily escitalopram led to reductions in depressive symptoms, as measured by the QIDS-SR-16 (Quick Inventory of Depressive Symptomatology-Self-Report).

While the psilocybin group showed a slightly larger reduction in QIDS-SR-16 scores compared to the escitalopram group, the difference was not statistically significant. This study suggests that psilocybin may be as effective as conventional antidepressants in treating MDD, potentially offering a novel treatment approach for those who do not respond to or cannot tolerate traditional medications.

Rapid and Sustained Antidepressant Effects

One of the most promising aspects of psilocybin therapy is the rapid onset of antidepressant effects, which far outlasts the presence of the drug in the body. In the Johns Hopkins study, participants in the immediate treatment group experienced a substantial decrease in depression scores, as measured by the GRID-HAMD (Hamilton Depression Rating Scale) and QIDS-SR, within a week after the first psilocybin session.

This rapid response contrasts with traditional antidepressants, which can take several weeks or months to produce optimal improvement. Moreover, the antidepressant effects of psilocybin appear to be sustained over time, with participants in various studies reporting continued symptom reduction and improved functioning at follow-up intervals ranging from several weeks to several months after treatment.

Potential Mechanisms of Action

While the exact mechanisms underlying psilocybin’s antidepressant effects are not fully understood, researchers have proposed several potential explanations. As an agonist acting on the serotonin 5-HT2A receptor, psilocybin may modulate neural circuits involved in mood regulation, cognitive flexibility, and emotional processing.

Additionally, the intense, often mystical-like experiences induced by psilocybin may facilitate psychological and cognitive shifts, leading to changes in perspective, increased mindfulness, and a greater sense of connectedness – factors that could contribute to improved mental well-being and reduced depressive symptoms.

Limitations and Future Directions

Despite the promising findings, several limitations in the current research should be acknowledged. Many studies have relatively small sample sizes, and there is a lack of population representativeness, with most studies conducted in the United States and the United Kingdom. Additionally, the influence of factors such as participant expectations, prior experience with psychedelics, and the specific therapeutic approach employed (e.g., music therapy, cognitive-behavioral therapy) warrants further investigation.

Future research could explore the potential benefits of psilocybin therapy in conjunction with various psychotherapeutic modalities, as well as its efficacy in treating other mental health conditions, such as anxiety disorders, substance use disorders, and post-traumatic stress disorder. Additionally, investigating the potential benefits of microdosing psilocybin in non-clinical populations may yield valuable insights.

Overall, the research on psilocybin therapy for depression highlights its potential as a novel and effective treatment approach, particularly for individuals who do not respond to or cannot tolerate traditional antidepressants. While further research is needed to address limitations and explore its full therapeutic potential, the current findings are promising and contribute to a growing body of evidence supporting the therapeutic value of psychedelic compounds.

Limitations of the Case Study

Lack of Control Groups in Early Studies

Many of the initial clinical studies investigating the potential therapeutic utility of psychedelics like psilocybin were open-label, meaning they did not include a control group for comparison. While this is a common approach when exploring novel treatments, it severely limits the conclusions that can be drawn about the intervention’s efficacy.

For instance, a recent open-label study followed 27 patients with major depressive disorder (MDD) after administering two doses of psilocybin alongside supportive psychotherapy. A year later, around 60% of the participants were no longer depressed. The authors concluded that there were ‘substantial antidepressant effects of psilocybin-assisted therapy.’ However, without a control group, it is impossible to determine whether the recovery was due to the psilocybin intervention or other factors.

To put the 60% recovery rate into perspective, an analysis of 19 studies showed that the expected 12-month recovery rate for individuals with MDD who do not receive any treatment is around 53%. Demonstrating a decline in mental disorder severity or diagnostic prevalence during treatment, without comparing recovery rates to a placebo group, does not establish evidence that the treatment itself is efficacious.

Regression to the Mean

Another limitation in open-label studies is the potential for regression to the mean, a statistical phenomenon where extreme values tend to move closer to the average over time. In clinical trials, including psychedelic studies, participants are often required to meet a specific threshold of mental health problem severity for enrollment. This selection based on extreme values can lead to a decrease in scores over time, independent of the treatment’s effects.

Taken together, these issues imply that improvements observed in open-label psychedelic studies cannot be causally attributed to the treatment itself. Including a control condition is a crucial first step to increase the internal validity of these studies.

Small Sample Sizes and Inflated Effect Sizes

The most recent meta-analysis of the seven available randomized controlled trials (RCTs) for psychedelic therapy for MDD and anxiety-related disorders showed a significant reduction in symptoms up to five weeks following the intervention. However, the number of participants per treatment arm was small, with more recent studies having somewhat higher statistical power than earlier studies.

Underpowered studies typically result in imprecise and inflated effect size estimates, especially when questionable research practices and publication bias are present. As larger, preregistered studies are conducted, it is likely that the resulting effect sizes for psychedelic therapy will be lower than those previously reported.

Selection Bias and Limited Generalizability

Participants in psychedelic clinical trials often learn about the studies through media reports, trial advertisements, or clinician referrals. This, combined with prior experiences, introduces various types of selection biases. For example, a recent study’s inclusion criteria required participants to be right-handed, have mild-to-moderate depressive symptoms without psychotic features, abstain from medication, drugs, and alcohol (including tapering off antidepressant medication), be in good physical health, and have no suicide risk.

Consequently, only a highly selective group of patients is eligible to participate in these studies, limiting the generalizability of the findings to broader populations with diverse demographic and clinical characteristics.

While the limitations discussed above do not negate the promising results observed in psychedelic research, they highlight the need for larger, well-controlled studies with representative samples to establish the true efficacy and safety of psilocybin therapy for depression and other mental health conditions.

Conclusion

The exploration of psilocybin therapy for depression represents a significant step towards addressing the unmet needs of individuals suffering from treatment-resistant forms of this debilitating condition. While the findings from clinical trials and case studies are promising, indicating rapid and sustained antidepressant effects, it is crucial to approach this novel treatment modality with cautious optimism. Larger, well-controlled studies with diverse and representative samples are necessary to establish the true efficacy and safety profile of psilocybin-assisted psychotherapy.

Nonetheless, the current research highlights the potential of psychedelic compounds like psilocybin to revolutionize the treatment landscape for depression and other mental health disorders. As we continue to expand our understanding of the human mind and the mechanisms underlying these substances, we may unlock new avenues for effective interventions. Through online therapy and psychotherapy, you can gain valuable insights, learn effective communication strategies, and develop the tools necessary to cultivate a healthy and fulfilling relationship. Prioritizing mental health and well-being is crucial, and professional support can be a valuable partner on the journey to a happier and more connected future.

FAQs

What is the latest advancement in depression treatment?

The newest advancement in the treatment of depression is Esketamine (Spravato), a fast-acting antidepressant approved by the FDA in 2019. Designed for individuals with treatment-resistant depression, Esketamine is administered via a nasal spray, allowing rapid absorption into the bloodstream and quicker effects on the brain compared to traditional oral medications.

How prevalent is treatment-resistant depression (TRD)?

Treatment-resistant depression (TRD) is notably widespread across the globe. International epidemiological data suggest that over 100 million people worldwide are affected by TRD, making it a significant concern in the general population.

What is the most effective treatment strategy for treatment-resistant depression?

For individuals dealing with treatment-resistant depression, the recommended strategy often involves a combination of an oral antidepressant with either esketamine or ketamine. Additionally, healthcare providers may prescribe medications for concurrent conditions, including anti-anxiety drugs, antipsychotics, mood stabilizers, and thyroid hormones. Undertaking pharmacogenetic testing is also suggested to tailor treatment to the individual’s genetic makeup.

Which medication is preferred for individuals with treatment-resistant depression?

Ketamine is the preferred medication for individuals suffering from treatment-resistant depression. It is an anesthetic that can begin to alleviate symptoms within a few hours for some patients. Ketamine is typically administered via injection, but a nasal spray form known as esketamine is also available.

Here are few certified therapists who you can get in touch and book a therapy session with:

Nicola Demetriou

Roxanne Bigwood

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