Psychedelics reopen the social reward learning critical period

The study addresses whether reopening of a critical period for social reward learning—previously shown for MDMA—generalizes across diverse psychedelics. Psychedelics are traditionally categorized by subjective effects, chemical classes, or primary receptor targets (for example, 5-HT2A, monoamine transporters, KOR, NMDAR), yet many across these categories show therapeutic promise for PTSD, depression, and addiction. Critical periods are developmental windows of heightened plasticity; methods to reopen them are of therapeutic interest. Prior work identified a social reward learning critical period and demonstrated that adult reopening by MDMA correlates with therapeutic features such as rapid onset, durability, and context dependence, whereas cocaine does not reopen it. The central hypothesis is that the altered state common to psychedelics, rather than specifically empathogenic effects, reflects the subjective correlate of critical period reopening and thus this property might be shared across psychedelic classes.

Background highlights include: (1) Psychedelics produce altered perceptions of self, time, and space and have been used medicinally and spiritually; contemporary trials show efficacy in depression, PTSD, and addiction. (2) Attempts to subcategorize psychedelics by subjective effect, structure, or receptor target have unclear relevance for therapy. (3) A critical period for social reward learning has been described; MDMA reopens it in adults with oxytocin-dependent mechanisms, mirroring clinical features of MDMA-assisted psychotherapy for PTSD. (4) Cocaine fails to reopen this critical period, aligning with its lack of similar therapeutic profile. These prior findings motivate testing whether critical period reopening is a shared mechanism across psychedelics and how this relates to their acute subjective durations and therapeutic durability.

• Behavioral assay: Social reward conditioned place preference (sCPP) in mice. Adult male mice (P96) received a single intraperitoneal (i.p.) pretreatment with a psychedelic or saline; sCPP magnitude was assessed 48 h later (P98) or at later time points (1–4 weeks) depending on experiment.
• Drugs and doses: Psilocybin 0.3 mg/kg i.p.; LSD 1 µg/kg i.p. (also tested 50 µg/kg for duration); ketamine 3 mg/kg i.p.; ibogaine 40 mg/kg i.p.; MDMA 10 mg/kg i.p. (in referenced prior work); saline and cocaine controls where indicated. Dose–response examined in Extended Data; juvenile pretreatment tested for ceiling effects.
• Developmental benchmarking: A natural spline regression model of developmental sCPP (knots at P35 and P98) defined open versus closed states for comparison.
• Duration studies: sCPP measured at 1 week (ketamine, psilocybin), 2 weeks (psilocybin, LSD), 3 weeks (psilocybin, LSD), and 4 weeks (LSD, ibogaine) post-pretreatment to chart open-state duration.
• Electrophysiology (metaplasticity): Ex vivo whole-cell voltage-clamp recordings from nucleus accumbens (NAc) medium spiny neurons (MSNs) in acute slices prepared 48 h or 2 weeks after pretreatment. A 10-min bath application of oxytocin assessed changes in miniature excitatory postsynaptic current (mEPSC) frequency and amplitude to probe oxytocin-mediated LTD-like plasticity.
• Pharmacology: To test 5-HT2A receptor involvement, ketanserin (0.1 mg/kg) was administered 30 min before psychedelic pretreatment; sCPP assessed 48 h later.
• Genetics: β-arrestin-2 knockout mice were used to test requirement of β-arr2 signaling for psychedelic-induced reopening. Baseline developmental sCPP profile confirmed in β-arr2 KO; adult responses to psychedelics compared between wild-type and KO.
• Transcriptomics: RNA-seq of microdissected NAc at 48 h and 2 weeks after saline, cocaine, ketamine, LSD, or MDMA. Strand-specific libraries; three replicates per condition. Differential expression contrasted conditions corresponding to open-state (48 h MDMA, 48 h ketamine, 48 h and 2 weeks LSD) versus closed-state (48 h and 2 weeks saline, 48 h and 2 weeks cocaine, 2 weeks ketamine). Gene set enrichment analyses performed.
• Statistics: Two-tailed paired and unpaired t-tests (with Welch’s correction where applicable), one-way ANOVA for electrophysiology, comparisons to the natural spline model to classify open versus closed state; data reported as mean ± s.e.m., with n denoting biologically independent mice or cells as appropriate.

• Critical period reopening across psychedelics (48 h post-pretreatment): Adult mice pretreated with psilocybin (0.3 mg/kg), LSD (1 µg/kg), ketamine (3 mg/kg), or ibogaine (40 mg/kg) displayed significant sCPP, whereas saline controls did not. Example statistics: psilocybin: n=15, paired t=-3.741, P=0.002; LSD: n=9, t=-7.095, P<0.001; ketamine: n=18, t(17)=-3.826, P<0.002; ibogaine: n=12, t=-2.690, P=0.02; saline examples not significant.
• Alignment with developmental open-state: Relative to a natural spline model of developmental sCPP, psilocybin-, LSD-, ketamine-, and ibogaine-pretreated groups exhibited significant mean shifts into the open-state range (for example, psilocybin P=1.12×10^-9; LSD P=1.76×10^-6), whereas saline did not (P≥0.72).
• Duration of open state varies by compound and parallels human acute subjective durations:
  • Ketamine: No significant sCPP at 1 week (n=16, t(15)=0.204, P=0.841); metaplasticity also not sustained at 2 weeks.
  • Psilocybin: Significant at 1 week (n=17, t(16)=-2.959, P=0.009) and 2 weeks (n=22, t(21)=-3.542, P=0.002), not at 3 weeks (n=16, t(15)=-0.405, P=0.691). Group comparisons significant vs ketamine at 1 week (normalized: t(27)=-2.700, P=0.011; subtracted: t(27)=-2.113, P=0.043).
  • LSD: Significant at 2 weeks (n=18, t(17)=-4.360, P<0.001) and 3 weeks (n=23, t(22)=-3.671, P=0.001), not at 4 weeks (n=17, t(16)=-0.441, P=0.665). At 3 weeks, LSD > psilocybin (normalized: t(34)=3.050, P=0.004; subtracted: t(34)=2.471, P=0.018).
  • Ibogaine: Significant at 4 weeks (n=20, t(19)=-3.004, P=0.007); ibogaine > LSD at 4 weeks (normalized: t(31)=-2.045, P=0.048; subtracted: t(31)=-2.283, P=0.029).
  • Across compounds, open-state durations scale with human acute subjective effect durations.
• Metaplasticity in NAc: Oxytocin application decreased mEPSC frequency (but not amplitude) in NAc MSNs from mice pretreated with MDMA, LSD, ketamine, and ibogaine at 48 h; not after saline or cocaine. One-way ANOVA showed significant treatment effect on frequency (F=5.99, P=0.0002) but not amplitude (P=0.39). The decrease persisted at 2 weeks after LSD but not after ketamine.
• Receptor/signaling requirements: Ketanserin (5-HT2A antagonist) blocked psilocybin- and LSD-induced reopening but did not block MDMA- or ketamine-induced reopening. β-arrestin-2 was required for LSD- and MDMA-induced reopening (no effect in β-arr2 KO), but not for ketamine or ibogaine.
• Transcriptomics: Comparing open-state versus closed-state conditions identified 65 differentially expressed genes (q≤0.1) enriched for endothelial development, angiogenesis regulation, vascular development, and tissue morphogenesis. Many top hits relate to extracellular matrix (ECM) remodeling, including Fn1, Mmp16, Trpv4, Tinagl1, Nostrin, Cxcr4, Adgre5, Robo4, and Sema3g; immediate early genes Fos, Junb, Arc, and Dusp were also differentially expressed. Without controlling for psychedelic-specific response, only 39 genes (q≤0.15) were detected and showed no significant ontology enrichment, with limited overlap.
• Specificity: Psychedelic pretreatment did not alter cocaine reward learning or amphetamine-induced locomotor sensitization, indicating effects on social reward learning rather than generalized addiction-like behaviors.

Findings demonstrate that reopening of the social reward learning critical period is a common property across chemically and pharmacologically diverse psychedelics, addressing the research question that MDMA’s effect generalizes beyond empathogenic agents. The durations of the open state map onto human subjective durations, providing a mechanistic basis for the importance of post-treatment integration windows in clinical practice. Electrophysiology indicates psychedelics induce metaplasticity (enhanced capacity for oxytocin-mediated LTD in the NAc) rather than broad hyperplasticity, aligning with durable, context-dependent therapeutic effects and distinguishing them from addictive drugs. Mechanistic diversity at the receptor level (5-HT2A dependence for LSD/psilocybin but not for MDMA/ketamine; β-arr2 requirement for LSD/MDMA but not for ketamine/ibogaine) converges downstream at transcriptional regulation of ECM components, suggesting ECM remodeling as a shared permissive mechanism enabling metaplasticity and critical period reopening. These insights support retaining the broad psychedelic classification based on shared biological outcomes rather than receptor binding alone and suggest a potential unifying framework for their therapeutic efficacy.

The study proposes a unifying mechanism for psychedelic therapies: reopening of a social reward learning critical period via metaplasticity and ECM remodeling. Across multiple psychedelics, the duration of this open state in mice parallels the duration of acute subjective effects in humans, offering a mechanistic rationale for therapeutic timing and integration. Molecular profiling highlights convergent transcriptional regulation of ECM-related genes during the open state. These results suggest psychedelics could act as a ‘master key’ for reopening various critical periods beyond social reward learning, potentially extending therapeutic applications to conditions such as autism, stroke, deafness, and blindness. Future work should test critical period reopening across other behavioral domains and delineate precise ECM-related pathways and biomarkers to guide development of novel therapeutics with optimal efficacy and safety profiles.