In this Phase I trial of 25 mg psilocybin in 14 healthy adults, transient but clinically tolerable increases in blood pressure and heart rate were observed with no unexpected or long-term adverse events, supporting focused, limited cardiovascular screening for safe clinical use. Participants also reported full mystical experiences and a statistically significant reduction in QIDS-SR16 scores at eight weeks, indicating preliminary therapeutic benefit.
This Phase I trial aims to inform the development of safety protocols for psilocybin-assisted therapy. Psychedelics, including psilocybin, are increasingly being recognized as a successful treatment option for many mental health concerns. In order to decrease the risks associated with its clinical use, more data is required regarding its physiological effects in healthy individuals. Safety assessments (heart rate, blood pressure, temperature, and ECG data), as well as adverse event evaluations were the primary outcome measures used to assess the physiological effects of 25 mg of psilocybin extract administered to 14 healthy individuals. We hypothesized that there would be a transient, clinically insignificant rise in both blood pressure and heart rate that would not result in any long-term adverse effects. No unexpected effects were observed, blood pressure and heart rate returned to normal as drug effects waned, and all participants had normal two-month follow-ups. Mean peak systolic and diastolic blood pressures during the psilocybin session were 145.93 ( SD = 19.01) and 93.93 ( SD = 9.75), respectively. While this represents a significant increase from baseline ( p < 0.0001), a healthy cardiovascular system is capable of tolerating such levels for a longer time period than the brief duration of drug effects. Therefore, we suggest implementing focused and limited screening protocols to balance patient safety and accessibility. Secondary outcomes of this trial centered on the subjective effects of psilocybin, assessed via the QIDS-SR16 and the MEQ-30. There was a statistically significant decrease in QIDS-SR16 scores from baseline scores ( M = 3.50, SD = 2.35) to eight-week follow-up scores ( M = 1.86, SD = 0.86), p = 0.018. Mean MEQ-30 scores, assessed on day two and seven after the psilocybin session, indicate participants had full mystical experiences.
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Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)
Carhart-Harris, R. L., Goodwin, G. M. · Neuropsychopharmacology (2017)
Gukasyan, N., Nayak, S. · Preprints (2020)
Hartogsohn, I. · Journal of Psychopharmacology (2016)
R. and colleagues conducted a Phase I safety trial in 14 healthy participants who each received a single 25 mg dose of psilocybin extract. The primary safety measures were vital signs (heart rate, blood pressure, temperature) and ECG data, together with recording of adverse events and serious adverse events. Two self-report questionnaires were used as exploratory secondary outcomes: the QIDS-SR16 to assess depressive symptoms and the MEQ-30 to assess mystical-type experiences. Physiological results showed statistically significant, transient increases in blood pressure and mean arterial pressure during the psilocybin session. Mean peak systolic blood pressure was 145.93 mmHg (SD = 19.01) and mean peak diastolic blood pressure was 93.93 mmHg (SD = 9.75); these increases from baseline were significant (p < 0.0001). The authors report mean increases from baseline of 11.53 mmHg for systolic and 9.87 mmHg for diastolic pressure. Heart rate also rose transiently during the drug effect and returned to baseline as effects waned. One participant experienced a peak blood pressure of 193/108 mmHg during an emotionally intense period; this resolved without pharmacological intervention to 157/99 mmHg after 25 minutes and the participant had no symptoms of end-organ damage. All participants' blood pressure and heart rate returned to baseline and remained normal at the eight-week follow-up. ECG findings did not show a significant change in corrected QT interval (QTc) at this dose. Three participants exhibited ventricular extrasystoles on an intra-session ECG reading; these resolved by the next reading and were not present at eight-week follow-up. The authors note that previously reported QTc effects have been observed at substantially higher doses and that at the 25 mg dose the expected QTc change is small and not clinically concerning. On secondary, exploratory psychological measures, QIDS-SR16 scores (a 0–27 self-report measure of depressive symptoms) were lower at days two, seven and week eight compared with baseline, but only the week eight decrease reached statistical significance (baseline mean 3.50, SD = 2.35; week eight mean 1.86, SD = 0.86). The authors note that baseline scores were in the non-depressed range for almost all participants (only 1 of 14 crossed a threshold for depression), limiting the sensitivity of this scale in a healthy sample. MEQ-30 scores (a 30-item measure of mystical-type experience; score ≥ 3 indicates a full mystical experience) were collected on days two and seven; most participants met the threshold, with only three of 14 not scoring ≥ 3. At eight weeks participants commonly reported subjective improvements in well-being (descriptions such as feeling "better", "happier", and "lighter").
R. and colleagues interpret the findings as supportive of a predictable and manageable cardiovascular effect profile for a single 25 mg dose of psilocybin in healthy individuals. The observed elevations in systolic and diastolic blood pressure and mean arterial pressure were expected based on known serotonergic mechanisms of classic psychedelics, and the authors emphasise that these elevations were transient and resolved without long-term consequences in the study sample. They compare their magnitude of blood pressure change to pooled estimates reported in earlier analyses and note that their observed increases are broadly comparable. Regarding QTc, the authors state that clinically meaningful QTc prolongation has been observed in some studies at much higher doses, but at the therapeutic 25 mg dose the expected psilocin concentrations and associated QTc changes are small. Their data did not show significant QTc prolongation, and the transient ventricular extrasystoles seen in three participants were judged not clinically significant. The authors draw practical implications for clinical protocols. They argue for focused, limited screening for apparently healthy individuals to balance accessibility and safety, rather than routine exhaustive laboratory testing for everyone. Specific recommendations include screening for known cardiovascular disease, poor exercise tolerance, or use of QTc-prolonging medications; performing ECG and electrolyte panels for those with QTc concerns or abnormal ECGs; and addressing uncontrolled hypertension or exercise-induced myocardial ischaemia before psilocybin administration. They advise against routine measurement of blood pressure on the day of administration prior to ingestion because pre-session anxiety can elevate readings and potentially impede treatment, and because over-medicalisation may reduce therapeutic efficacy. The authors recommend that clinicians have rescue medications available (examples given: labetalol, nitroglycerin, and benzodiazepines such as lorazepam or diazepam) for hypertensive emergencies or intense anxiety, and they note that antipsychotic medications generally do not have a role in the acute setting. The authors acknowledge limitations in their psychological outcome measurement and monitoring. They state that the QIDS-SR16 is not well suited to detect changes in mood among healthy participants because baseline scores were low; they suggest instruments that measure well-being or self-actualisation would be more appropriate in non-clinical samples. They also note that a minority of participants experienced transient increases in depressive symptoms during the first week post-treatment, and recommend follow-up during this period to support integration and safety. The extracted text does not clearly report detailed trial design or broader generalisability limits beyond the healthy participant sample.
R. and colleagues conclude that a single 25 mg dose of psilocybin in healthy adults produced transient but statistically significant increases in blood pressure and heart rate that were manageable and returned to baseline without lasting adverse effects. No clinically meaningful QTc prolongation was observed at this dose, and ECG abnormalities that did occur were transient and resolved. Most participants experienced a full mystical-type experience and reported subjective improvements in well-being at eight weeks. The authors recommend focused screening for higher-risk individuals, avoidance of routine pre-session blood pressure checks that could provoke anxiety, availability of rescue medications, and follow-up during the early post-treatment period to support integration and safety.
The primary objective of this Phase I clinical trial was to collect data regarding the safety of psilocybin when administered to healthy individuals. Safety was assessed by documenting vital signs and recording adverse events (AEs) and serious adverse events (SAEs). The secondary exploratory objective utilized two self-assessment questionnaires (the QIDS-SR16 and the MEQ-30). These questionnaires were intended to evaluate the general nature of the subjective effects occasioned by the consumption of psilocybin and to determine its impacts on the participants' mental health following their experimental session.
The most significant finding from this safety analysis was the effect psilocybin has on blood pressure. Statistically significant elevations in both MAP, and systolic and diastolic blood pressure were seen. However, this observed increase in blood pressure and heart rate were expected adverse events, based on the known effects that classic psychedelics have on the cardiovascular system via certain serotonergic receptors (e.g., 5-HT 3 and 5-HT 2A ). These receptors are not only directly related to the modulation of heart rate, but also affect vasoconstriction. While these events were expected, it was also predicted that such events would be transient and manageable in healthy participants, and this has been documented in other studies such as inand. Whiledid not find an overall significant main effect of psilocybin on MAP, they extended their analysis further to assess whether blood pressure increased at a particular time during psilocybin treatment; it was found that MAP was significantly elevated at 60 minutes post-administration. In a similar manner, DBP was only significantly elevated at 90 minutes post-administration.conducted a meta-analysis that analyzed psilocybin's effect on the cardiovascular system as a secondary outcome. Compared with placebo, psilocybin treatment was associated with a significant increase in both systolic and diastolic blood pressure; an average increase of 19.00 mmHg and 8.66 mmHg was observed, respectively. This is comparable to the results of our study, in which there was an average increase in systolic and diastolic blood pressure from baseline by 11.53 mmHg and 9.87 mmHg, respectively. In a manner similar to the aforementioned studies, all 14 participants' blood pressures and heart rates in our study returned to baseline levels as drug effects waned, and these levels remained normal at the eight-week follow-up appointments. Another parameter of interest was the QTc interval.conducted a study to determine the concentration-QTc relationship of psilocybin/psilocin. They determined that in the high dose group (ranging from 42-59 mg), at the time of C max , the upper limit of the 90% confidence interval of the mean ΔQTc exceeded the threshold level of regulatory concern (10 ms) at a psilocin concentration of 31.1 ng/mL. Such doses are much larger than the therapeutic psilocybin dose of 25 mg. At 25 mg, the mean psilocin C max is about 18.7 ng/mL, with an associated ΔQTc of 2.1 ms (and 90% upper confidence level mean of 6.6 ms). Therefore, while psilocybin does have an effect on QTc interval, at therapeutic doses, the increase is not cause for clinical concern. Our study did not show a significant change in QTc interval, thus providing further evidence that, in healthy individuals, QTc prolongation is not a significant concern. The only atypical occurrence seen on three participants' ECGs were ventricular extrasystoles, which resolved by the following reading. These are not considered clinically significant, as ventricular extrasystoles only become a cause for concern if they occur frequently or are symptomatic. No ventricular extrasystoles were seen on the eight-week follow-up ECGs. Clearly, some individuals will experience blood pressure elevations during psilocybin use that extend into the hypertensive range; however, because such elevations are transient and manageable, we do not consider this clinically significant. The cardiovascular system is resilient enough to endure this brief increase, similarly to which both systolic blood pressure and heart rate increase during aerobic exercise. This research is also supported by emergency medicine studies that show no adverse outcomes in individuals presenting with hypertension to the Emergency Department in the ensuing two years. As described by, in general, it is normally not necessary to treat hypertensive urgencies, and it is often advised against due to the danger of unnecessary rapid correction that could lead to hypoperfusion. Virtually all episodes of hypertension with psilocybin use are without end-organ damage and do not require treatment. If hypertension presents with symptoms of end-organ damage, such as headache, dizziness, shortness of breath, chest pain, vomiting, or vision changes, then further evaluation is required. End-organ damage secondary to hypertension generally requires intravenous treatment, and therefore, transfer to the Emergency Department is required; it would be advisable to give an oral antihypertensive agent while waiting for transport. However, for most patients who experience hypertension due to drug effect, blood pressure will rapidly correct itself, especially with the administration of a benzodiazepine if warranted. As seen with one of the participants in our study, blood pressure increased to 193/108 mmHg during an emotionally intense period; this participant did not show symptoms of end-organ damage, and as expected, blood pressure corrected itself to 157/99 mmHg after 25 minutes, without pharmacological intervention. This participant's peak blood pressure is an outlier in this study, as demonstrated by Figureand Figure. For context, despite significant clinical research, there are no examples of significant adverse physiological events, and despite extensive and longstanding recreational use, there is very scant evidence of associated physiological adversity. Adverse physiological effects that have occurred are generally a result of the concomitant use of other recreational drugs, including alcohol. We would hypothesize that use of psilocybin in the clinical setting would further diminish the risk of adverse physical outcomes. The only case of psilocybin intoxication resulting in cardiovascular dysfunction that we could find in the literature is described by. This case described an 18-year-old man who was hospitalized following seizures and cardiopulmonary arrest after consumption of Psilocybe semilanceata mushroomsthe species of Psilocybe mushrooms containing the highest psilocybin concentration. This individual reported frequent psilocybin use, and investigations eventually revealed Wolff-Parkinson-White syndrome, which presumably contributed to arrhythmia (SVT) and myocardial infarction following use of the drug in this case. This individual had frequently consumed an unknown amount of a potent species of mushroom without prior evaluation from his physiciansuch uncontrolled conditions would not occur in a clinical setting. Therefore, it would seem that psilocybin has a remarkably benign cardiovascular safety profile, and we expect that apparently heathy individuals can safely tolerate the therapeutic use of psilocybin without laboratory investigations or complete physical examinations. This will increase the accessibility of this treatment for many patients, without significantly compromising safety. Blood pressure assessment is a simple screening measure to conduct for all individuals seeking psilocybin-assisted therapy; however, we discourage measuring blood pressure prior to psilocybin ingestion on the day of treatment for several reasons. First, blood pressure is easily affected by anxiety; it can add another layer of stress if the message is that the patient will not be able to proceed with the treatment session if his/her blood pressure is too high. Second, in terms of maximizing efficacy, the process should not be over-medicalized. Some basic screening measures are appropriate for individuals with known cardiovascular disease, poor exercise tolerance, or on QTc prolonging medications. In the case of those on QTc prolonging medications or those with known QTc concerns, an ECG and electrolyte panel should be performed prior to psilocybin administration. Any patient with uncontrolled hypertension or exercise-induced myocardial ischemia should have these concerns treated prior to psilocybin administration. Bloodwork (sodium, potassium, bicarbonate, urea, creatinine, calcium, and magnesium) should be conducted in those with abnormal or borderline ECGs, on diuretics, or with malnourishment. While thorough screening is necessary to attenuate the risk of adverse events from occurring in the first place, practitioners should have rescue medication (e.g., labetalol, nitroglycerin, and lorazepam and/or diazepam) on hand in the unlikely event a hypertensive emergency (or intense anxiety/agitation) occurs. Thus far, research and historical experience does not suggest that antipsychotic medications have a role in the acute setting. The secondary outcome of our study was to assess the psychological effects of psilocybin; the specific psychological outcomes assessed were mood and mystical experience. The QIDS-SR16 was administered to participants on four occasions to evaluate mood: two days before the psilocybin session to obtain a baseline score, as well as two days, seven days, and eight weeks after the psilocybin session. Although the mean scores on days two, seven, and week eight were all lower than baseline (M = 3.50, SD = 2.35), only week eight showed a statistically significant lower score (M = 1.86, SD = 0.86). The QIDS-SR16 is a self-administered questionnaire that evaluates depressive symptomatology and correlates with the nine DSM-IV symptom criteria for depression; it is scored from 0-27, with higher scores indicating more severe depressive symptoms. Scores from 0-5 indicate no depression, 6-10 indicate mild depression, 11-15 moderate depression, 16-20 severe depression, and 21-27 very severe depression. Although a statistically significant decrease was seen from baseline to week eight, it does not represent a clinically significant difference when the overall scoring of the questionnaire is considered. This scale is designed to measure depression, whereas only one out of 14 participants' baseline scores crossed the threshold for depression (with a score of 10). The mean scores of 3.50 at baseline and 1.86 at week-eight both signify no depression. As such, a limitation of our study was that this questionnaire was not the most sensitive tool to assess mood in healthy participants. A questionnaire that assesses mental well-being, such as the Brief Index of Self-actualization (BISA) revised, is likely a more appropriate tool to use to assess healthy participants; measurements of self-actualization are based on the idea that mental well-being should consider more than just the absence of disease, and should examine the extent to which personal potential is realized and achieved. However, given the decrease in QIDS-SR16 scores in participants not suffering from clinical depression, we hypothesize that a commensurate or greater decrease would be seen in those suffering from depressive disorders. Despite the fact that the QIDS-SR16 was not a sensitive tool for the assessment of mood in healthy participants, there are several clinically useful conclusions that can be drawn from the scores observed in our study. Although only experienced by a minority of participants (n = 3), it is important for practitioners to recognize the possibility that depressive symptoms may temporarily increase during the first week following a psilocybin treatment. Therefore, practitioners should follow-up with their clients during this time to ensure their well-being. It is widely accepted that this is a fertile time period for integration of the psychedelic experience, and it is hypothesized that the associated neuroplastic effects of psilocybin may help instantiate the therapeutic effects of therapy during this timeframe. With therapy, the brain can retain the new neural connections that the psychedelic state has cultivated. Essentially, in addition to the psilocybin-induced insights and biological changes that occur as a result of the acute drug effects, psilocybin also primes the brain for learning and healing in the weeks immediately following psilocybin use. The MEQ-30 was the tool used to evaluate another subjective effect induced by psilocybin -the mystical experience. It is a 30-question, self-report questionnaire that assesses four different factors of the mystical experience: mysticism, positive mood, transcendence of space and time, and ineffability. Each question is scored on a scale of 0-5 and the final score is an average of all 30 questions. A score ≥ 3 represents a full mystical experience. In studies to date, the mystical experience appears to be positively associated with the therapeutic effects of psilocybin, and it is ultimately the combination of both physiological modifications in the brain and emotionally meaningful insights that drive the transformational changes that the patient experiences. In our study, the MEQ-30 was completed on days two and seven after the psilocybin session. Participants' perception of their mystical experience (or lack thereof) was not significantly different between the two measurements. Only three of 14 participants did not score ≥ 3. The mystical experience is often determined by "set" (factors related to the individual's mindset as they enter the psychedelic session, including idiosyncratic personality dynamics, mood, past experiences, and expectations of the psilocybin experience), "setting" (the environment in which the psilocybin session occurs, including the cultural, physical, and social environment), dose, and individual pharmacokinetic characteristics. A 25 mg dose of psilocybin is equivalent to approximately 4-5 g of dried Psilocybe cubensis mushrooms. We speculate that one of our participants is a fast metabolizer of psilocybin, due to the fact that this participant only had a 30-minute experience, characterized by relaxation but not by the typical psychedelic effects. Of note, while this participant did not have a mystical experience, an increase in well-being was still described. During the eight-week follow-up appointments, participants described the common experience of feeling "better," "happier," and "lighter" after the psilocybin session, despite not having perceived themselves as anxious prior to the session. Participants suggested that they had previously become accustomed to their prior levels of anxiety, as they did not have a reference point for comparison. After experiencing improvements in their mental well-being following psilocybin use, many participants felt optimistic that they would experience a greater sense of well-being in the future.
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