A Phase I trial to inform clinical protocols for the safe administration of psilocybin-assisted psychotherapy

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.