Natural language signatures of psilocybin microdosing.

RATIONALE: Serotonergic psychedelics are being studied as novel treatments for mental health disorders and as facilitators of improved well-being, mental function, and creativity. Recent studies have found mixed results concerning the effects of low doses of psychedelics ("microdosing") on these domains. However, microdosing is generally investigated using instruments designed to assess larger doses of psychedelics, which might lack sensitivity and specificity for this purpose. OBJECTIVES: Determine whether unconstrained speech contains signatures capable of identifying the acute effects of psilocybin microdoses. METHODS: Natural speech under psilocybin microdoses (0.5 g of psilocybin mushrooms) was acquired from thirty-four healthy adult volunteers (11 females: 32.09 ± 3.53 years; 23 males: 30.87 ± 4.64 years) following a double-blind and placebo-controlled experimental design with two measurement weeks per participant. On Wednesdays and Fridays of each week, participants consumed either the active dose (psilocybin) or the placebo (edible mushrooms). Features of interest were defined based on variables known to be affected by higher doses: verbosity, semantic variability, and sentiment scores. Machine learning models were used to discriminate between conditions. Classifiers were trained and tested using stratified cross-validation to compute the AUC and p-values. RESULTS: Except for semantic variability, these metrics presented significant differences between a typical active microdose and the inactive placebo condition. Machine learning classifiers were capable of distinguishing between conditions with high accuracy (AUC [Formula: see text] 0.8). CONCLUSIONS: These results constitute first evidence that low doses of serotonergic psychedelics can be identified from unconstrained natural speech, with potential for widely applicable, affordable, and ecologically valid monitoring of microdosing schedules.

Automated text-level semantic markers of Alzheimer's disease.

INTRODUCTION: Automated speech analysis has emerged as a scalable, cost-effective tool to identify persons with Alzheimer's disease dementia (ADD). Yet, most research is undermined by low interpretability and specificity. METHODS: Combining statistical and machine learning analyses of natural speech data, we aimed to discriminate ADD patients from healthy controls (HCs) based on automated measures of domains typically affected in ADD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words). To test for specificity, we replicated the analyses on Parkinson's disease (PD) patients. RESULTS: Relative to controls, ADD (but not PD) patients exhibited significant differences in both measures. Also, these features robustly discriminated between ADD patients and HC, while yielding near-chance classification between PD patients and HCs. DISCUSSION: Automated discourse-level semantic analyses can reveal objective, interpretable, and specific markers of ADD, bridging well-established neuropsychological targets with digital assessment tools.

The entropic tongue: Disorganization of natural language under LSD.

Serotonergic psychedelics have been suggested to mirror certain aspects of psychosis, and, more generally, elicit a state of consciousness underpinned by increased entropy of on-going neural activity. We investigated the hypothesis that language produced under the effects of lysergic acid diethylamide (LSD) should exhibit increased entropy and reduced semantic coherence. Computational analysis of interviews conducted at two different time points after 75 µg of intravenous LSD verified this prediction. Non-semantic analysis of speech organization revealed increased verbosity and a reduced lexicon, changes that are more similar to those observed during manic psychoses than in schizophrenia, which was confirmed by direct comparison with reference samples. Importantly, features related to language organization allowed machine learning classifiers to identify speech under LSD with accuracy comparable to that obtained by examining semantic content. These results constitute a quantitative and objective characterization of disorganized natural speech as a landmark feature of the psychedelic state.

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports.

The real or perceived proximity to death often results in a non-ordinary state of consciousness characterized by phenomenological features such as the perception of leaving the body boundaries, feelings of peace, bliss and timelessness, life review, the sensation of traveling through a tunnel and an irreversible threshold. Near-death experiences (NDEs) are comparable among individuals of different cultures, suggesting an underlying neurobiological mechanism. Anecdotal accounts of the similarity between NDEs and certain drug-induced altered states of consciousness prompted us to perform a large-scale comparative analysis of these experiences. After assessing the semantic similarity between ≈15,000 reports linked to the use of 165 psychoactive substances and 625 NDE narratives, we determined that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine consistently resulted in reports most similar to those associated with NDEs. Ketamine was followed by Salvia divinorum (a plant containing a potent and selective κ receptor agonist) and a series of serotonergic psychedelics, including the endogenous serotonin 2A receptor agonist N,N-Dimethyltryptamine (DMT). This similarity was driven by semantic concepts related to consciousness of the self and the environment, but also by those associated with the therapeutic, ceremonial and religious aspects of drug use. Our analysis sheds light on the long-standing link between certain drugs and the experience of "dying", suggests that ketamine could be used as a safe and reversible experimental model for NDE phenomenology, and supports the speculation that endogenous NMDA antagonists with neuroprotective properties may be released in the proximity of death.

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines.

Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user ("set") and the surroundings ("setting"). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of "set" and "setting," to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands ("functional selectivity"). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to "in silico" estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid's Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

Corrigendum: The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports.

[This corrects the article on p. 7 in vol. 12, PMID: 29403350.].

The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports.

Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology ("what it feels like" to experience these states) is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception ("see," "visual," "face," "reality," "color"), emotion ("fear"), setting ("outside," "inside," "street," "front," "behind") and relatives ("mom," "dad," "brother," "parent," "family") were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non-invasive measurements of brain physiology.