This is the first modern study (n=12) on psilocybin and its effects on treatment-resistant depression (TRD). It shows that two sessions with psilocybin (10mg and 25mg) in combination with psychological support can reduce depressive symptoms over periods of one week to three months after treatment. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred.
“Background Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
Methods In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was the patient-reported intensity of psilocybin’s effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.
Findings Psilocybin’s acute psychedelic effects 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 difference −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.
Interpretation This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.”
Authors: Robin L. Carhart-Harris, Mark Bolstridge, James Rucker, Camilla M. J. Day, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A. Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H. Curran & David J. Nutt
This study is included in a meta-analysis by Goldberg et al. (2020).
It was followed up by Carhart-Harris et al. (2017) who looked at the effects 6-months later (and added 8 patients). And Roseman et al. (2018) looked at the influence of the quality of the experience and its prediction on outcomes. Watts et al. (2017) explored the therapeutic mechanisms.
“Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression”
“The acute effects of psilocybin were well tolerated by all of the patients and no serious or unexpected adverse events occurred. Mean self-rated intensity of psilocybin experience was 0·51 (SD 0·36) for the low-dose session and 0·75 (0·27) for the high-dose session (difference 0·24 [95% CI 0·06–0·41], Z –2·4, p=0·019).
The most common adverse events were transient anxiety (mostly mild) during drug onset (n=12), transient confusion or thought disorder (n=9), mild and transient nausea (n=4), and transient headache (n=4; table 2). These adverse events were expected psychological effects of psilocybin. Subacute headache typically presented 1 day after the psilocybin session and subsided after 1–2 days. Paranoia presented in only one patient, but this was mild and transient. No prolonged psychotic symptoms were observed in any of the patients. One patient contacted the study psychiatrists during the 3 months of follow-up due to the deterioration of their depression and was referred to their general practitioner.
“Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment’s therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% (n=8) at 1 week after treatment (HAM-D and BDI), and seven of these eight patients also met criteria for remission. Moreover, 58% (n=7) of the patients maintained their response for 3 months, and 42% (n=5) remained in remission. It is also worth noting that psilocybin has a favourable toxicity profile and is not associated with compulsive drug-seeking behaviours in animals or human beings. The side-effects that we noted were minor, and expected in light of previous studies of psilocybin.”
Because of the small sample, definitely more (double-blinded) research is necessary. Also, because there was therapeutic support before, during, and after the session, the relative effects of psilocybin are undetermined.
“One should be cautious of the potential for inflated effect sizes in early trials, particularly when the sample size is small. That all patients showed some improvement in their depressive symptoms for up to 3 weeks after treatment could be suggestive of an expectancy bias. It may also be relevant that most patients in this trial were self-referring and, thus, actively sought this treatment. Psychedelics are known to promote suggestibility, which might have further enhanced positive outcomes.“
Again, double-blinded research randomized control trials are of paramount importance to determine the effects of psilocybin in this group. Although one could also argue that you can exploit this bias through the selection of patients with strong positive expectations.
Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression (Roseman et al., 2018)
Summary of Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study
Psilocybin is a naturally occurring plant alkaloid found in the Psilocybe genus of mushrooms. It has been found to have cognitive, associative learning, cortical neural plasticity, and antidepressant effects and has been shown to reduce blood flow in the medial prefrontal cortex.
Psychedelics have been found to reduce anxious, depressive, and obsessive-compulsive symptoms and addictive behaviours, often for several months after just one or two exposures.
Psilocybin was investigated in patients with treatment-resistant depression to determine if it was safe and effective. The treatment was well tolerated and depressive symptoms were substantially reduced from baseline at all assessment points.
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Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study
Open Access | Google Scholar | Backup | 🕊
May 16, 2016
Depression Treatment-Resistant Depression
Authors associated with this publication with profiles on BlossomRobin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).
Mendel Kaelen is a neuroscientist and entrepreneur, researching and developing a new category of psychotherapeutic tools for care-seekers and care-providers. Mendel has researched the incomparable effects of music on the brain during LSD-assisted psychotherapy. His work has determined how LSD increases enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. This gives light to how music can be used as another dimension in helping psychotherapists create the ideal setting for their patients.
Amanda is the Founder and Director of the Beckley Foundation. She's called the 'hidden hand' behind the renaissance of psychedelic science, and her contribution to global drug policy reform has also been pivotal and widely acknowledged.
Institutes associated with this publicationImperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.
The psychedelics given at which dose and how many timesPsilocybin 10 - 25
mg | 2x
Linked Research Papers
Notable research papers that build on or are influenced by this paperChanges in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression
This re-analysis (n=15) of a trial with psilocybin (25mg) for depression (TRD) finds that music-evoked emotions are increased after treatment. The finding correlates with decreased anhedonia (inability to feel pleasure). fMRI measures also show a decrease in connectivity (FC) between the nucleus accumbens (NAc, music-related area) and the default mode network (DMN).
Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression
This between-subjects study (n=33) investigated whether psilocybin alters emotional processing biases in patients with treatment-resistant depression (TRD) when compared to healthy controls without TRD or psilocybin use. Two sessions of psilocybin with psychological support did improve the processing of emotional faces in treatment-resistant depression and this correlated with reduced anhedonia.
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This open-label study (n=20) found that dosages of psilocybin (10, 25mg) in a supportive setting, for those with treatment-resistant depression (TRD), changed their personality. At 3-month follow-up, Neuroticism was decreased, Extraversion and Openness were increased. The changes were similar (but more pronounced) to changes after conventional antidepressant treatment.
Patients’ accounts of increased connectedness and acceptance after psilocybin for treatment-resistant depression
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Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression
This open-label study (n=20) found that the quality of the psychedelic experience (10-25mg psilocybin, measured with the ASC - specifically oceanic boundlessness) predicted therapeutic effect (lower depression scores).
Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
This open-label study (n=20) expands on earlier work by Carhart-Harris and colleagues on the use of psilocybin-assisted therapy for treatment-resistant depression (TRD).
Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression
Psychedelics work differently than SSRIs and are hypothesized to treat the underlying disconnect with emotions, getting someone in touch with them again. This analysis of an open-label study (n=20) supports this argument with fMRI studies that showed increased amygdala responses to emotional stimuli.
Linked Clinical TrialPsilocybin for depression
This open-label trial (n=12), also known as PSILODEP-PILOT is the first to test psilocybin in patients in the UK. The study found psilocybin (10-25mg, x2) to be well-tolerated.