2025
The polypharmacology of psychedelics reveals multiple targets for potential therapeutics
Jain M, Gumpper R, Slocum S, Schmitz G, Madsen J, Tummino T, Suomivuori C, Huang X, Shub L, DiBerto J, Kim K, DeLeon C, Krumm B, Fay J, Keiser M, Hauser A, Dror R, Shoichet B, Gloriam D, Nichols D, Roth B. The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron 2025 PMID: 40683247, DOI: 10.1016/j.neuron.2025.06.012.Peer-Reviewed Original ResearchPost-traumatic stress disorderAction of psychedelicsStress disorderPsychedelic effectsNeuropsychiatric conditionsSerotonin receptorsAcid diethylamidePsychedelicsDrug abuseCase of LSDG protein-coupled receptorsAdrenergic receptorsAction in vivoCluster headacheLSDClinical studiesPsilocybinSerotoninDopamineTherapeutic potentialAnxietyMescalineDiethylamideEfficacious actionDepressionAddressing blinding in classic psychedelic studies with innovative active placebos
Aday J, Simonsson O, Schindler E, D’Souza D. Addressing blinding in classic psychedelic studies with innovative active placebos. The International Journal Of Neuropsychopharmacology 2025, 28: pyaf023. PMID: 40183712, PMCID: PMC12038243, DOI: 10.1093/ijnp/pyaf023.Peer-Reviewed Original ResearchConceptsActive placeboClassic psychedelicsPsychedelic studiesAcute psychoactive effectsModerate-to-high dosesPlacebo conditionNeuropsychiatric disordersPsychoactive effectsAcute physiological effectsTherapeutic effectPsychedelicsLow-dose administrationBlind integrationLack of therapeutic effectAcute effectsReview interventionsPlaceboShort-actingClinical trialsPharmacological agentsImproved blindingAncillary strategiesTrialsPhysiological effectsDisordersPsilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors
Shao L, Liao C, Davoudian P, Savalia N, Jiang Q, Wojtasiewicz C, Tan D, Nothnagel J, Liu R, Woodburn S, Bilash O, Kim H, Che A, Kwan A. Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors. Nature 2025, 642: 411-420. PMID: 40175553, PMCID: PMC12188471, DOI: 10.1038/s41586-025-08813-6.Peer-Reviewed Original ResearchConceptsMedial frontal cortexFrontal cortexMouse medial frontal cortexSingle dose of psilocybinDose of psilocybinImpact of psilocybinDensity of dendritic spinesPyramidal cell typesStress-related behaviorsDendritic spinesStress-related phenotypesCell-type-specific electrophysiologyPsilocybin effectsPT neuronsSerotonergic psychedelicsRemodeling of dendritic spinesCell typesElevated firing ratesPyramidal tractPsilocybinIT neuronsPsychedelicsStructural plasticityFiring rateCalcium transientsThe therapeutic effects of psychedelics for opioid use disorder: A systematic review of clinical studies
Weleff J, Pulido-Saavedra A, Aghaei A, Ing K, Arakelian M, Fontenele R, Nero N, Barnett B, Anand A, Bassir Nia A, Angarita G. The therapeutic effects of psychedelics for opioid use disorder: A systematic review of clinical studies. Psychiatry Research 2025, 348: 116446. PMID: 40147088, DOI: 10.1016/j.psychres.2025.116446.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsOpioid use disorderStudies of psychedelicsSystematic review of clinical studiesUse disorderReview of clinical studiesTherapeutic effects of psychedelicsEffects of psychedelicsOpioid receptor systemApplications of psychedelicsClinical studiesMu-opioid receptorsNaturalistic studySerotonergic psychedelicsOpioid withdrawalPlacebo-controlled trialPsychedelicsSubstance useUnited States Food and Drug AdministrationStates Food and Drug AdministrationMu-opioidFood and Drug AdministrationSystematic reviewReceptor systemClinical study designDouble-blindA Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research
Yaden D, Graziosi M, Owen A, Agin-Liebes G, Aaronson S, Allen K, Barrett F, Bogenschutz M, Carhart-Harris R, Ching T, Cosimano M, Danforth A, Davis A, Garcia-Romeu A, Griffiths R, Grob C, Gründer G, Gukasyan N, Heinzerling K, Hendricks P, Holze F, Horton D, Johnson M, Kelmendi B, Peck S, Koslowski M, Liechti M, Mertens L, Moreno F, Nayak S, Nicholas C, Preller K, Rieser N, Ross S, Sergi K, Sloshower J, Smigielski L, Stenbæk D, Vollenweider F, Weiss B, Wolff M, Yaden M. A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research. Psychedelic Medicine 2025, 3: 1-18. PMID: 40351554, PMCID: PMC12060849, DOI: 10.1089/psymed.2024.0019.Peer-Reviewed Original ResearchResearch settingsSerotonin 2A receptor agonistAcute subjective effectsReflexive thematic analysisPsychological safetyPsychedelic treatmentIdentified themesSerotonergic psychedelicsSubjective effectsPsychological supportThematic analysisMedical staffPsychedelic experienceStates of consciousnessFamily historyPsilocybinReceptor agonistsWell-beingPsilocybin studiesDecades of researchPsychedelicsPsychoeducationPotential contraindicationsLevel of riskAnticipated outcomesThe Contribution of Psychotherapy in Potential Therapeutic Effects of Psychedelics for Treatment of Opioid Use Disorder
Bassir Nia A, Farahmand Y, Griffith G, Ardavan M, Angarita G, Anand A, Pittenger C. The Contribution of Psychotherapy in Potential Therapeutic Effects of Psychedelics for Treatment of Opioid Use Disorder. Current Addiction Reports 2025, 12: 20. DOI: 10.1007/s40429-025-00638-7.Peer-Reviewed Original ResearchEffects of psychedelicsOpioid use disorderConcurrent psychotherapyUse disorderTherapeutic effects of psychedelicsContribution of psychotherapyImpact of psychedelicsSubstance use disordersOpioid withdrawal symptomsTreatment of opioid use disorderFDA-approved medicationsOpioid use disorder treatmentPsychotherapy modalitiesPsychedelic treatmentPsychotherapy componentWithdrawal symptomsPsychotherapyPsychedelic trialsTherapy modelPsychedelicsAcute effectsDisordersAssociated with higher ratesTreatment discontinuationPotential therapeutic effectsCould psychedelics be fine-tuned to relieve anxiety but skip the ‘trip’?
Knox C, Kwan A. Could psychedelics be fine-tuned to relieve anxiety but skip the ‘trip’? Nature 2025, 639: 45-46. PMID: 39966585, DOI: 10.1038/d41586-025-00454-z.Peer-Reviewed Original ResearchClassification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression
Aboharb F, Davoudian P, Shao L, Liao C, Rzepka G, Wojtasiewicz C, Indajang J, Dibbs M, Rondeau J, Sherwood A, Kaye A, Kwan A. Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression. Nature Communications 2025, 16: 1590. PMID: 39939591, PMCID: PMC11822132, DOI: 10.1038/s41467-025-56850-6.Peer-Reviewed Original ResearchConceptsAcute fluoxetinePsychoactive drugsMarkers of neural plasticityImmediate early gene expressionC-fos expressionChronic fluoxetineNative brain tissueBehavioral effectsPsychedelic propertiesBrain regionsChance levelEarly gene expressionPsychoactive compoundsNeural plasticityFluoxetinePsilocybinMDMAMeasuring drug actionTested malesPsychedelicsPreclinical assaysDrug actionKetamineFemale miceDrug classificationEffects of psychedelics on opioid use disorder: a scoping review of preclinical studies
Pulido-Saavedra A, Oliva H, Prudente T, Kitaneh R, Nunes E, Fogg C, Funaro M, Weleff J, Nia A, Angarita G. Effects of psychedelics on opioid use disorder: a scoping review of preclinical studies. Cellular And Molecular Life Sciences 2025, 82: 49. PMID: 39833376, PMCID: PMC11747050, DOI: 10.1007/s00018-024-05519-2.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsOpioid use disorderUse disorderPreclinical studiesClinical studiesReview of preclinical studiesConditioned place preferenceOpioid Self-AdministrationEffects of psychedelicsPreclinical in vivo studiesOpioid use disorder treatmentFrequency of administrationPlace preferencePotential therapeutic effectsSelf-AdministrationWithdrawal symptomsPreclinical findingsMechanism of actionSafety profilePain studiesPsychedelicsMethodological quality assessmentClinical evidenceCardiovascular riskOpioidWeb of ScienceSupportive Touch in Psychedelic Assisted Therapy
Neitzke-Spruill L, Beit C, Averill L, McGuire A. Supportive Touch in Psychedelic Assisted Therapy. The American Journal Of Bioethics 2025, 25: 29-39. PMID: 39804300, DOI: 10.1080/15265161.2024.2433428.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderPsychedelic-assisted therapyTreating post-traumatic stress disorderPsychedelic assisted therapyMDMA-ATStress disorderPsychological interventionsUnlicensed therapistsIncidents of misconductPsychedelicsCases of misconductFuture abuseSexual misconductHarm reductionAssisted TherapyClinical contextMisconductWhole clothU.S. Food and Drug AdministrationMDMADrug AdministrationTherapistsAbuseDisordersFood and Drug Administration
2024
The potential of non-psychedelic 5-HT2A agents in the treatment of substance use disorders: a narrative review of the clinical literature
Pulido-Saavedra A, Borelli A, Kitaneh R, Alrafayia M, Jalilian-Khave L, Funaro M, Potenza M, Angarita G. The potential of non-psychedelic 5-HT2A agents in the treatment of substance use disorders: a narrative review of the clinical literature. Expert Opinion On Pharmacotherapy 2024, 26: 133-146. PMID: 39708346, PMCID: PMC11786980, DOI: 10.1080/14656566.2024.2446623.Peer-Reviewed Original ResearchConceptsTreatment of substance use disordersSubstance use disordersTreating substance use disordersPsychedelic agentsNarrative reviewReceptor agonistsClinical literatureReceptor antagonistNovel interventionsClinical evidenceFDA approvalPublic health issueDisordersReceptorsAgonistsTreatmentCravingPositive resultsPsychedelicsAbstinenceReviewed literatureAgentsHealth issuesAntagonistPrimary affinityMDMA and MDMA-Assisted Therapy
Wolfgang A, Fonzo G, Gray J, Krystal J, Grzenda A, Widge A, Kraguljac N, McDonald W, Rodriguez C, Nemeroff C. MDMA and MDMA-Assisted Therapy. American Journal Of Psychiatry 2024, 182: 79-103. PMID: 39741438, DOI: 10.1176/appi.ajp.20230681.Peer-Reviewed Original ResearchConceptsMDMA-assisted therapyPosttraumatic stress disorderControlled clinical settingRecreational useMDMA administrationNeurobiological mechanismsStress disorderEgo functionsSelf-CompassionMDMAEfficacious treatmentPreliminary evidenceHeightened trustTherapeutic settingNonclinical settingsDiagnostic criteriaFood and Drug AdministrationBreakthrough therapiesClinical settingNonmedical settingsConsiderable bodyPsychotherapyPsychedelicsLong-term follow-upDrug AdministrationSynergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology
Shinozuka K, Jerotic K, Mediano P, Zhao A, Preller K, Carhart-Harris R, Kringelbach M. Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology. Translational Psychiatry 2024, 14: 485. PMID: 39632810, PMCID: PMC11618481, DOI: 10.1038/s41398-024-03187-1.Peer-Reviewed Original ResearchConceptsFunctional connectivityBetween-network functional connectivityLevels of analysisWithin-network FCBetween-drug differencesMeta-analysesD2 receptorsPsychedelic effectsSerotonergic psychedelicsNeuroimaging resultsNeuropsychiatric disordersStates of consciousnessPsychedelicsNeural fingerprintsAltered statesNeuroimagingPsilocybinHigh dosesLSDSignificantly higher ratesMolecular pharmacologySystematic reviewAddictionDepressionPhenomenologyVentral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI
Tiwari P, Davoudian P, Kapri D, Vuruputuri R, Karaba L, Sharma M, Zanni G, Balakrishnan A, Chaudhari P, Pradhan A, Suryavanshi S, Bath K, Ansorge M, Fernandez-Ruiz A, Kwan A, Vaidya V. Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI. Neuron 2024, 112: 3697-3714.e6. PMID: 39321791, PMCID: PMC11581910, DOI: 10.1016/j.neuron.2024.08.016.Peer-Reviewed Original ResearchAnxiolytic actionVentral hippocampusParvalbumin (PV)-positive interneuronsAnxiety-like behaviorAction of DOIPV-positive interneuronsPsychedelic DOIAnxiolytic responseAnxiolytic effectsSerotonergic psychedelicsFast-spiking cellsParvalbumin interneuronsGABAergic interneuronsVHPCFiring rateDOIHippocampusInterneuronsTherapeutic potentialReceptorsPsychedelicsCellular triggersGenetic approachesElectrophysiologyDistinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI
Anderson T, Keady J, Songrady J, Tavakoli N, Asadipooya A, Neeley R, Turner J, Ortinski P. Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI. Progress In Neurobiology 2024, 240: 102660. PMID: 39218140, PMCID: PMC11444019, DOI: 10.1016/j.pneurobio.2024.102660.Peer-Reviewed Original ResearchConceptsAnterior cingulate cortexEffects of 5-HTExcitatory postsynaptic currentsPsychedelic hallucinogensLevels of serotonin (5-HTSerotonin (5-HTPsychedelic drug actionReceptor-mediated excitatory postsynaptic currentsClaustrum activationCingulate cortexSerotonergic regulationSerotonin receptorsBehavioral responsesGlutamatergic neuronsClaustrumClaustrum neuronsNeuronal activityReceptor subtypesCortical targetsPostsynaptic currentsPsychedelicsElectrophysiological recordingsDOIDrug actionHallucinogensNeocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals
Sankar A, Ziersen S, Ozenne B, Dam V, Beaman E, Kessing L, Fisher P, Budtz-Jørgensen E, Knudsen G, Miskowiak K, Frokjaer V. Neocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals. Nature Mental Health 2024, 2: 1231-1238. DOI: 10.1038/s44220-024-00299-x.Peer-Reviewed Original ResearchRisk of depressionFacets of neuroticismPersonality trait neuroticismPathophysiology of depressionSerotonin 2A receptorMolecular brain imagingHigh neuroticismTrait neuroticismDepressive episodeNeuroticismDepression diagnosisHealthy individualsDepressionReceptor bindingBrain imagingDanish registersCause-specific Cox regression analysesEvaluation of clinical strategiesIndividualsCox regression analysisPsychotherapyClinical strategiesPsychedelicsSerotoninRegression analysisAn Integrated theory of false insights and beliefs under psychedelics
McGovern H, Grimmer H, Doss M, Hutchinson B, Timmermann C, Lyon A, Corlett P, Laukkonen R. An Integrated theory of false insights and beliefs under psychedelics. Communications Psychology 2024, 2: 69. PMID: 39242747, PMCID: PMC11332244, DOI: 10.1038/s44271-024-00120-6.Peer-Reviewed Original ResearchPsychotropic Drugs Reemerging as Headache Medicines
Schindler E. Psychotropic Drugs Reemerging as Headache Medicines. CNS Drugs 2024, 38: 661-670. PMID: 39037675, DOI: 10.1007/s40263-024-01107-x.Peer-Reviewed Original ResearchRacial Stress, Racial Trauma, and Evidence-Based Strategies for Coping and Empowerment
Holmes S, Zare M, Haeny A, Williams M. Racial Stress, Racial Trauma, and Evidence-Based Strategies for Coping and Empowerment. Annual Review Of Clinical Psychology 2024, 20: 77-95. PMID: 38346289, DOI: 10.1146/annurev-clinpsy-081122-020235.Peer-Reviewed Original ResearchRacial stressCognitive defusionCognitive restructuringSelf-CompassionPsychological symptomsExpressive writingBehavioral responsesDiscriminatory experiencesRacial traumaSocial supportRacial/ethnic identityEvidence baseSelf-CareExpected final online publication dateSense of empowermentOnline publication datePsychedelicsDefusionTraumaIndividualsCopingAnnual ReviewMindfulnessSocial actionRevised estimatesBeyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder
Page C, Epperson C, Novick A, Duffy K, Thompson S. Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Molecular Psychiatry 2024, 29: 3802-3813. PMID: 38816586, PMCID: PMC11692567, DOI: 10.1038/s41380-024-02625-2.Peer-Reviewed Original ResearchDepressive disorderTreatment of MDDEmotional brain circuitsMental health crisisMonoaminergic antidepressantsSerotonergic antidepressantsEmotional processingDeficit hypothesisBrain circuitsMDDBehavioral functionsHypothesis explanationAntidepressantsInsufficient supportive evidenceSerotoninNeuromodulation techniquesPreclinical researchNegative biasDisordersPersistent negative biasSupportive evidenceCliniciansPsychotherapyEffective treatmentPsychedelics
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