Summary: Psilocybin and ketamine demonstrate significant antidepressant effects, offering new hope for patients with major depressive disorder. A recent study found that psilocybin and ketamine outperform theta burst stimulation (TBS) and placebo in both efficacy and long-term outcomes. Researchers found that ketamine provides rapid relief from depression, while psilocybin provides more sustained relief. These findings could transform how depression is treated, potentially paving the way for more effective and faster-acting therapies.
Key facts:
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Psilocybin and ketamine outperform conventional therapies.
Psilocybin and ketamine showed superior antidepressant effects compared to theta burst stimulation (TBS) and placebo in a head-to-head study.
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Ketamine for short-term benefits, psilocybin for long-term results.
While ketamine provided rapid symptom relief, psilocybin exhibited antidepressant effects for longer and with fewer doses.
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Psilocybin and ketamine address limitations of conventional treatments.
The study highlights the potential of these therapies to address the limitations of traditional antidepressants, such as delayed onset and limited efficacy.
Major depressive disorder (MDD) is a debilitating mental health condition affecting millions globally. Symptoms such as persistent sadness, loss of interest, and impaired functioning significantly diminish the quality of life of those afflicted.
However, despite the availability of conventional antidepressants, many patients fail to achieve remission or must endure weeks of waiting before therapeutic effects begin. This delay, coupled with the undesirable side effects that up to 86% of patients experience, underscores the urgent need for innovative treatments that provide faster and more effective relief.
Depression is associated with disrupted neural circuits and impaired neuroplasticity—the brain’s ability to form and reorganize synaptic connections. Psilocybin and ketamine target these underlying mechanisms through distinct pathways. Psilocybin, a serotonin receptor agonist, promotes neuroplasticity by enhancing the growth of new synapses and dendritic spines. Ketamine, an NMDA receptor antagonist, rapidly increases synaptic connections by triggering the release of brain-derived neurotrophic factor (BDNF) and activating pathways linked to neural repair.
Theta burst stimulation (TBS), in contrast, uses magnetic pulses to stimulate specific brain regions. While non-invasive, its effects are often less pronounced and require multiple sessions to achieve modest benefits.
Against this backdrop, a research team from Japan investigated whether psilocybin, the active component in magic mushrooms, and ketamine could be the key to treating major depressive disorder. The study, led by Dr. Itsuki Terao from Ikokoro Clinic Nihonbashi and Dr. Wakako Kodama from Negishi Hospital was published in PCN Reports: Psychiatry and Clinical Neurosciences on December 4, 2024.
In this groundbreaking study, researchers directly compared the antidepressant effects of psilocybin, ketamine, TBS, and placebo. The findings revealed that psilocybin and ketamine significantly outperformed TBS and placebo in alleviating depressive symptoms. Ketamine’s rapid onset of action—often within hours—makes it particularly valuable for patients in crisis. Psilocybin, administered in a controlled therapeutic setting, showed sustained effects with fewer doses, highlighting its potential as a long-term solution.
These results underscore the transformative potential of psilocybin and ketamine in treating MDD by addressing the root biological deficits rather than merely masking symptoms. As research advances, these therapies could redefine mental health care, offering new hope for those who have not responded to traditional treatments.
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About this psychopharmacology research news.
Source: PCN Reports: Psychiatry and Clinical Neurosciences
Contact: Itsuki Terao – Department of Psychiatry, Ikokoro Clinic Nihonbashi
Original Research: Open access.
"Comparative antidepressant effects and safety of intravenous racemic ketamine, psilocybin and theta burst stimulation for major depressive disorder: A systematic review and network meta‐analyses of randomized controlled trials" by Itsuki Terao et al.
Abstract.
The individual efficacy and safety of intravenous racemic (IV) ketamine, psilocybin, and theta burst stimulation (TBS) for major depressive disorder have been demonstrated through meta‐analyses of randomized controlled trials (RCTs), but the comparative usefulness of these novel treatments has not yet been fully examined. We systematically searched the CENTRAL, Medline, CINHAL, and ClinicalTrials.gov databases for randomized controlled trials up to July 4, 2024. Random‐effects network meta‐analyses were conducted to compare the Comparative antidepressant effects and safety of intravenous racemic ketamine, psilocybin and theta burst stimulation for major depressive disorderantidepressant efficacy, tolerability, and acceptability of IV ketamine, psilocybin, and TBS. Twenty‐eight RCTs were included. All treatments were superior to placebo, with IV ketamine and psilocybin showing significantly greater antidepressant efficacy than TBS. No significant differences were detected between all treatments and placebo in tolerability and acceptability. In a subgroup analysis focusing on short periods of 1 week or less, only IV ketamine was significantly more effective than placebo. In another subgroup analysis focusing on periods of 4 weeks or longer, IV ketamine and psilocybin showed significantly better antidepressant effects than placebo. The confidence in the evidence ranged from very low to moderate. Specifically, there is a scarcity of studies on psilocybin and a lack of direct comparison trials. The findings suggest that IV ketamine and psilocybin may be more effective treatments compared to TBS. Additionally, IV ketamine may have an advantage in terms of rapid onset of action. The number of included studies is limited, especially for psilocybin, and therefore the current findings are preliminary, necessitating further accumulation of direct‐comparison RCTs.
Conclusion.
This study suggests that IV ketamine and psilocybin may be superior to TBS in the treatment of MDD, with IV ketamine alone demonstrating a significant antidepressant effect within the first week. However, due to various limitations, particularly the small number of included studies, especially for psilocybin, and the absence of direct comparative trials, these findings should be interpreted as preliminary. Future head‐to‐head RCTs should be designed to confirm these findings.
