New-Onset Seizures in an Adolescent Following Use of LSD while on Low-Dose Lithium Therapy: A Case Study.

This case report presents an occurrence of three generalized seizures within 30 minutes of ingestion of lysergic acid diethylamide (LSD) in a 15-year-old female patient with treatment-resistant depressive disorder recently started on low-dose lithium therapy. She had no personal or family history of seizure, brain injury or other neurological disorder. The patient had a history of monthly LSD use on several occasions in the setting of ongoing fluoxetine and longacting bupropion (Wellbutrin XL) treatment, with seizures occurring only after initiation of lithium. Although the definitive causal link cannot be established, this case report suggests an increased seizure risk with combination of LSD and lithium, even at subtherapeutic serum lithium levels. This case emphasizes the need for further research, careful clinical practice, and patient education regarding the potential dangers of using psychedelic substances with psychopharmacological treatment.

Tratamiento con microdosis de hongos con psilocibina en trastorno depresivo mayor: reporte de un caso.

La depresión mayor es una enfermedad de gran prevalencia e impacto mundial. Los tratamientos actuales presentan una tasa de no respuesta del 15 al 30 %, mientras que en casos de eficacia se suelen observar efectos adversos como el síndrome de apatía y la falta de respuesta emocional. Se postula que el tratamiento con hongos psilocibios genera la posibilidad de reducción de dosis y suspensión de psicofármacos clásicos y ocasiona cambios a nivel emocional y comportamental benéficos en pacientes con trastorno depresivo mayor. Este es un caso de un paciente no binario de 19 años de edad con diagnóstico de trastorno depresivo mayor. Se realizó unacompañamiento y asesoramiento del paciente apelando al derecho de autonomía, en el proceso de autoadministración de microdosis de psilocibina, para disminución de riesgos en salud y potenciar efectos benéficos probables, con evaluación semanal, durante un periodo de 7 meses; utilizando la anamnesis clínica, análisis de laboratorio y la escala validada de depresión de Hamilton. Como resultado de esta intervención se evidenció una remisión completa sintomática, la suspensión del tratamiento farmacológico convencional, sin síntomas de discontinuación y mejorías a nivel comunicacional, de interacción social y bienestar general. Estos hallazgos apoyan la idea de que los tratamientos con microdosis de psilocibina son una herramienta prometedora en los tratamientos de depresión. Se necesitan más estudios que aporten evidencia científica para comprobar dichos hallazgos.

Inter-individual variability in neural response to low doses of LSD.

The repeated use of small doses of psychedelics (also referred to as "microdosing") to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual's cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment.

Interrupting the Psychedelic Experience Through Contextual Manipulation to Study Experience Efficacy.

This quality improvement study investigates the association of interruptions during psychedelic therapy with ratings of intensity of experience.

State Cannabis and Psychedelic Legislation and Microdosing Interest in the US.

Importance: Despite growing interest in psychedelics, there is a lack of routine population-based surveillance of psychedelic microdosing (taking "subperceptual" doses of psychedelics, approximately one-twentieth to one-fifth of a full dose, over prolonged periods). Analyzing Google search queries can provide insights into public interest and help address this gap. Objective: To analyze trends in public interest in microdosing in the US through Google search queries and assess their association with cannabis and psychedelic legislative reforms. Design, Setting, and Participants: In this cross-sectional study, a dynamic event-time difference-in-difference time series analysis was used to assess the impact of cannabis and psychedelic legislation on microdosing search rates from January 1, 2010, to December 31, 2023. Google search rates mentioning "microdosing," "micro dosing," "microdose," or "micro dose" within the US and across US states were measured in aggregate. Exposure: Enactment of (1) local psychedelic decriminalization laws; (2) legalization of psychedelic-assisted therapy and statewide psychedelic decriminalization; (3) statewide medical cannabis use laws; (4) statewide recreational cannabis use laws; and (5) all cannabis and psychedelic use restricted. Main Outcome and Measures: Microdosing searches per 10 million Google queries were measured, examining annual and monthly changes in search rates across the US, including frequency and nature of related searches. Results: Searches for microdosing in the US remained stable until 2014, then increased annually thereafter, with a cumulative increase by a factor of 13.4 from 2015 to 2023 (7.9 per 10 million to 105.6 per 10 million searches, respectively). In 2023, there were 3.0 million microdosing searches in the US. Analysis at the state level revealed that local psychedelic decriminalization laws were associated with an increase in search rates by 22.4 per 10 million (95% CI, 7.5-37.2), statewide psychedelic therapeutic legalization and decriminalization were associated with an increase in search rates by 28.9 per 10 million (95% CI, 16.5-41.2), statewide recreational cannabis laws were associated with an increase in search rates by 40.9 per 10 million (95% CI, 28.6-53.3), and statewide medical cannabis laws were associated with an increase in search rates by 11.5 per 10 million (95% CI, 6.0-16.9). From August through December 2023, 27.0% of the variation in monthly microdosing search rates between states was explained by differences in cannabis and psychedelics legal status. Conclusion and Relevance: This cross-sectional study found that state-led legislative reforms on cannabis and psychedelics were associated with increased public interest in microdosing psychedelics.

Increased reactivity of the paraventricular nucleus of the hypothalamus and decreased threat responding in male rats following psilocin administration.

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior.

Decoupling of cortical activity from behavioral state following administration of the classic psychedelic DOI.

Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2A receptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving male mice after administration of the 5-HT2A/2C receptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results suggest that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties.

Psilocybin decreases neural responsiveness and increases functional connectivity while preserving pure-tone frequency selectivity in mouse auditory cortex.

Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted two-photon imaging experiments in auditory cortex of awake mice and collected video of free-roaming mouse behavior, both at baseline and during psilocybin treatment. In comparison with pre-dose neural activity, a 2 mg/kg ip dose of psilocybin initially increased the amplitude of neural responses to sound. Thirty minutes post-dose, behavioral activity and neural response amplitudes decreased, yet functional connectivity increased. In contrast, control mice given intraperitoneal saline injections showed no significant changes in either neural or behavioral activity across conditions. Notably, neuronal stimulus selectivity remained stable during psilocybin treatment, for both tonotopic cortical maps and single-cell pure-tone frequency tuning curves. Our results mirror similar findings regarding the effects of serotonergic psychedelics in visual cortex and suggest that psilocybin modulates the balance of intrinsic versus stimulus-driven influences on neural activity in auditory cortex.NEW & NOTEWORTHY Recent studies have shown promising therapeutic potential for psychedelics in treating neuropsychiatric conditions. Musical experience during psilocybin-assisted therapy is predictive of treatment outcome, yet little is known about how psilocybin affects auditory processing. Here, we conducted two-photon imaging experiments in auditory cortex of awake mice that received a dose of psilocybin. Our results suggest that psilocybin modulates the roles of intrinsic neural activity versus stimulus-driven influences on auditory perception.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

Novel extended-release transdermal formulations of the psychedelic N,N-dimethyltryptamine (DMT).

There is considerable evidence from the literature that psychedelics, such as N,N-dimethyltryptamine (DMT), are safe and effective treatments for depression. However, clinical administration to induce psychedelic effects and expensive psychotherapy-assisted treatments likely limit accessibility to the average patient. There is emerging evidence that DMT promotes positive behavioral changes in vivo at sub-hallucinogenic dosages, and depending on the target indication, subjecting patients to high, bolus dosages may not be necessary. Due to rapid metabolic degradation, achieving target levels of DMT in subjects is difficult, requiring IV administration, which poses risks to patients during the intense hallucinogenic and subjective drug effects. The chemical and physical properties of DMT make it an excellent candidate for non-invasive, transdermal delivery platforms. This paper outlines the formulation development, in vitro, and in vivo testing of transdermal drug-in-adhesive DMT patches using various adhesives and permeation enhancers. In vivo behavioral and pharmacokinetic studies were performed with lead patch formulation (F5) in male and female Swiss Webster mice, and resulting DMT levels in plasma and brain samples were quantified using LC/MS/MS. Notable differences were seen in female versus male mice during IV administration; however, transdermal administration provided consistent, extended drug release at a non-hallucinogenic dose. The IV half-life of DMT was extended by 20-fold with administration of the transdermal delivery system at sub-hallucinogenic plasma concentrations not exceeding 60 ng/mL. Results of a translational head twitch assay (a surrogate for hallucinogenic effects in non-human organisms) were consistent with absence of hallucinations at low plasma levels achieved with our TDDS. Despite the reported low bioavailability of DMT, the non-invasive transdermal DMT patch F5 afforded an impressive 77 % bioavailability compared to IV at two dosages. This unique transdermal delivery option has the potential to provide an out-patient treatment option for ailments not requiring higher, bolus doses and is especially intriguing for therapeutic indications requiring non-hallucinogenic alternatives.

Effects of a Single Dose of Ayahuasca in College Students With Harmful Alcohol Use: A Single-blind, Feasibility, Proof-of-Concept Trial.

BACKGROUND: Ayahuasca is a South American plant hallucinogen rich in the psychedelic N,N-dimethyltryptamine and ß-carbolines (mainly harmine). Preclinical and observational studies suggest that ayahuasca exerts beneficial effects in substance use disorders, but these potentials were never assessed in a clinical trial. METHODS: Single-center, single-blind, feasibility, proof-of-concept study, assessing the effects of one dose of ayahuasca accompanied by psychological support (without psychotherapy) on the drinking patterns (primary variable) of 11 college students with harmful alcohol consumption. Secondary variables included safety and tolerability, craving, personality, anxiety, impulsivity, self-esteem, and social cognition. FINDINGS: Ayahuasca was well tolerated (no serious adverse reactions were observed), while producing significant psychoactive effects. Significant reductions in days per week of alcohol consumption were found between weeks 2 and 3 (2.90 ± 0.28 vs 2.09 ± 0.41; P < 0.05, uncorrected), which were not statistically significant after Bonferroni correction. There were no statistically significant effects for other variables, except for a significant reduction in reaction time in an empathy task. CONCLUSIONS: A significant reduction in days of alcohol consumption was observed 2-3 weeks after ayahuasca intake, but this effect did not survive after Bonferroni correction. The lack of significant effects in alcohol use and other variables may be related to the small sample size and mild/moderate alcohol use at baseline. The present study shows the feasibility of our protocol, paving the way for future larger, controlled studies.

[MDMA-assisted therapy for PTSD].

MDMA is a potential novel treatment for post-traumatic stress disorder (PTSD). Our goal is to review current knowledge on MDMA and its use in MDMA-assisted psychotherapy for PTSD. Literature searches were done on PubMed, Web of Science and Google Scholar and references reviewed in identified articles. MDMA-assisted therapy for PTSD usually consists of a few preparatory sessions before two or three sessions where one or two oral doses of MDMA are given along with supportive psychotherapy. The therapy is delivered in the presence of two therapists for about eight hours each time. In addition, the patient receives up to 9 integrative sessions in due course. This use of MDMA as a part of psychotherapy for PTSD is proposed to lessen the psychological distress that often arises in the processing of traumatic events to facilitate the treatment process and reduce the risk of drop-out. Recent studies indicate that MDMA-assisted psychotherapy reduces PTSD symptoms and is generally well tolerated. These studies are necessary if this MDMA-assisted treatment is to be approved by licensing authorities. There is an urgent need for new effective treatments for PTSD and for comparisons between this MDMA-assisted psychotherapy and currently approved psychotherapies with and without MDMA-use.

Naturalistic use of psychedelics does not modulate processing of self-related stimuli (but it might modulate attentional mechanisms): An event-related potentials study.

Classic psychedelics are able to profoundly alter the state of consciousness and lead to acute experiences of ego dissolution - the blurring of the distinction between representations of self and the external world. However, whether repeated use of psychedelics is associated with more prolonged and permanent modifications to the concept of self remains to be investigated. Therefore, we conducted a preregistered, cross-sectional study in which experienced psychedelics users (15 or more lifetime experiences with psychedelics; N = 56) were compared to nonusers (N = 57) in terms of neural reactivity to a Self-name (i.e., each participant's own name) stimulus, which is known to robustly activate a representation of self. Two control stimuli were additionally used: an Other-name stimulus, as a passive control condition in which no reaction was required, and a Target-name stimulus, to which participants provided a manual response and which thus constituted an active control condition. Analysis of the amplitude of the P300 ERP component evoked by the Self- or Target-names revealed no difference between the psychedelics users and nonusers. However, psychedelic users exhibited increased P300 amplitude during perception of Other-names. In addition, in comparison to nonusers, psychedelics users exhibited a smaller increase in P300 amplitude when processing the task-relevant Target-names (in relation to both Self- and Other-names). Therefore, our data suggests that regular naturalistic use of psychedelics may not be related to long-term changes in the representation of self, but it might potentially affect the allocation of attentional resources to task-relevant stimuli.

Dynamic Functional Hyperconnectivity After Psilocybin Intake Is Primarily Associated With Oceanic Boundlessness.

BACKGROUND: Psilocybin is a widely studied psychedelic substance that leads to the psychedelic state, a specific altered state of consciousness. To date, the relationship between the psychedelic state's neurobiological and experiential patterns remains undercharacterized because they are often analyzed separately. We investigated the relationship between neurobiological and experiential patterns after psilocybin by focusing on the link between dynamic cerebral connectivity and retrospective questionnaire assessment. METHODS: Healthy participants were randomized to receive either psilocybin (n = 22) or placebo (n = 27) and scanned for 6 minutes in an eyes-open resting state during the peak subjective drug effect (102 minutes posttreatment) in ultrahigh field 7T magnetic resonance imaging. The 5-Dimensional Altered States of Consciousness Rating Scale was administered 360 minutes after drug intake. RESULTS: Under psilocybin, there were alterations across all dimensions of the 5-Dimensional Altered States of Consciousness Rating Scale and widespread increases in averaged brain functional connectivity. Time-varying functional connectivity analysis unveiled a recurrent hyperconnected pattern characterized by low blood oxygen level-dependent signal amplitude, suggesting heightened cortical arousal. In terms of neuroexperiential links, canonical correlation analysis showed higher transition probabilities to the hyperconnected pattern with feelings of oceanic boundlessness and secondly with visionary restructuralization. CONCLUSIONS: Psilocybin generates profound alterations at both the brain and the experiential levels. We suggest that the brain's tendency to enter a hyperconnected-hyperarousal pattern under psilocybin represents the potential to entertain variant mental associations. These findings illuminate the intricate interplay between brain dynamics and subjective experience under psilocybin, thereby providing insights into the neurophysiology and neuroexperiential qualities of the psychedelic state.

Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

A taxonomy of regulatory and policy matters relevant to psychedelic-assisted therapy in Australia.

OBJECTIVES: The Australian government recently rescheduled psilocybin and 3,4-methylenedioxymethamphetamine for limited clinical uses. This change has raised various regulatory concerns and challenges for the field of psychedelic-assisted therapy. To provide clarity, we aimed to comprehensively catalogue the matters relating to psychedelic-assisted therapy that are or could be regulated. METHODS: We conducted a desktop review of the literature and current regulatory sources, semi-structured interviews with professionals who had expertise in fields relating to psychedelic-assisted therapy and a framework analysis to generate a taxonomy of relevant regulatory matters. In relation to each matter, we further identified what type of regulation (if any) currently applies to that matter, any uncertainty as to how the matter should be addressed in clinical practice in the context of current regulation and whether there are conflicting views as to how the matter could or should be further regulated. RESULTS: The taxonomy is structured into six main regulatory domains, three of which have a substantial proportion of matters with uncertainty or conflicting views: Service Establishment, Practitioner, and Treatment Delivery. Key examples of such matters include the location of services and facilities required, which professionals are eligible to become psychedelic therapists, and with what qualifications and experience. Matters in the remaining three domains, Patient Evaluation, Drug Supply and Service Oversight, appear by comparison relatively settled, with regulation either well-established or thought unnecessary. CONCLUSIONS: The taxonomy provides a roadmap for health services establishing and implementing a psychedelic-assisted therapy program, or for government and other policymakers when determining areas that may require further regulation.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Psychedelics and the 'inner healer': Myth or mechanism?

BACKGROUND: Reference to an intrinsic healing mechanism or an 'inner healer' is commonplace amongst psychedelic drug-using cultures. The 'inner healer' refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived 'inner healing' effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or 'placebo' (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p < 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing. CONCLUSIONS: The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.