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

Abstract

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.

Fig. 1. Study schema.

A Experimental schedule. AE adverse event, ASC altered states of consciousness questionnaire, CEQ challenging experiences questionnaire, Con Med concomitant meds, CVLT California verbal learning task, DPES dispositional positive emotion scales, Drug tox urine drug screen, EBI emotional breakthrough inventory, MEQ mystical experiences questionnaire, NRSE narrative report of subjective experience, PEQ persisting effects questionnaire, PIQ psychological insight questionnaire, Preg pregnancy test, Vitals = blood pressure, heart rate, pO2; WEMWBS Warwick Edinburgh mental well-being scale. B Dosing day schedule. MDZ midazolam, OAA/S Observer’s assessment of arousal and sedation, Preg pregnancy test, PSIL psilocybin. *Vitals = blood pressure, heart rate, pO₂. **Participants 3–8 only. ***Participants 5–8 only.

Fig. 2. Dosing day assessments for the effects of midazolam.

A Performance on the California Verbal Learning Test (CVLT) administered 15 min after the initial midazolam bolus, as a function of midazolam (Midaz) target serum concentration. Each symbol represents one participant. Score range for the CVLT is 0 to 16. B Observer’s Assessment of Arousal and Sedation (OAA/S) scores averaged over the dosing session as a function of midazolam target serum concentration. Each symbol is the OAA/S score for one participant averaged across the assessment times during the dosing session. Error bars represent standard deviation. The two participants who exhibited memory impairment in Fig. 4 are indicated by filled symbols.

Fig. 3. Evidence for maintained subjective quality of the psychedelic experience when psilocybin is administered with midazolam.

A Time course of subjective quality of the psychedelic experience, plotted as Altered States of Consciousness (ASC) questionnaire scores averaged across questions and participants. Black symbols: all participants. Blue and red symbols: low and high midazolam (Midaz) dose, respectively (n = 4 for each dose range). Score range for the ASC is 0 to 100. B Scores on each question averaged across participants receiving low (top) and high (bottom) midazolam doses. C ASC scores on dosing day for each participant as a function of midazolam dose. Symbols show average of the maximum score on each question during the dosing session for each participant. Grey rectangles represent median and interquartile range for normative data for psilocybin alone (median = 55) [26] and for placebo (median = 3) [56]. The two participants who exhibited memory impairment in Fig. 4 are indicated by filled symbols. D Comparison of dosing-day responses on the ASC to normative data set [26]. Error bars display mean +/− SEM. See Supplementary Table 5 for full text of ASC questions.

Fig. 4. Evidence for impaired memory of the psychedelic experience when psilocybin is administered with midazolam.

A Altered States of Consciousness (ASC) questionnaire scores on Day 1 for each participant as a function of midazolam (Midaz) dose. Symbols show average of the scores on the 6 asked during the dosing session for each participant. (See Supplementary Table 1.) Grey rectangles represent median and interquartile range for normative data for psilocybin alone (median = 55) [26] and for placebo (median = 3) [56]. B Memory accuracy (d’) on day 1 for ASC items presented on dosing day. C Memory accuracy (d’) on day 8 for ASC items presented on day 1. D CVLT performance as a function of dosing day memory accuracy (d’; Day 1 versus dosing day). Filled symbols indicate the two participants who exhibited memory impairment. Score range for d’ is 0 to 3.48.

Fig. 5. Relationship between change in well-being and memory of the psychedelic experience.

Change in Warwick Edinburgh Mental Well-being Scale (A, ΔWEMSBS) and change in Dispositional Positive Emotion Scales (B, ΔDPES), measured as value on Day 8 minus baseline, is plotted as a function of ASC memory accuracy (d’; right). Each symbol represents one participant. Note that smaller d’ indicates greater memory impairment. The two participants who exhibited memory impairment in Fig. 4 are indicated by filled symbols.

Fig. 6. Eyes-closed (EC) electroencephalography (EEG) alpha power is suppressed by psilocybin in the presence of midazolam.

A Power spectrum at electrode Pz averaged across all subjects during baseline (pre-drug) eyes-open, baseline eyes-closed, and eyes-closed at t = 2 h. after psilocybin administration. Note the prominent alpha peak (8–12 Hz) during pre-drug eyes-closed that is suppressed during pre-drug eyes-open and during eyes-closed with psilocybin. Data clouds represent standard errors of the mean. B Eyes-closed alpha power ratio (psilocybin/baseline) for each participant as a function of target midazolam (Midaz) dose. The two participants who exhibited memory impairment in Fig. 4 are indicated by filled symbols. C Distribution of alpha power across the EEG electrode array showing that eyes-closed alpha during baseline (center) is focused in the back of the brain and is profoundly suppressed at t = 2 h. after psilocybin administration.