Psilocybin, an ingredient found in some mushrooms which is commonly known to produce hallucinations, has become a surprising new candidate for treating the worst cases of depression and anxiety. While psilocybin is listed as a Schedule 1 drug in the United States and the stigma of “frying of one's brain,” new research is showing that this classic hallucinogen not only alleviates symptoms of anxiety and depression but might do so better than any drug currently on the market [1, 2]. Old narratives surely die hard, new research on psilocybin is paving the way for researchers to carry out more extensive and revealing studies, suggesting that our current approach to these disorders should be seriously reconsidered. As you’ll find out, psilocybin appears to provoke positive and sustained changes in thought and perception and possibly does so through changing how our brain responds to a myriad of emotional stimuli [1, 2, 3].
Psilocybin Mechanism of Action
Psilocybin and its metabolite psilocin are considered to be responsible for the hallucinogenic properties derived from different species of mushrooms [1, 5]. While the use of psilocybin for ritual and spiritual practices dates back centuries or further, psilocybin only became popularized within the United States in the late 1950's and early 1960's in a clinical setting [1, 5, 6, 7]. However, once reports of psilocybin's “consciousness-expanding” effects hit the public, it gained a recreational following, prompting its placement on the list of scheduled substances in the United States .
Prior to its label as an illicit drug, western scientists began to recognize that psilocybin could facilitate positive changes to thought and perception when used in a therapeutic setting. They also found that it did so through similar pathways as lysergic acid diethylamide, otherwise known as LSD [6, 7]. Researchers found that psilocybin and its metabolite psilocin act as agonists for the 5-HT2A and 5-HT2C serotonin receptors. Studies confirmed this notion by using antagonists of these receptors alongside psilocybin, effectively blocking its effects . While psilocybin's effect begins through these receptors, research indicates that it appears to alter the function of fundamental brain structures associated with emotion, like the amygdala . Further, despite a biological influence, psilocybin appears to provide benefit by changing the perception of different aspects of mental health such as the ability to cope and deal with emotional trauma through what some would call “spiritual” or “mystical” experiences .
Research On Psilocybin & Depression
Psilocybin has been used across many different cultures for medicinal, spiritual, and religious purposes for many years. Unfortunately, due to the nature of psilocybin and other schedule 1 drugs, its use, even for spiritual reasons has been demonized, making study and therapeutic use of the drug difficult. Importantly, psilocybin’s stigma and legal status make it difficult to carry out research. However, contemporary research is attempting to readdress psilocybin’s efficacy in the clinical setting. When paired with a therapy, these studies show consistent and significant effects on depressive symptoms, even for those considered to be untreatable [1, 2].
Psilocybin & Treatment-Resistant Depression
In one study, researchers recruited twelve individuals who reported long-term, treatment-resistant depression and provided them with psilocybin alongside therapeutic practices. To be included in this study, participants were required to rank within moderate to severe levels of depression based on the 21-point Hamilton Depression Rating scale; a test meant to assess varying facets of depression and the level of severity for each individual . To be considered “treatment-resistant,” accepted participants needed to have undergone at least two attempts at using antidepressant medication with no significant change to feelings or depressive symptoms .
Participants met with psychiatrists for preliminary sessions with the opportunity to explore their depression, such as with standard therapy. While psilocybin and traditional antidepressants might exert a positive influence, research suggests that a combination of therapy and pharmaceuticals is more effective than either alone . Though this factor does call in to question whether psilocybin alone is useful, any positive findings suggest that a promising alternative to traditional antidepressants in combination with therapy exists.
Procedures & Dosing
During the initial treatment session, participants were given a low dose of 10mg of psilocybin and allowed to experience the effects of the drug in a calm environment before moving on to a higher dosage. Despite the presence of a psychiatrist throughout the experience, their influence was minimal, allowing the subjects to experience the drug fully, except for periodic assessments to ensure safety and comfort. One week after the initial dose, subjects returned to the lab and were given a higher dose at 25mg of psilocybin under similar conditions.
After completion of both sessions, the participants were reassessed using the Quick Assessment of Depressive Symptoms (QIDS) survey. This procedure allowed researchers to have an objective metric of change based on using the drug. Finally, each subject completed a QID survey at multiple time points after the high dose for an additional three months to assess any long-term influence of the drug.
This study indicates just 1-2 doses of psilocybin appears to have a radical and sustained influence on feelings of depression . In fact, all twelve participants showed a drastic improvement in depression ratings just one week after the high dose session with eight of the twelve participants showing complete remission at this time point . One session of high dose psilocybin completely eradicated feelings of depression for the majority of participants, while those with the most severe depression reduced to potentially more manageable levels. This alleviation of depressive symptoms was sustained for greater than three months for roughly 41% of the participants. While some individuals did see reemergence of depressive symptoms, only one individual returned to the severity experienced before the study .
The open-label nature of this study cannot be ignored. The fact that subjects understood what they were taking and why they were taking it presents the possibility of a placebo effect. The inclusion of therapeutic practices does also offer the possibility that psilocybin was not the sole reason for improvement. Given the context, however, it seems quite clear that psilocybin, in combination with therapy, had a strong positive influence on these symptoms. Further, the same consideration of a placebo effect can be attributed to using a traditional antidepressant along with psychotherapy, so this factor doesn’t negate the results. The significance of this study is in its comparison with other, more traditional anti-depressants. In fact, traditional anti-depressants have never been shown to have such a drastic and sustained influence after a single-use.
These findings are incredibly meaningful as one meta-analysis indicates that the use of traditional anti-depressants are only slightly more effective than placebo, with some reports being in the range of only 20% [13, 14]. In contrast, this small study employing psilocybin indicates significant improvement for most users after only two doses while sustaining these effects for months afterward. Further, this study indicates some positive influence on all subjects that used psilocybin . These findings at the very least call into question our typical treatments of depression and challenge the stigma around the use of psilocybin therapeutically .
Psilocybin For Treating Cancer Related Depression & Anxiety
The diagnosis of cancer, regardless of being life-threatening, is a traumatic event which can produce strong feelings of anxiety and of course, depression. The thought of impending death can present a significant and seemingly insurmountable obstacle, often leading to feelings of dread and existential anxiety over one of life’s biggest fears. In an attempt to alleviate these ailments, researchers have turned towards psilocybin in the hopes that its ability to produce experiences might improve quality of life and future outlook for those diagnosed.
Using a double-blind, crossover method, researchers recruited 51 subjects diagnosed with life-threatening cancer to understand the potential influence of psilocybin on feelings of depression associated with their cancer diagnosis. Each individual displayed a clinically significant level of anxiety or mood disorder, including chronic adjustment disorder; depression brought on by the inability to adjust to daily living following a traumatic and life-changing event . Subjects in this study experienced two psilocybin sessions. One session employed a therapeutic dose of 22 to 30mg of psilocybin per 70kg of body weight, while the other used a “placebo” dose of 1 to 3mg of psilocybin per 70kg of body weight. Due to the crossover design, each subject consumed both doses across two sessions.
At first glance, the mention of a low dose of psilocybin being considered placebo is a red flag. Surely using the active ingredient is the antithesis of placebo. Because of the nature of psilocybin, however, using it in a placebo-controlled study is challenging. When one uses a high dose of psilocybin, the effects are apparent, and the user expects them to occur. If, for instance, the subject consumes the high dose on the first session, they'll expect the placebo on the second, adversely affecting results. Previous research has also shown that psilocybin's effect on ratings of depression is potentially related to dose, with higher doses having a more profound impact. This suggests that a higher dose would have a stronger influence, regardless of if the person knows they're using psilocybin or not . Since this was a possibility, subjects understood they would be using psilocybin during both sessions, but the dose would vary. This way, participants could only expect that an effect would occur but would remain blind to the size of the dosage .
Psilocybin Significantly Reduced Depression & Anxiety
The results of this study indicate a drastic improvement with regards to most of the clinical measurements that were obtained . Before participating in psilocybin sessions, subjects completed multiple questionnaire assessments meant to provide insight over the severity of their depression and anxiety as well as to pinpoint specific symptoms the individual was experiencing. These questionnaires assessed symptoms such as:
- Total Mood Disturbance
- An Inventory of Experienced Symptoms
- Quality of Life
- Perception of a Meaningful Existence
- Outlook on Death Prognosis
- Optimism 
After completing both sessions, participants repeated these assessments, at multiple time points, such as immediately after the first and second sessions, as well as six months after the second session. While these assessments provided deeper insight into the effect of psilocybin, two specific tests, including the GRID-HAMD (depression) and HAM-A (anxiety) assessments were used. These were considered to be the clinical benchmarks for effectiveness. As the authors note, a change of 50% or higher from baseline scores were deemed significant . Psilocybin helped facilitate significant improvements in almost every assessment .
The data indicate that at the 6-month time point, 78% of participants showed a significant reduction in depressive symptoms, while 83% showed a significant change in their severity of anxiety . 65% of participants showed remission from depression, while over 50% displayed remission from anxiety-related symptoms at the six-month time point. More than half of participants no longer suffered from their depression or anxiety six months after participating in just two psilocybin sessions, with one of these doses being considered too low for a therapeutic response .
Considerations of The Findings
The results from this study show that using psilocybin in a clinical setting can produce significant changes to depression and anxiety after only one to two uses . Further, the findings of this study suggest a lasting effect without reusing the drug, which could last up to or longer than six months after treatment . Considering that most traditional anti-depressants take weeks or months to provide relief and are possibly only marginally better than placebo, these findings indicate the potential efficacy of psilocybin [14, 17]. With regards to the study design, however, the emergence of new research on micro-dosing calls into question the “placebo” part of this study.
This emerging research shows that individuals using tiny doses of psychedelics like LSD and psilocybin display improved emotional well being, open-mindedness, and creativity compared to people not micro-dosing [18, 19]. While these findings suggest that the design of the study could have been shortsighted, it doesn't necessarily negate the results. For instance, most, if not all users of anti-depressants know they are taking them and no study to date has shown as as much of a benefit after 1-2 doses, such as this study.
Finally, this study reports only mild adverse side effects mostly associated with the immediate time around dosing with psilocybin. These effects ranged from an increase in blood pressure and nausea and vomiting to psychological distress when subjects consumed the higher dose . Despite being mild, the possibility of these effects being present strengthen the notion of using psilocybin in a controlled and therapeutic setting, rather than in isolation. Dosing in this study was precise, and the environment the participant was in was controlled. These findings also do not suggest that merely eating psilocybin-containing mushrooms once will significantly improve symptoms of depression or anxiety. Accidentally taking too high of a dose in the wrong environment could exacerbate these adverse effects, leading to unknown consequences.
How Psilocybin Changes Brain Activity
Located just in front of the hippocampus are structures known as the amygdala. These structures are regions of the brain that allow us to recognize, dissect, and ultimately respond to emotional input . Due to its association with emotional processing, the amygdala structures have become an area of interest when treating depression. Studies suggest that when exposed to events that provoke negative emotions, the amygdala may display increased sensitivity to these emotions and do so to a greater extent in depressed individuals [3, 21].
SSRIs (Selective Serotonin Reuptake Inhibitors), which are popular for the treatment of depression, have been shown to function partly through adjusting how the amygdala responds to emotional input such as fear and our emotional responses to others . Due to similarities between how SSRIs and psilocybin interact with the amygdala, scientists have employed techniques such as functional Magnetic Resonance Imaging (fMRI) to observe how these drugs influence amygdala activity in depressed individuals when presented with situations that provoke negative emotions. Despite SSRIs often being effective, researchers believe that these powerful anti-depressants might work through masking the emotional trauma these individuals are experiencing.
It is thought that the use of psilocybin might result in compelling, psychological experiences, which are not present with SSRIs. In doing so, it is hypothesized that these experiences might help the individual work through the trauma, rather than merely dampening their emotional distress . This hypothesis seems to be the case. One study using fMRI techniques and two sessions of psilocybin indicates a significant elevation in amygdala activity when presented with emotional stimuli after the “high” has subsided . SSRIs, however, have been shown to decrease this activity, potentially confirming this masking effect of traditional antidepressants [3, 23].
The researchers found that by using psilocybin, the subjects experienced increased emotional responses to the stimuli presented. When questioned about their experience, participants suggested a “greater willingness to accept all emotions,” including the negative ones . These results suggest a different method of action with regards to SSRIs and psilocybin. While SSRIs seem to treat the symptoms of depression effectively, psilocybin treatment appears to improve emotional maturity and treat depression and its symptoms at a deeper level.
Is Psilocybin A Feasible Treatment?
The results of the currently available studies on psilocybin indicate that it could be considered as a potential treatment for long-term depression, regardless of the cause. The research highlighted here indicates a positive effect on the user’s emotional well being, outlook on life, and symptoms of depression and anxiety. These changes seem to be afforded after only a few uses, are sustained long-term, and come at minimal cost in terms of side effects. These findings are in contrast to the traditional model of treating depression and anxiety, which typically involves potent antidepressants and anxiolytics that come with a myriad of side effects in addition to requiring long term use .
The studies here employed a controlled, therapeutic setting, including supervision by medical professionals. Using psilocybin outside of a clinical setting comes with different risks. Mushrooms found in nature or purchased illegally could contain poisonous or additional, unintended substances. Additionally, doses can vary widely across different species leading to unknown consequences. While these results are promising, an expansion of acceptance for psilocybin in conjunction with psychotherapy is a must for this practice to become mainstream. If future research provides similar findings, the use of psilocybin and other psychedelics will likely become a first-line treatment for ailments such as treatment-resistant depression and anxiety.
Safety & Addiction Potential Of Psilocybin
Overall, research suggests that psilocybin is relatively safe and non-toxic. Of the current literature available, there have been no reports of any serious or long-term adverse side effects through using psilocybin in a clinical environment . One study in the early 1960's even provided psilocybin to a pregnant woman at two-week intervals. While unethical, it provided some insight into psilocybin’s safety; for at least one year post-pregnancy, no adverse effects on the mother or child were reported, suggesting a strong safety profile of the substance alone [6, 7]. However, researchers argue that psilocybin's safety profile relies heavily on the subject's understanding of the effects and the environment in which they use the drugs .
Because psilocybin can produce hallucinations, using the drug in a non-supportive environment could prove detrimental. While uncommon, a “bad trip” or inability to deal with the effects of psilocybin could lead to adverse effects. Anecdotally, recreational users suggest that psilocybin should only be used in a comfortable, familiar, and safe environment along with those that are supportive and trusting. Unsurprisingly, this in parallel with the setting that the majority of current studies use when evaluating the drug's effects [1, 2].
As for addiction, any positive or rewarding substance can produce tolerance and potentially even dependence and this must be considered. However, research on psilocybin suggests that while participants express the desire to go through the experience again, this is far different from a physical and mental dependence often seen with other recreational or even prescription drugs [6, 7, 26].
Final Thoughts on Psilocybin
The present evidence suggests that the power of psilocybin taken in a therapeutic environment cannot be ignored. These studies show a profound and immediate effect on feelings of depression and anxiety that are otherwise untreatable [1, 2, 6, 7]. Further, we see a drastic improvement in feelings of depression and outlook on life even for those with life-threatening illnesses, which provide us with insight into psilocybin's potential ability as a medication . No evidence exists suggesting that traditional anti-depressants would be as or more effective as using psilocybin along with therapeutic practices. At least, not according to these studies. These findings beg the question of whether the long-standing narrative of psychedelic drugs being dangerous is rooted in truth or simply a persistent stigma from a bygone age. At the very least, the current research suggests that psilocybin may very well be one of the best options available for treating depression and anxiety. Because of this reality, further research must commence. Whether the general public will overcome the deeply ingrained stigma of psychedelic use remains to be revealed.
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