Modulation of Social Cognition via Hallucinogens and “Entactogens”.

Kirkpatrick and colleagues performed a narrative review of experimental, controlled human studies; they explicitly excluded animal work, survey data, and studies of recreational users except where cross-sectional data were discussed separately. The review focuses mainly on MDMA and GHB (entactogens) and psilocybin and LSD (hallucinogens), and organises evidence into clinical-population findings, acute effects in healthy volunteers, long-lasting effects in healthy participants, and neuropharmacological mechanisms. The extracted text does not present a formal, reproducible search strategy, inclusion/exclusion criteria, database list, or date range; therefore, this appears to be a selective review of controlled experimental literature rather than a systematic review or meta-analysis with a pre-specified protocol. Outcome domains covered include emotional and cognitive empathy (assessed with tasks such as the Multifaceted Empathy Task, MASC, RMET, and FERT), moral and altruistic behaviour (economic allocation and moral dilemma tasks), social rejection sensitivity (Cyberball), sexual arousal and perception of romantic relationships, social influence and suggestibility, and neurobiological measures (neuroendocrine markers, fMRI, EEG, MRS). Pharmacological challenge and receptor-blocking studies are also summarised where available.

Clinical populations: The review summarises preliminary clinical findings that MDMA-assisted psychotherapy can reduce social anxiety in autistic adults up to 6 months post-treatment and that many PTSD patients report improved relationships and social functioning at follow-up. Open-label psilocybin studies in addiction and treatment-resistant depression reported clinically meaningful behaviour changes and self-reported increases in interpersonal connection: for example, 12 of 15 treatment-seeking smokers were abstinent at 6 months after two to three psilocybin sessions, and patients with treatment-resistant depression showed increases in extraversion and openness at three months. In a small sample of depressed patients, psilocybin increased amygdala reactivity to fearful faces the morning after dosing, despite acute reductions seen in healthy volunteers; patients reported restored connectedness with others as a key change process. Acute effects in healthy volunteers: Across controlled trials, MDMA, LSD and psilocybin robustly increased emotional empathy as measured by the MET, with MDMA effects often strongest for positive emotions and in some studies more pronounced in male participants. GHB generally did not alter emotional empathy. Cognitive empathy and mentalizing were largely unchanged by MDMA, GHB and psilocybin on measures such as the MASC and MET, whereas LSD (100–200 μg) decreased cognitive empathy on the MET in some studies. On emotion recognition tasks, higher or psychedelic doses of MDMA, LSD and psilocybin tended to reduce recognition of negative facial emotions (fear, anger, sadness), while MDMA in several studies increased attention to happy faces and increased subjective closeness and trust (for example, a 125 mg MDMA dose increased self-reported closeness and trust by around 25% during peak effects). Neural measures paralleled behavioural effects: psilocybin and LSD reduced amygdala responses to fearful faces in some studies, and psilocybin altered amygdala connectivity during discrimination of angry and happy faces. Moral and altruistic behaviour: Findings were mixed but generally indicated increased altruistic or prosocial choices under some conditions. MDMA increased altruistic choices at higher doses (125 mg) and increased altruism toward friends rather than strangers in some paradigms. LSD (100–200 μg combined) increased altruism on the Social Value Orientation test. GHB produced increased altruistic allocations in some analyses but results depended on baseline altruism and analytic choices. MDMA and psilocybin reduced costly altruistic punishment in Ultimatum Game studies in male participants. No consistent effects were found on moral decision making in classic moral dilemma tasks. Social rejection sensitivity: MDMA (0.75–1.5 mg/kg) reduced self-reported negative mood and self-esteem changes following social exclusion in Cyberball, though higher MDMA doses also sometimes increased perceived receipt of ball throws (which may indicate altered perception of exclusion). Microdoses of LSD (<30 μg) did not modulate rejection responses. Psilocybin (0.215 mg/kg) decreased subjective feelings of exclusion and reduced dorsal anterior cingulate and middle frontal gyrus activity during exclusion; this neural reduction correlated with decreased aspartate content (MRS) and with alterations in self-processing (experience of unity). Sexual arousal and romantic perception: Hallucinogens have not been experimentally tested for effects on sexual arousal or romantic perception in controlled studies. MDMA at higher doses (125 mg and 1.5 mg/kg in different paradigms) produced subjective increases in sexual arousal and increased disclosure on relationship discussion tasks, while GHB (20–35 mg/kg) produced dose-independent increases in self-reported sexual arousal even to neutral stimuli, consistent with a prosexual profile. Social influence processing: Limited data (two LSD studies) suggest LSD enhances suggestibility and increases conformity to group opinions that are not too discrepant from the participant's own views; associated increases in medial prefrontal BOLD were reported. These findings raise clinical implications given the therapeutic context but are based on small samples. Long-lasting effects: Objective long-term data are scarce. Cross-sectional studies of recreational MDMA users reported higher cognitive empathy but not emotional empathy; self-report studies after psilocybin and LSD have described increases in interpersonal closeness and prosocial effects lasting months, and one controlled report after a psilocybin retreat found increased emotional empathy the morning after and at seven days (for negative emotions). The authors note that cross-sectional recreational data cannot establish causality and emphasise the need for controlled longitudinal studies. Neuropharmacology: Pharmacologically, MDMA promotes serotonin, norepinephrine and modest dopamine release and raises plasma oxytocin, prolactin and cortisol; GHB agonises GHB and GABAB receptors and modulates multiple neurotransmitter systems; psilocin (the active metabolite of psilocybin) is a high-affinity agonist at 5-HT2A (and other serotonin) receptors with emerging evidence for 5-HT1A involvement; LSD has agonist activity at multiple 5-HT receptor subtypes and dopamine receptors. Blockade studies implicate 5-HT2A receptor activation in many hallucinogen-induced social effects: ketanserin blocks several LSD- and psilocybin-induced social-cognitive changes. Attempts to link MDMA's prosocial effects to oxytocin increases in plasma have not produced consistent correlations in human studies, and receptor-blocking work (e.g. pindolol, duloxetine, reboxetine, clonidine) has yielded mixed results, though serotonin mechanisms appear important overall. Comparisons with other stimulants and modafinil indicate MDMA produces a distinct profile, with serotonergic mechanisms relating to empathy and dopaminergic mechanisms relating more to sexual drive. The authors caution that the role of many receptor systems remains incompletely tested and that further selective blockade studies are needed.

Kirkpatrick and colleagues conclude that controlled experimental literature demonstrates that entactogens and hallucinogens are potent modulators of social cognition and behaviour. MDMA, LSD and psilocybin show consistent prosocial effects, particularly increasing emotional empathy and, in many studies, altruistic behaviour; GHB appears to have a distinct prosexual profile rather than acting as a canonical entactogen. The 5-HT2A receptor is identified as a likely common mechanism for many prosocial effects of classic hallucinogens and possibly MDMA, which has implications for developing novel therapeutics targeting social deficits in psychiatric disorders. The authors emphasise clinical implications: reinstating social reward processing may help in addiction, reducing social withdrawal and improving help-seeking in anxiety and mood disorders, and acute prosocial effects may enhance the therapeutic relationship during assisted psychotherapy. However, they highlight significant knowledge gaps, including the need for dose–response data (especially for psilocybin and microdoses), investigation of hallucinogens beyond LSD and psilocybin, sex-specific effects, objective post-acute outcomes, detailed receptor-specific pharmacology, and objective measures of social behaviour within therapeutic contexts. The review concludes that systematically addressing these gaps could advance mechanistic understanding and the clinical application of these substances for trans-diagnostic social-cognitive impairments.