Co-administration of midazolam and psilocybin: Differential effects on subjective quality versus memory of the psychedelic experience

Serotonergic psychedelics such as psilocybin produce acute subjective experiences that have been linked to durable improvements in mental health and wellbeing. Prior studies report that particular features of the psychedelic session—often characterised as mystical, insight, or breakthrough experiences—predict longer‑term therapeutic benefit. However, it remains unclear whether those benefits arise from the immediate phenomenology of the session itself, from the neural plasticity induced during the acute drug action, or from subsequent memory and integration of the experience. Distinguishing the contribution of experience versus its memory is important for mechanistic models of psychedelic‑assisted therapy and for understanding how post‑dosing integration supports durable change. Nicholas and colleagues aimed to separate the occurrence of a psychedelic experience from its later recollection by co‑administering the amnestic benzodiazepine midazolam with psilocybin in a small pilot dose‑finding study. Their objective was to identify a midazolam dosing strategy that would permit a conscious psychedelic experience while partially impairing memory for that experience, enabling subsequent tests of whether memory mediates persistent behavioural effects. The study therefore focused on feasibility, safety, and initial signals relating midazolam dose, subjective experience during dosing, and post‑dosing memory and wellbeing measures.

This was an open, within‑subject dose‑finding pilot involving eight medically and psychiatrically healthy volunteers (4 female). Ethical approval was obtained from the University of Wisconsin Institutional Review Board and written informed consent was collected. Participants underwent preparatory sessions prior to dosing and integration sessions afterwards; dosing occurred in a clinical research unit with an anaesthesiologist and research staff present, and participants remained overnight with discharge approximately 24 hours after psilocybin administration. Supplementary materials were referenced for full inclusion/exclusion criteria and demographic details. All participants received a single oral dose of psilocybin (25 mg). Midazolam was administered intravenously as an initial bolus followed by additional boluses over the next 3.5 hours, with target plasma concentrations adjusted in real time based on functional tests and a prior pharmacokinetic model. Target serum ranges during the study were broadly 25–95 ng/ml for conscious amnesia, with later participants receiving higher target concentrations (up to ~125 ng/ml adjustments) after early participants did not meet amnesia criteria. Sedation was monitored with the Observer's Assessment of Arousal and Sedation (OAA/S); the study aimed to maintain conscious engagement (OAA/S mostly 4 or 3) while inducing amnesia. Short‑term memory during dosing was assessed with the California Verbal Learning Test (CVLT) and dosing‑day functional assessments guided midazolam titration. The primary endpoints were: (1) occurrence of a psychedelic experience on dosing day, operationalised as scoring >50% of normative scores on selected items from the Altered States of Consciousness (ASC) questionnaire; and (2) occurrence of memory impairment for that experience on Day 1, defined as scoring <50% of the mean normative ASC scores. During the dosing session participants repeatedly answered selected ASC items chosen because earlier work linked them to therapeutic outcomes; they also provided 60‑second free narrative reports (NRSE) from which short phrases were extracted for later memory testing. Secondary and exploratory endpoints included recognition memory for ASC items (yes/no old/new tasks analysed with d' signal‑detection metrics) on Days 1 and 8, CVLT performance, PEQ items assessing persisting meaningfulness and change in wellbeing on Day 8, dispositions and insight measures (DPES, WEMWBS, PIQ, EBI), and high‑density resting‑state EEG analyses focusing on eyes‑closed alpha power. Adverse events and vital signs were collected throughout. Statistical analysis was exploratory: linear regressions of outcomes on midazolam dose and memory measures emphasised confidence intervals and adjusted R2, with the authors noting the study was not powered for hypothesis testing.

Dose finding and sedation: Midazolam dosing was escalated across participants. The first four participants (labelled the low‑dose group) targeted lower plasma concentrations (initially 25–45 ng/ml) and did not reach the predefined amnestic criterion on the CVLT. Subsequent participants (the high‑dose group) received increased target concentrations (targeting ~65–95 ng/ml), and all achieved the dosing‑day CVLT criterion for amnesia while showing only mild to moderate sedation (OAA/S mostly 4 or 3). One participant briefly became more sedated between scheduled OAA/S checks and the dose was reduced. Primary endpoints—subjective experience and memory: All eight participants met the study definition of having a psychedelic experience during dosing: each scored >50% of the normative ASC values on the selected ASC items during the session. Time courses of ASC item scores peaked around two hours post‑psilocybin and were similar to prior psilocybin studies; in fact, many participants exceeded the normative median. By contrast, memory for the dosing‑day experience was impaired in some participants. None of the low‑dose participants met the Day‑1 memory impairment criterion, whereas two of four participants in the high‑dose group scored <50% of the mean normative ASC score on Day 1 (targets at ~70 ng/ml and 95 ng/ml). Secondary memory and cognitive measures: Recognition accuracy (d') for ASC items on Day 1 paralleled the ASC score comparisons: the same two high‑dose participants who met the primary memory criterion showed reduced d' relative to others. There was a modest trend for ASC d' to decline with increasing midazolam dose. Memory assessed on Day 8 for items shown on Day 1 did not show a dose‑related trend, suggesting that the impairment was most apparent for memory of the dosing period. Dosing‑day CVLT performance correlated strongly with Day‑1 memory measures, indicating that amnesia assessed during dosing predicted later impaired recall/recognition. EEG and other physiological outcomes: Resting‑state high‑density EEG showed the expected suppression of eyes‑closed alpha (8–12 Hz) power during psilocybin in 7 of 8 participants; this suppression appeared independent of midazolam dose and topography confirmed posterior visual‑cortex attenuation. Vital signs changes (heart rate, blood pressure) were consistent with prior psilocybin studies. Wellbeing and persisting effects: Changes in wellbeing measures were modest. There was a trend for WEMWBS change to decrease with increasing midazolam dose and an observed association between decreased WEMWBS and lower ASC d' on Day 1, suggesting memory impairment might relate to less favourable short‑term wellbeing changes. DPES and other dispositional measures showed mixed or weaker patterns. Safety and tolerability: Six of eight participants experienced adverse events that were mild to moderate and mostly resolved within 24 hours; reported events included headache (n=4), migraine (n=1), nausea, jaw tightness, heavy limbs, back pain, urinary incontinence, emotional distress and acid reflux. No serious adverse events were reported. The authors emphasised that the co‑administration was tolerable within the monitored clinical setting. The small sample size limited inferential claims and all analyses were presented as hypothesis‑generating.

Nicholas and colleagues interpret these pilot data as demonstrating that midazolam can be titrated to permit a conscious psychedelic experience comparable in subjective quality to psilocybin alone while producing partial impairment of memory for that experience in some participants. Preservation of subjective effects was supported by repeated ASC measures showing elevated scores during dosing and by EEG evidence of suppressed eyes‑closed alpha power—a signature previously linked to visual phenomenology under serotonergic psychedelics—independent of midazolam dose. At the same time, higher midazolam exposures were associated with dosing‑day amnesia on the CVLT and with reduced recognition accuracy for ASC items in two high‑dose participants, and there was a modest inverse association between midazolam dose and memory accuracy more broadly. The investigators discuss these findings in the context of mechanisms underlying therapeutic effects of psychedelics. They propose that memory and the neural plasticity that supports memory formation may contribute to persistent behavioural effects, and that midazolam—because it suppresses cortical plasticity and impairs encoding—could be used experimentally to dissociate the roles of acute subjective experience and drug‑induced plasticity. The authors also note alternative and interacting pathways: midazolam's anxiolytic action could suppress stress‑related components of the psychedelic session, which in turn may modify both subjective ratings during dosing and memory formation. They highlight that partial blockade of memory was associated with attenuated measures of insight, emotional salience and some aspects of wellbeing, suggesting that accessible memory of the experience could be important for post‑dosing integration and lasting benefit. Several limitations acknowledged by the authors temper these interpretations. The sample was very small and the study was not controlled or blinded, so expectancy, suggestibility, and therapeutic alliance were not assessed. Normative ASC comparators derived from a patient sample 24 hours after dosing were not matched to healthy volunteers during the session. Intermittent somnolence occurred in some participants and the study did not include dedicated, in‑session measures of insight and emotional salience; the NRSE methodology requires further validation. The authors also caution that although midazolam blocks plasticity in some cortical regions, its effects in prefrontal cortex are not established and benzodiazepines can produce subcortical plasticity changes. Planned next steps include a fully powered, placebo‑controlled follow‑up trial with direct measures of neural plasticity, more comprehensive in‑session assays of insight and salience, and refined memory paradigms (including metacognitive and dual‑process approaches) to clarify whether and how memory mediates the therapeutic effects of psilocybin.

In this dose‑finding pilot, the investigators identified a midazolam dosing approach that allowed a conscious psilocybin experience of similar intensity and subjective quality to psilocybin alone while producing partial impairment of memory for that experience in some participants. Midazolam dose and degree of memory impairment tended to associate inversely with measures of salience, insight and shifts in wellbeing. These results suggest that memory may play a role in the persistent behavioural effects following psilocybin dosing and support using midazolam as a tool to disentangle contributions of cortical neural plasticity versus subjective experience. The authors recommend a fully powered, placebo‑controlled follow‑up study to more rigorously test these mechanistic hypotheses.