Ayahuasca enhances the formation of hippocampal-dependent episodic memory without impacting false memory susceptibility in experienced ayahuasca users: An observational study

Doss and colleagues situate this study within growing interest in how psychedelics affect episodic memory, that is, the conscious re-experiencing of past events. They note ayahuasca is a brew containing DMT (from Psychotria viridis) and β-carbolines (from Banisteriopsis caapi); β-carbolines render DMT orally active by inhibiting monoamine oxidase A (MAO-A) and have their own psychoactive properties. Previous human and animal work shows psychedelics and other psychoactive drugs can differentially affect memory phases (encoding, consolidation, retrieval) and distinct memory processes, especially recollection (hippocampal-dependent retrieval of contextual detail) and familiarity (a cortical-dependent sense that a stimulus has been encountered). Those earlier findings are mixed: pre-encoding psilocybin and MDMA often impair recollection, whereas familiarity can be spared or even enhanced, and drugs administered around retrieval have been associated with increased false memories for some compounds. This observational study aimed to characterise how ayahuasca acutely influences true and false episodic memory, recollection versus familiarity, and metamemory in a sample of experienced Santo Daime members. The investigators tested participants both sober and while acutely intoxicated by a self-selected ceremonial ayahuasca batch, using a three-phase false-memory paradigm (encoding, misinformation, retrieval) designed to probe suggestion-driven distortions as well as objective measures of recollection and familiarity. They emphasised examining memory when drug effects spanned encoding, misinformation, and retrieval, a situation ecologically relevant to frequent ceremonial use but rarely modelled experimentally.

This was a within-subject, fixed-order observational study in which 24 Santo Daime members completed assessments first while sober (baseline) and then in a second session 24 hours later during which they consumed a self-selected dose of ayahuasca in a ceremonial context. The sample comprised 24 participants (14 males) with extensive prior ayahuasca exposure (mean membership duration 14.2 years; mean reported ceremony attendance 563 events), mean age 55.2 years. Exclusion criteria included pregnancy, recent use of interacting drugs or other psychedelics, recent alcohol use, and MRI contraindications; urine and breath tests were used to confirm recent substance abstinence where relevant. A single batch of ayahuasca prepared by the church was analysed by high-performance liquid chromatography–mass spectrometry; the sample concentrations were reported as 0.14 mg/mL DMT, 4.50 mg/mL harmine, 0.51 mg/mL harmaline, and 2.10 mg/mL tetrahydroharmine, yielding average doses per participant of 3.36 mg DMT and 170.64 mg combined β-carbolines (average liquid dose 24 mL, range 11–40 mL). The primary cognitive probe was a three-phase false-memory task (encoding, misinformation, retrieval). During encoding, participants viewed three of six illustrated scenes (e.g., classroom, beach, ayahuasca ceremony) for 40 s each and rated scene familiarity. After a short filler, participants listened to three narratives purportedly from previous participants that described the scenes but included suggested items (four items actually present and four semantically related items that were not). After another filler, retrieval comprised 72 self-paced cued recollection trials: for each test item the participant indicated whether the object had been present (yes/no) followed by a 4-point confidence rating. Item categories per session were targets, suggested targets, suggested lures, related lures, and unrelated lures; due to a computer error some participants were missing single-item data points in each condition. Analyses focused on hit rates, several false-alarm rates (suggested, related, unrelated), and derived measures intended to control for response bias such as accuracy (hit rate minus unrelated-lure false alarm rate) and precision (hit rate minus related-lure false alarm rate). The investigators also computed suggested-precision and measures isolating the effects of suggestion and relatedness. Repeated-measures t-tests (α = 0.05) compared baseline versus ayahuasca conditions. To estimate recollection and familiarity they applied the dual-process signal detection (DPSD) model, using a bootstrapping procedure (10,000 iterations sampling 24 participants with replacement) to derive distributions and 95% confidence intervals for difference scores. Metamemory (metacognitive efficiency) was estimated via hierarchical Bayesian meta-d′ modelling (HMeta-d Toolbox) with 3 Markov Chain Monte Carlo chains, discarding the first 1,000 samples and retaining 10,000 samples per chain; multiple permutations of targets and lure sets were explored. Exploratory correlations between memory measures and plasma alkaloid concentrations and consumed dose were reported in supplemental material and interpreted cautiously given multiple tests.

Familiarity ratings collected during encoding did not differ between sober and ayahuasca sessions, indicating similar visual exploration of scenes across conditions. Contrary to the pre-registered prediction that pre-encoding ayahuasca would impair true memory, several indicators showed enhanced memory under ayahuasca: hit rates increased (CI = [0.01 to 0.12], t(23) = 2.44, p = 0.023, d = 0.50), overall memory accuracy (hit rate minus unrelated false alarms) increased (CI = [0.01 to 0.13], t(23) = 2.30, p = 0.031, d = 0.47), high-confidence hit rates increased (CI = [0.04 to 0.15], t(23) = 3.34, p = 0.003, d = 0.68), and high-confidence accuracy increased (CI = [0.05 to 0.17], t(23) = 3.90, p < 0.001, d = 0.80). There was a near-significant reduction in high-confidence unrelated-lure false alarms (CI = [-0.00 to 0.04], t(23) = 1.82, p = 0.081, d = 0.37), but these rates were low overall. DPSD modelling indicated a clear enhancement in recollection under ayahuasca (mean difference M = 0.20, SD = 0.08, CI = [0.08 to 0.34], p < 0.001). Familiarity estimates did not differ between conditions (M = 0.07, SD = 0.14, CI = [-0.21 to 0.30], p > 0.250), though the authors note that familiarity estimates at baseline and under ayahuasca were relatively elevated compared with prior datasets. Metamemory (meta-d′/d′) showed no reliable effect of ayahuasca across several operationalisations (e.g., all targets/all lures M = 0.07, SD = 0.12, CI = [-0.17 to 0.26], p > 0.250; other target-lure combinations similarly non-significant). Across the false-memory metrics (suggested, related, unrelated lures), ayahuasca did not increase false alarms; the planned analyses therefore combined scenes and treated the null findings on false-memory measures as robust within this experienced-user sample. Exploratory correlations between plasma alkaloids and memory measures were reported in supplemental material; the authors highlight a negative correlation between plasma harmine and improvements in high-confidence hit rates but advise caution in interpretation.

Doss and colleagues interpret their principal finding—an enhancement of recollection-based episodic memory under pre-encoding ayahuasca in experienced Santo Daime users—as surprising given prior reports of memory impairment from pre-encoding administration of prototypical psychedelics such as psilocybin and MDMA. They emphasise that the enhancement selectively affected hit rates, accuracy, high-confidence hits, and DPSD-derived recollection estimates, while familiarity and metamemory were unchanged. Importantly, susceptibility to false-memory formation (suggestion- and relatedness-driven false alarms) did not increase when encoding, misinformation, and retrieval all occurred under acute ayahuasca effects in these frequent users. The investigators consider several mechanisms. One possibility they outline is pharmacological: the relatively high combined β-carboline dose (170.64 mg) and low measured DMT dose (3.36 mg) might favour MAO-A inhibition or β-carboline-specific actions (for example, harmine-related effects) that enhance hippocampal-dependent encoding. Alternatively, frequent ceremonial use may produce receptor adaptations—such as downregulation of inhibitory hippocampal 5-HT2A receptors—that reduce the encoding-impairing influence otherwise seen with acute 5-HT2A activation. The authors also note the paradox that measured plasma DMT concentrations and subjective effects were comparable to studies with higher DMT doses, leaving multiple pharmacodynamic explanations open. Several limitations and uncertainties are acknowledged. The fixed-order observational design lacked a placebo control and a comparison group of infrequent or naïve users, so effects might reflect practice or other session-order confounds despite attempts to minimise practice effects (use of a practice version prior to baseline, counterbalancing of stimuli). The authors argue practice alone is unlikely to explain the magnitude and selectivity of the recollection enhancement, citing power considerations and comparisons with prior repeated-testing datasets, but they do not rule it out. Another limitation is that ayahuasca was active across encoding, consolidation, and retrieval in the second session, which complicates temporal attribution of effects; the short encoding–retrieval delay also reduces the capacity to isolate consolidation-specific effects. The sample was relatively homogenous and highly experienced, so the findings cannot be generalised to inexperienced populations. For future work the authors recommend controlled trials with placebo and infrequent-user control groups, studies that isolate the timing of drug administration (pre-encoding, post-encoding, pre-misinformation, etc.), and dose–response investigations to disentangle contributions of DMT versus β-carbolines. They note that if β-carbolines can enhance hippocampal-dependent encoding, co-administration strategies might be relevant for therapeutic contexts, but this possibility requires rigorous testing given mixed correlations in the present data and the observational design.