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Psilocybin on treatment-resistant depression

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 Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study





Psilocybin’s acute psychedelic eff ects typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0–1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS diff erence –11·8, 95% CI –9·15 to –14·35, p=0·002, Hedges’ g=3·1) and 3 months (–9·2, 95% CI –5·69 to –12·71, p=0·003, Hedges’ g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.



Serotonergic antidepressants have been found to downregulate the primary receptor target of psilocybin (the 5-HT2A receptor) and attenuated subjective responses to psychedelics have previously been reported in individuals chronically medicated with serotonergic antidepressants.29 Thus, patients may be required to withdraw from concurrent antidepressant medication before receiving psilocybin and this should only ever be done with care. In conclusion, we sought to assess the safety and tolerability of psilocybin plus psychological support in patients with unipolar treatment-resistant depression. Our fi ndings support the feasibility of this approach and the magnitude and duration of the post-treatment reductions in symptom severity motivate further controlled research. Psilocybin has a novel pharmacological action in comparison with currently available treatments for depression (ie, 5-HT2A receptor agonism)





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"Psychological support was provided before, during, and after each session"

that's the key here.

10mg (low dose) and 25mg (high dose)


according to this:



there's 4.48 mg Psilocybin per gram in my shrooms.

but, they also have 0.4 mg Psylocin (Psilocin is the pharmacologically active agent in the body after ingestion of psilocybin or some species of psychedelic mushrooms) per gram.

so the low dose in the study took the equivalent of 2 grams, while the high dose took 5 gram

that's a nice dose from my experience. the most I ever took was 2.5 G, and that was an awesome trip.

its interesting that the subjects were in "treatment resistant depression", meaning they tried medication, so possible theyir 5HT-2A receptors were down regulated enough so they will feel this dose subjectively as milder than I did. (although they rated the experience pretty strongly. 5 G of shrooms! you bet...)

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It's too bad they didn't bother to include a placebo group. Placebo response in depression studies is surprisingly high, and placebo response rates are actually increasing in recent depression studies for whatever reason.


It's not hard to imagine that the psychedelic experience could enhance the placebo effect significantly, given the propensity for psychedelics to increase suggestibility and generate an artificial sense of revelation.


But then again, maybe it doesn't matter if it's placebo effect or not if the end result is a happier patient. The limitation here is duration of the remission and repeatability. The study only followed patients for 3 months, but depression scores were slowly creeping back up after the first month. Even a temporary remission would be valuable for treatment-resistant patients, but extrapolating to longer periods of illness might be difficult. If there really is something here, I would guess that it's more useful as an adjunct to psychotherapy and for kick-starting healthy life changes and elimination of negative thought patterns rather than as a chronic-type treatment like SSRIs.


It's interesting that almost half of the small sample size in the study had previous experience with psilocybin, although only one of them within any recent timeframe. If the study recruiting mentioned the specifics of the study (psychedelic treatment for depression) it's very likely that the patients were self-selected "true believers" from the start.


It would be interesting to perform a study in which the patients were sedated first, then given either a 5-HT2A agonist psychedelic or placebo. The sedation would very obviously interfere with the trip aspect, but if there's any substance to the 5-HT2A downregulation theory then it might very well be revealed in such a study. I'm skeptical, though, because I'm not yet convinced that a single dose would have such long-lasting direct effects on the 5-HT2A system. If anything, I'd expect induction of some downstream changes similar to the way Ketamine seems to work in depression.

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more useful as an adjunct to psychotherapy and for kick-starting healthy life changes and elimination of negative thought patterns rather than as a chronic-type treatment like SSRIs.


It's interesting that almost half of the small sample size in the study had previous experience with psilocybin,


I'm not yet convinced that a single dose would have such long-lasting direct effects on the 5-HT2A system. If anything, I'd expect induction of some downstream changes similar to the way Ketamine seems to work in depression.

You raise very good points.


There are interesting clues that very low doses of such drugs might be useful as a chronic treatment. There are no major studies that I know of, however.


The previous use of psilocybin is a complicating factor. Maybe the subjects were exposed to drug use because they had a "disadvantaged" background, or the opposite. It will be hard to generalize these findings to a wider population.


In other studies, the arguments that one neurotransmitter or receptor explains results rarely make a convincing argument. They tend to ignore learning as a psychological mechanism because it is still hard to measure.

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Actually with psychedelics almost all research points to "the more the better" (with therapy ofcourse). I've lost my copy of the research though, just have my points, but look in "psychadelic therapy" book where advice matches my subjective (lengthy) experience - that lower doses tend to be may more varied in results than higher ones.

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Actually with psychedelics almost all research points to "the more the better" (with therapy ofcourse). I've lost my copy of the research though, just have my points, but look in "psychadelic therapy" book where advice matches my subjective (lengthy) experience - that lower doses tend to be may more varied in results than higher ones.


Psychedelic research is difficult for many reasons. The legal status and stigma tend to attract researchers who are already true believers, while scaring the more career-minded researchers away from being associated with such research. Of what little psychedelic research is available, I find a lot of it to be either suspiciously positive or negative.


It's also notoriously difficult to do placebo control in these studies, although they would all benefit from at least one control group given a sugar pill and being told that it would also produce the desired effects.


Placebo response is crazy high in depression studies, but I often wonder if psychedelics just make for exceptionally good placebos due to their ability to induce suggestibility and a sense of enlightenment. If the placebo effect is robust enough, though, it may not matter as long as the end result is reasonable enough.




Psychedelics are really trendy right now with all of the talk about microdosing and other experiments, but the exuberance is very one-sided and proponents are quick to dismiss any negatives. Any talk about negative long-term effects or bad trips quickly turns in to a blame-the-victim conversation about set and setting or pre-existing mental illness. Also, I've probably heard or read the story of Kary Mullis attributed the discovery of PCR to his LSD use 50 times in the past few years, but no one seems to want to acknowledge that Kary Mullis is also an AIDS denialist with a strong belief in astrology who swears he had an actual encounter with a glowing green raccoon in the woods in 1985.

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  • 3 years later...

Science News
Antianxiety and antidepressant effects from a single dose of psychedelic drug persist years later in cancer patients
January 28, 2020

Following up on their landmark 2016 study, researchers at NYU Grossman School of Medicine found that a one-time, single-dose treatment of psilocybin, a compound found in psychedelic mushrooms, combined with psychotherapy appears to be associated with significant improvements in emotional and existential distress in cancer patients. These effects persisted nearly five years after the drug was administered.


In the original study, published in the Journal of Psychopharmacology, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual well-being, and increased quality of life. At the final 6.5-month follow-up assessment, psilocybin was associated with enduring antianxiety and antidepressant effects. Approximately 60 percent to 80 percent of participants continued with clinically significant reductions in depression or anxiety, sustained benefits in existential distress and quality of life, as well as improved attitudes toward death.


The present study, publishing online Jan. 28 in the same journal, is a long-term follow-up (with assessments at about 3 years and 4.5 years following single-dose psilocybin administration) of a subset of participants from the original trial. The study reports on sustained reductions in anxiety, depression, hopelessness, demoralization, and death anxiety at both follow-up points.

Approximately 60 percent to 80 percent of participants met criteria for clinically significant antidepressant or anxiolytic responses at the 4.5 year follow-up. Participants overwhelmingly (71 to 100 percent) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives.


"Adding to evidence dating back as early as the 1950s, our findings strongly suggest that psilocybin therapy is a promising means of improving the emotional, psychological, and spiritual well-being of patients with life-threatening cancer," says the 2016 parent study's lead investigator, Stephen Ross, MD, an associate professor of psychiatry in the Department of Psychiatry at NYU Langone Health. "This approach has the potential to produce a paradigm shift in the psychological and existential care of patients with cancer, especially those with terminal illness."

An alternative means of treating cancer-related anxiety and depression is urgently needed, says Ross. According to statistics from several sources, close to 40 percent of the global population will be diagnosed with cancer in their lifetime, with a third of those individuals developing anxiety, depression, and other forms of distress as a result. These conditions, experts say, are associated with poorer quality of life, increased rates of suicide, and lowered survival rate. Unfortunately, conventional pharmacologic treatment methods like antidepressants work for less than half of cancer patients and tend to not work any better than placebos. In addition, they have no effect whatsoever on existential distress and death anxiety, which commonly accompany a cancer diagnosis and are linked to a hastened desire for death and increased suicidality, says Ross.


The researchers say psilocybin may provide a useful tool for enhancing the effectiveness of psychotherapy and ultimately relieving these symptoms. Although the precise mechanisms are not fully understood, experts believe that the drug can make the brain more flexible and receptive to new ideas and thought patterns. In addition, previous research indicates that the drug targets a network of the brain, the default mode network, which becomes activated when we engage in self-reflection and mind wandering, and which helps to create our sense of self and sense of coherent narrative identity. In patients with anxiety and depression, this network becomes hyperactive and is associated with rumination, worry, and rigid thinking. Psilocybin appears to acutely shift activity in this network and helps people to take a more broadened perspective on their behaviors and lives.


For the original study, the NYU Langone team provided 29 cancer patients with nine psychotherapy sessions, as well a single dose of either psilocybin or an active placebo, niacin, which can produce a physical flush sensation that mimics a psychedelic drug experience. After seven weeks, all participants swapped treatments and were monitored with clinical outcome measures for anxiety, depression, and existential distress, among other factors. Although researchers found that the treatment's antianxiety and antidepressant qualities persisted 6.5 months after the intervention, little was known of the drug's effectiveness in the long term. The new follow-up study is the longest-spanning exploration of psilocybin's effects on cancer-related psychiatric distress to date, the study authors say.


"These results may shed light on how the positive effects of a single dose of psilocybin persist for so long," says Gabby Agin-Liebes, PhD candidate, lead investigator and lead author of the long-term follow-up study, and co-author of the 2016 parent study. "The drug seems to facilitate a deep, meaningful experience that stays with a person and can fundamentally change his or her mindset and outlook," she says. Agin-Liebes, who is pursuing her PhD in clinical psychology at Palo Alto University in California, cautions that psilocybin does not inherently lead to positive therapeutic effects when used in isolation, and in uncontrolled, recreational settings, and "should be taken in a controlled and psychologically safe setting, preferably in conjunction with counseling from trained mental health practitioners or facilitators," she adds.


Next, the researchers plan to expand this research with larger trials in patients from diverse socioeconomic and ethnic groups who have advanced cancer-related psychiatric and existential distress. "This could profoundly transform the psycho-oncologic care of patients with cancer, and importantly could be used in hospice settings to help terminally ill cancer patients approach death with improved emotional and spiritual well-being," says Ross.



Journal Reference:

Gabrielle I Agin-Liebes, Tara Malone, Matthew M Yalch, Sarah E Mennenga, K Linnae Ponté, Jeffrey Guss, Anthony P Bossis, Jim Grigsby, Stacy Fischer, Stephen Ross. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology, 2020; 34 (2): 155 DOI: 10.1177/0269881119897615

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It appears that psilocybin may work in the brain like shaking up an Etch-A-Sketch by disrupting established neuronal pathways and forcing the brain to re-establish them.



Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. We demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.




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As an aside, our State Supreme Court just ruled in favor of a guy who was arrested for possession of mushrooms.  His defense was that he used them for religious purposes and the court agreed, finding that our state constitution's protection of religious liberty was more far reaching than the BOR and did, in fact, prohibit the state from enforcing the controlled substances act in this instance.


A ruling that should have a lot of interesting repercussions. 

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