Psilocybin for depression: The psychoactive ingredient in magic mushrooms has demonstrated clinical efficacy for depression when paired with psychotherapy.
Overview: Psilocybin, the psychoactive compound found in magic mushrooms, has gained attention from researchers for its potential in treating mental illnesses like depression. Studies have shown that psilocybin-assisted therapy can reduce symptoms of depression and anxiety in cancer patients and those with treatment-resistant or major depression. However, further research is needed to fully understand the potential of psilocybin therapy for depression.
Psychedelic research has been on the rise lately, with certain compounds such as LSD, psilocybin (the psychoactive substance in magic mushrooms), and DMT showing potential therapeutic effects for various mental illnesses. Among these, psilocybin has gained special attention from scientists.
In 2006, researchers at Johns Hopkins University reported that psilocybin could produce experiences that were deeply personal and spiritually significant to those who ingested it. The study found that for two-thirds of the healthy participants who took psilocybin, it was the most meaningful experience of their lives or at least one of the top five.
These findings spurred an explosion of psychedelic research around the world, with numerous pharmaceutical companies and research institutions now involved in the field. Recent studies have shown that psilocybin can help alleviate depression, prompting the US Food and Drug Administration (FDA) ro grant “Breakthrough Therapy” status to psilocybin for major depressive disorder and treatment-resistant depression.
In 2011, a small study led by Dr. Charles Grob showed promising results for psilocybin in reducing symptoms of depression and anxiety in cancer patients.
Inspired by this, Dr. Roland Griffiths and his colleagues administered high doses of psilocybin in conjunction with supportive therapy to 50 cancer patients and found that it significantly decreased symptoms of depression, anxiety, and mood disturbance, while increasing quality of life, life meaning, death acceptance, and optimism.
Researchers at New York University, led by Stephen Ross and his team, also discovered that when combined with therapy, a single moderate dose (0.3 mg/kg) of psilocybin showed long-lasting effects in relieving anxiety and depression in cancer patients experiencing psychological distress.
Around the same time, researchers at Imperial College London investigated psilocybin's antidepressant effects on individuals with treatment-resistant major depression for an average of 17.8 years. Their pilot study found that 67% of participants achieved complete remission after 1 week and 58% continued to meet the criteria for an antidepressant response 3 months after the psilocybin session. Reductions in depression remained significant 6 months after treatment.
A 2021 study conducted by researchers at Imperial College London compared the effectiveness of psilocybin-assisted psychotherapy with the commonly prescribed antidepressant medication escitalopram (Cipralex/Lexapro).
In this trial, psilocybin-assisted psychotherapy produced larger reductions in depression. However, changes in depression scores on the Quick Inventory of Depressive Symptomatology (QIDS) at week 6 did not show a significant difference between psilocybin and escitalopram. Notably, QIDS was the only measure out of multiple depression measures that didn't show a significant difference.
Secondary outcomes, including well-being, satisfaction with life, suicidal ideation, anxiety, anhedonia (inability to feel pleasure), and sexual dysfunction, tended to favor psilocybin over escitalopram. However, the analyses of these outcomes were not corrected for multiple comparisons, meaning the researchers did not adjust the statistical analysis to account for the increased risk of falsely detecting significant results.
More research with larger sample sizes is needed before any definitive conclusions can be made about which treatment might be more effective.
In 2022, researchers associated with the psychedelic bioscience company, Compass Pathways, published the largest randomized, controlled, double-blind psilocybin therapy clinical trial conducted to date in the New England Journal of Medicine. The trial consisted of 233 participants with treatment-resistant depression.
The researchers administered a single dose of COMP360, a synthetic version of psilocybin from pharmaceutical company Compass Pathways, at doses of either 1 mg (placebo), 10 mg, or 25 mg. Patients received psychological support alongside the psilocybin session and were followed up for 12 weeks after.
At 3 weeks, depression scores were at least halved in 37% of participants in the 25 mg group, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), while 29% were observed to be in remission. Twice as many participants in the 25 mg group had a sustained response at week 12 compared to the placebo group.
It is worth noting that adverse events occurred in a high percentage of participants (77%), which is not entirely unexpected due to the nature of psilocybin's subjective effects and the treatment population. Furthermore, this study featured much less psychotherapy than previous trials conducted at Imperial College and Johns Hopkins. This is likely contributed to the high number of adverse events.
In future research, researchers will investigate the causes or factors that led to these events.
A 2022 Johns Hopkins study found that psilocybin-assisted psychotherapy significantly reduced depression in 75% of Major Depressive Disorder patients and 58% were in remission after a 12-month follow-up.
A recent clinical trial conducted by researchers at the University of Zurich in Switzerland found that a single moderate dose of psilocybin (0.215 mg/kg body weight) significantly reduced depressive symptoms for at least two weeks when compared to a placebo, in a double-blind, placebo-controlled, randomized design. The researchers observed that at the end of the treatment, 54% of participants who received psilocybin were in remission according to the MADRS criteria.
In a recent study, individuals with moderate to severe major depressive disorder were given a placebo followed by psilocybin 4 weeks later in a manualized course of psychotherapy. Results showed that both placebo and psilocybin improved depression and anxiety, with no significant difference between the two. However, this study was small and did not have enough participants to detect meaningful or significant differences between the treatment groups.
Notably, psilocybin had larger antidepressant effects and higher rates of response and remission (66.7% and 46.7%, respectively) compared to the placebo. The antidepressant effects of psilocybin lasted for an average of two months, and there were lasting improvements in mood-related quality of life domains.
Psilocybin has been gaining attention for its antidepressant effects observed under supportive conditions. However, the question remains: what is responsible for these therapeutic benefits?
Psilocybin primarily functions as a prodrug for its metabolite, psilocin. Unlike psilocybin, psilocin can freely cross the blood-brain barrier where it binds to a subtype of the serotonin receptor family known as the 5-HT2A serotonin receptor and elicits its psychedelic effects.
Some researchers believe that these psychedelic effects experienced during a psilocybin trip are necessary for positive therapeutic outcomes. These subjective effects can include positive mood, insights into thought and behavior patterns, processing of difficult emotions and memories, and mystical experiences. In studies, participants frequently report their psychedelic experiences as some of the most meaningful of their lives.
On the other hand, some researchers propose that the therapeutic effects of psilocybin can be attributed to its ability to promote structural and functional neural plasticity in the prefrontal cortex, which enhances of the brain’s ability to form new connections between neurons and to modify and adapt its structure and function in response to experience. Another neurobiological model suggests that psilocybin's antidepressant effects are linked to brain network reorganization.
In particular, some brain imaging research suggests that psilocybin may work by decreasing the activity in an interconnected network of brain regions called the default mode network (DMN). The DMN comes alive when people are at rest and engaged in the ruminative, negative mental chatter and self-judgment that is associated with mood disorders. However, other brain imaging studies have observed larger effects in other brain networks.
The psychedelic experience, altered brain connectivity, and increased neural plasticity likely all contribute to psilocybin’s clinical efficacy for depression. The question of which, if any, is more important remains the subject of
much scientific investigation.
To sum up, psilocybin-assisted therapy, alongside supportive psychotherapy, appears to be a promising treatment for depression. It's important to recognize that positive therapeutic outcomes are not solely due to psilocybin, but also to preparatory therapy sessions, a controlled therapeutic environment, and integrative therapy sessions, which are all vital components of psilocybin-assisted psychotherapy
It's also crucial to consider the limitations of the studies that examine psilocybin’s efficacy, such as small sample sizes. Additional research with larger sample sizes is necessary to confirm the findings and explore the long-term effects of psilocybin on depression.
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