This open-label study (n=8) co-administered psilocybin (25mg) with the amnestic benzodiazepine midazolam to assess the role of memory in the therapeutic effects of psilocybin. It finds that midazolam partially impaired memory while allowing a conscious psychedelic experience, with memory impairment inversely associated with salience, insight, and well-being induced by psilocybin, suggesting a role for memory in its therapeutic effects.
Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.
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.
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Krediet, E., Bostoen, T., Breeksema, J. J. et al. · International Journal of Neuropsychopharmacology (2020)
Weston, N. M., Gibbs, D., Bird, C. I. V. et al. · Depression and Anxiety (2020)
Goldberg, S. B., Pace, B. T., Nicholas, C. R. et al. · Psychiatry Research (2020)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
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.
Because this was a dose-finding study, it was not powered to detect effects of midazolam or memory impairment on any of the outcome measures. Thus, the analyses presented here are solely for the purposes of generating hypotheses and should be interpreted with caution in the context of generalizing from these results. Linear regression analyses were applied to outcome measures as a function of midazolam dose and measures of memory, with the emphasis on the confidence intervals of regression slopes and adjusted coefficients of determination (r 2 ).
There is considerable interest in identifying the mechanisms underlying the therapeutic activity of serotonergic psychedelics, given accumulating evidence of positive outcomes in both clinical and healthy samples.. The relationship of the subjective quality of the psychedelic experience with clinical outcomesand evidence of pro-neuroplastic effects in rodent modelssuggest that the therapeutically-relevant effects of psychedelics reflect a complex interplay between subjective effects, especially salience and insight, and cellular and molecular effects. Within a standard PAT model, the post-dose integration phase requires that memory for the psychedelic experience be accessible and intact to harness the drug's therapeutic benefit. In this pilot study, we used the co-administration of midazolam with psilocybin to conduct an initial exploration of the mechanistic role of acute experiential and pharmacological effects versus memory for the psychedelic experience. Midazolam is a benzodiazepine that induces "conscious sedation" and amnesia, permitting acute conscious experiences while suppressing the memory for these experiences. Here, we identified a dosing strategy for midazolam that when co-administered with psilocybin produced minimal sedation and allowed the occurrence of an acute psychedelic experience comparable to normative data but that appeared sufficient to attenuate memory of the psychedelic experience. Identifying this dosing strategy is a prerequisite for a subsequent placebo-controlled trial examining the role of memory and conscious experience in therapeutic outcomes in patient populations treated with psilocybin. The dosing day evaluation of the acute psychedelic experience using selected questions from the ASC showed that all participants exhibited a psychedelic experience in the presence of midazolam comparable to normative ASC psilocybin data without midazolam. Five of 6 ASC items presented during the dosing session were selected based on strong associations with therapeutic benefit in a previous study involving psilocybin monotherapy. All participants had average scores on these ASC items that were >50% of the normative data comparison, as specified in the study design, an effect that appeared to be independent of midazolam dose. Indeed, 7 of 8 participants rated the subjective quality of the experience higher than the normative median, suggesting that midazolam might enhance the perceived quality of the psychedelic experience during its occurrence at the doses administered here. Maintenance of the subjective quality of the acute psychedelic experience during midazolam is also supported by exploratory analysis of eyes-closed EEG alpha power, which was reduced in 7 of 8 participants independent of midazolam dose. Suppressed alpha power has previously been reported for serotonergic psychedelics, likely due to the prevalence of visual hallucinations. These data indicate that key features of the psychedelic experience were preserved in the presence of midazolam. The effects on memory were more subtle. Although dosing day CVLT scores indicated profound amnestic effects of midazolam in the high dose group, only 2 participants had post-dosing ASC scores <50% of the normative data, the specified study endpoint for memory. However, secondary analyses of dosing-day ASC items suggest an inverse relationship between midazolam dose and memory accuracy, consistent with impaired memory. Complementary exploratory analyses of dosing-day CVLT items and narrative elements yielded weaker effects but were also consistent with memory impairment. Safety data indicate that the co-administration of midazolam and psilocybin was safe and welltolerated. Modest elevations in blood pressure were observed, presumably in response to psilocybin administration, as reported previously. Post-dosing memory assessments indicated partial memory impairment but not complete amnesia. This contrasts with the pronounced amnestic effects of these midazolam doses in previous studies. It is possible that the experiential activation, i.e., the profound alterations in sensory and cognitive processing, induced by psilocybin in the current study, competed against the amnestic properties of midazolam observed in previous studies. Memory of the psychedelic experience relies on (likely cortical) neural plasticity induced during the acute experience. Based on its amnestic effects and its ability to block cortical neural plasticity, midazolam may be a pharmacological tool to disambiguate the mechanistic contribution of neural plasticity compared to the psychedelic experience in the therapeutic effects of psychedelics. This is relevant given the central role proposed for neural plasticity in the mechanisms of psychiatric disorders, especially in key brain regions including prefrontal cortex. Blunted neural plasticity is a presumed biological substrate of being "stuck" in a constricted worldview with "rigid priors," i.e., psychological inflexibility, and has been described as a transdiagnostic factorwith regards to symptom severity and expression in psychiatric disorders, and more broadly to diminished flourishing and negativity bias. Although purely speculative, midazolam may also block cortical neural plasticity in areas such as the prefrontal cortex that are postulated to contribute to the therapeutic effects of psilocybin. There are several important caveats to this idea. First, the plasticity underlying memory and the plasticity underlying persistent behavioral effects of psilocybin are likely distinct, though possibly overlapping. Second, although midazolam blocks plasticity outside of hippocampus, its effects in prefrontal cortex are untested. Third, benzodiazepines not only block cortical neural plasticity, but they can also induce subcortical neural plasticity, e.g., in dopaminergic circuits, which may form the basis for their addictive potential. Testing this idea would require a follow-up study in which neural plasticity is measured directly during administration of psilocybin +/-midazolam. Psilocybin also affects memory, likely via its actions on serotonin 5HT2A receptors in areas of the brain responsible for memory encoding and retrieval. This may be the mechanism whereby these drugs promote post-dosing psychological flexibility. In preclinical models, serotonergic psychedelics modulate behavioral phenotypes and induce rapid (within hours) and long-lasting (weeks) neural plasticity, paralleling the time course of rapid symptomatic relief in patients. Acutely induced changes in gene expression may alter circuits in prefrontal cortex and connected regions controlling emotional processing. These changes may facilitate subsequent behavioral changes during the post-dosing psychotherapeutic "integration" sessions that are standard practice in clinical trials. A challenge in determining the relative contribution of experience versus plasticity to psilocybin's long-term behavioral effects is that their dose ranges entirely overlap, and thus it is difficult to separate them experimentally. Indeed, the interaction between the two may be important, and thus both may contribute. Midazolam may help disentangle these different mechanisms. Serotonergic psychedelics induce a biochemical stress response in preclinical modelsand human participants, as well as fear-and anxiety-producing experiences. There is uncertainty about the potential contribution of these stressful components of the experience to its therapeutic benefit. Acute stress also modulates memory formation, adaptively promoting memory of the stressor and suppressing memory of peripheral elements of the experience. Benzodiazepines are anxiolytic at doses even lower than those causing amnesia (e.g., <40 ng/ml serum conc.), and thus are expected to suppress the psilocybin-induced biochemical stress response and any stressful components of the psychedelic experience. In the current study, decreased stress may have contributed to the observation that ASC scores on dosing day were high relative to normative data and remained elevated for longer during the dosing session for high-dose compared to low-dose midazolam. It is also possible that midazolam's effects on the stress response contributed indirectly to impaired memory for the experience on Day 1 and Day 8. The observed effects of psilocybin administered with midazolam on well-being were more modest than those reported in response to psilocybin alone. It is likely that this was due at least in part to a ceiling effect, as baseline scores on the WEMWBS in the current study were already elevated compared to normative data for these measures. However, we did observe a trend for WEMWBS to decrease with increasing memory impairment. The absence of comparable effects on DPES may be due to the latter measure capturing only an aspect of well-being, i.e., positive emotions related to self and others, although an inverse association was observed between midazolam dose and DPES score. In addition, in contrast to the partial effect of midazolam on memory of the psychedelic experience, the effects on measures of insight and emotional salience (EBI, PIQ, PEQ) were more dramatic. These data suggest that even partial blockade of memory blunts the long-term behavioral effects of psilocybin. Alternatively, it is also possible that midazolam acutely suppressed insight and emotional salience during the dosing session, and that these aspects of the psychedelic experience were not captured by the selected ASC items administered during dosing. That is, the effect of midazolam on post-dose measures of psychological insight, emotional breakthrough, and meaningfulness may have been secondary to an acute effect on these features during the psychedelic experience. If so, this acute effect may also contribute to the amnestic effects of midazolam, given the dependence of memory on emotion 100 . Indeed, both the acute stress response induced by serotonergic psychedelicsand the emotional and personal salience of the experience may modulate memory formation 100, 101 , likely through effects on attention 102 . Midazolam would be predicted to suppress these memory-supporting mechanisms, raising the possibility that it could be used experimentally to distinguish between specific subjective features of the psychedelic experience (e.g. higher-order personal salience vs hallucinogenic effects).
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