Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Pharmacological Reviews
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Pharmacological Reviews

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit Pharm Rev on Facebook
  • Follow Pharm Rev on Twitter
  • Follow ASPET on LinkedIn
Review ArticleReview Article
Open Access

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Michael Nader, ASSOCIATE EDITOR
Pharmacological Reviews January 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056
Antonio Inserra
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Danilo De Gregorio
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gabriella Gobbi
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Nader
Roles: ASSOCIATE EDITOR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Article Figures & Data

Figures

  • Tables
  • Additional Files
  • Fig. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 1.

    Neuroplastic effects of psychedelic compounds relevant to psychiatric disorders and comorbidities. The main outcomes elicited by psychedelic compounds on neuroplastic and neurogenesis-related pathways are reported in the green box (purple brain). The resulting outcomes on psychiatric symptoms are reported in the blue box (orange brain). For each compound, or group of compounds with similar pharmacology, the main classes of transcription factors and signaling pathways activated that are thought to mediate the effects of the compound on synaptic and neuronal plasticity are reported. In the bottom part of the figure, the main receptors involved in signal transduction for each compound or group of compounds with similar pharmacology and the resulting neurotransmitter released are reported. AR, androgen receptor; ALT, alternative lengthening of telomeres; ANIA3, activity and neurotransmitter-induced early gene 3; CAMK2, calcium/calmodulin-dependent protein kinase 2; CEBPB, CCAAT/enhancer-binding protein beta; COMT, catechol O-methyltransferase; CREB, cAMP response element-binding protein; MKP1, mitogen-activated protein kinase phosphatase; NOR1, neuron-derived orphan receptor-1; IKB, inhibitor of kB kinase.

  • Fig. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 2.

    Anti-inflammatory and immunomodulatory effects of psychedelic compounds relevant to psychiatric disorders and comorbidities. The main outcomes elicited by psychedelic compounds on inflammation and immunity-related pathways are reported in the blue box (purple brain). The resulting outcomes on psychiatric symptoms are reported in the purple box (orange brain). For each compound, or group of compounds with similar pharmacology, the main classes of cytokines, chemokines, hormones, transcription factors, and signaling pathways activated, which are thought to mediate the effects of the compound on inflammation and immunity-related pathways, are reported. In the bottom part of the figure, the main receptors involved in signal transduction for each compound or group of compounds with similar pharmacology and the resulting neurotransmitter released are reported. ADRA, alpha adrenergic receptor; ADRB, beta adrenergic receptor; ALPHA2, alpha 2 adrenergic receptor; CCL5, C-C motif chemokine 5; CORT, cortisol; CX3CL1, fractalkine; CXCL10, C-X-C motif chemokine 10; GLU, glutamate; HRH, histamine receptor; I1, imidazoline receptor 1; IKBA, NF-kappa-B inhibitor alpha; ICAM1, intercellular adhesion molecule 1; M3, muscarinic receptor subtype 3; M5, muscarinic receptor subtype 5; SIGMAR, sigma receptor; TAAR, trace amine-associated receptor; TLR, toll-like receptor; TSH, thyroid stimulating hormone; VCAM1, vascular cell adhesion protein 1.

  • Fig. 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Fig. 3.

    Effects of psychedelic compounds on the serotonergic, dopaminergic, glutamatergic, and GABAergic neurotransmitter systems relevant to psychiatric disorders and comorbidities. For each compound, or group of compounds with similar pharmacology, the main known modulatory effects over the serotonergic, dopaminergic, glutamatergic, and GABAergic neurotransmitter systems in different areas of the brain are reported.

Tables

  • Figures
  • Additional Files
    • View popup
    TABLE 1

    Clinical trials available on ClinicalTrials.gov investigating the use of MDMA as a potential therapeutic approach for PTSD and other psychiatric disorders

    For completed trials, the references of published work were added if available either from the ClinicalTrials.gov web site or PubMed upon searching the NCT identifier. If information was available on the main findings of the study, it was added. If the trial was not completed or it was completed but no information was available in the form of a published original manuscript, we reported the main research question(s) the study aims to address.

    CompoundCohortRegimenResearch Question/Main FindingsStatusReference
    MDMAPost-traumatic stress disorder30, 75, or 125 mg, orally, followed by a supplemental half dose 1.5–2 h later, thriceMDMA-assisted psychotherapy is safe and efficacious for PTSD. MDMA induces large-magnitude effect size decreases in PTSD symptoms. Two-thirds of participants no longer meet PTSD criteria 12 mo after treatmentCompletedClinicalTrials.gov identifier: NCT03485287, NCT03282123, NCT01211405 (Mithoefer et al., 2018; Gorman et al., 2020)
    MDMAPost-traumatic stress disorder125 mg, orally, followed by a supplemental half dose 1.5–2 h later, thriceDecrease in PTSD scores. Rate of clinical response 10 of 12 (83%) in the active treatment group vs. 2 of 8 (25%) in the placebo group. No drug-related serious adverse events or clinically significant blood pressure increases. No relapse 17–74 mo after the original final sessionCompletedClinicalTrials.gov identifier: NCT00090064 (Mithoefer et al., 2011, 2013)
    MDMAPost-traumatic stress disorder30, 75, or 125 mg, orally, followed by a supplemental half dose 1.5–2 h later, onceIdentify psychotherapeutic processes in MDMA-assisted psychotherapy for PTSDCompletedClinicalTrials.gov identifier: NCT02102802
    MDMAPost-traumatic stress disorder25 or 125 mg, orally, followed by a supplemental half dose 2 h later, thriceSafety and efficacy of MDMA-assisted psychotherapy for PTSDCompletedClinicalTrials.gov identifier: NCT01958593, NCT01689740
    MDMAPost-traumatic stress disorder62.5, 125, or 125 + 62.5 mg, orallyAdditional MDMA psychotherapy for people who relapsed 1 yr after the first trialCompletedClinicalTrials.gov identifier: NCT01458327
    MDMAWar- or terrorism-related PTSD25 and 125 mg, orally, followed by a supplemental half dose 2–2.5 h later, twiceMDMA-assisted psychotherapy for people with war- or terrorism-related PTSDTerminated due to staff turnover and its effects on data collectionClinicalTrials.gov identifier: NCT00402298
    MDMAPost-traumatic stress disorder1.5 mg/kg, orally, onceEffects of MDMA on prefrontal and amygdala activation. Relationship between neural changes and acute behavioral effects in patients with PTSDRecruitingClinicalTrials.gov identifier: NCT03752918
    MDMAPost-traumatic stress disorder80 and 120 mg, orally, followed by a supplemental half dose 1.5–2 h later, thriceMultisite phase III study of MDMA-assisted psychotherapy for PTSDActive, not recruitingClinicalTrials.gov identifier: NCT03537014
    MDMAPost-traumatic stress disorder80 and 120 mg, orally, followed by a supplemental half dose 1.5–2 h later, twiceFirst multisite study of MDMA-assisted psychotherapy for PTSD in Europe. Exploration of findings’ reproducibility from FDA-regulated trials in a multisite format to further confirm the phase III study designNot yet recruitingClinicalTrials.gov identifier: NCT04030169
    MDMACombat-related post-traumatic stress disorderFirst session: 80 mg, orally, followed by a supplemental half dose 1.5–2 h later; second and third sessions: 120 mg, orally, followed by a supplemental half dose 1.5–2 h laterEfficacy of MDMA-assisted psychotherapy in veterans with combat-related, refractory PTSDNot yet recruitingClinicalTrials.gov identifier: NCT04264026
    MDMACBCT in dyads with one member with post-traumatic stress disorderFirst session: 75 mg, orally, followed by a supplemental half dose 1.5 h later; second session: 75 or 100 mg, orally, followed by a supplemental half dose 1.5 h laterSafety and effect size of a combination of CBCT and MDMA-assisted psychotherapy in 10 pairs of people, one with and one without PTSD. Changes in PTSD symptoms and relationship issues before and after the course of psychotherapyCompletedClinicalTrials.gov identifier: NCT02876172
    Autism Spectrum Disorder
    MDMAAutism spectrum disorderFirst session: 75 or 100 mg, orally; second session: 100 or 125 mgMDMA-assisted psychotherapy is safe and elicits rapid and durable therapeutic improvements in social anxiety symptoms in adults with ASDCompletedClinicalTrials.gov identifier: NCT02008396 (Danforth et al., 2018)
    MDMAAutism spectrum disorder1.5 mg/kg, orallyAssess whether MDMA affects the response to affective touch in individuals with a range of autistic traits and healthy volunteersRecruitingClinicalTrials.gov identifier: NCT04053036, NCT03790618
    Substance, Alcohol, and Tobacco Abuse
    MDMAAlcohol use disorder125 mg, orally, followed by a supplemental half dose 2 h later, twiceFeasibility of MDMA-assisted psychotherapy in patients with AUD who have recently undergone detoxificationActive, not recruitingClinicalTrials.gov identifier: NCT04158778
    MDMASubstance abuse disorder125 mg, orally, onceOxytocin receptor gene variants may modulate aspects of the prosocial effects of MDMA. MDMA produces significantly greater feelings of trust in rs1042778 TT genotypes compared with G allele carriers. MDMA significantly increases plasma oxytocin. MDMA and oxytocin plasma concentrations do not differ among oxytocin genetic variantsCompletedClinicalTrials.gov identifier: NCT01270672 (Vizeli and Liechti, 2018)
    MDMASubstance abuse disorder125 mg, orally, onceEffects of MDMA on social and emotional processingCompletedClinicalTrials.gov identifier: NCT01465685 (Hysek et al., 2014; Vizeli and Liechti, 2018)
    MDMASubstance abuse disorder1.6 mg/kg, orally, onceEvaluate the effects of MDMA on thinking and the relationship between plasma MDMA levels and brain function (fMRI)CompletedClinicalTrials.gov identifier: NCT01148342
    Others
    MDMALife-threatening illness125 mg, orally, followed by a supplemental half dose 1.25–2.5 later, thriceSafety and efficacy of MDMA-assisted psychotherapy in people with anxiety related to a life-threatening cancer or neurologic illness. Effects of MDMA on neural correlates of emotional processing and anxietyCompletedClinicalTrials.gov identifier: NCT02427568, NCT02954562
    MDMAHepatic impairment80 mg, orally, onceAssess the effect of moderate hepatic impairment in the pharmacokinetics of MDMA and its active metabolite MDA to decide whether dosage adjustment is required for moderate hepatic impairmentRecruitingClinicalTrials.gov identifier: NCT03606538
    MDMARecreational usersDepending on self-administrationEcstasy use is associated with tissue changes in the globus pallidus. Lower cortical postsynaptic 5-HT2A in recent users. Higher 5-HT2A in the occipital cortex of ex-MDMA users. MDMA abuse associated with neuronal damage. Greater MDMA abuse associated with higher depressive scores. No decrease in SERT density in former MDMA abusersCompletedClinicalTrials.gov identifier: NCT00235768 (Reneman et al., 2001a,b, 2002b; de Win et al., 2004)
    MDMARecreational usersDepending on self-administrationMDMA users report somatic complaints on day 1, and symptoms of reduced energy, increased fatigue, and weakness persisted up to 4 days post–drug ingestionCompletedClinicalTrials.gov identifier: NCT01400204
    Healthy Volunteers
    MDMAHealthy volunteers1.5 mg/kg, orally, onceFemale subjects experience more intense physiologic (heart rate and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determine greater cardiovascular effects, and (met/* or s/s) determines negative subjective effects (dizziness, anxiety, sedation). MDMA inhibits CYP2D6 activity. Recovery of CYP2D6 activity half-life 46.6 h. Full recovery after 10 daysCompletedClinicalTrials.gov identifier: NCT01447472 (O’Mathuna et al., 2008; Yubero-Lahoz et al., 2011; Pardo-Lozano et al., 2012)
    MDMAHealthy volunteers125 mg, orally, onceDopamine and norepinephrine transporter-mediated release of norepinephrine is involved in MDMA cardiostimulant effect. No modulatory role of dopamine. MDMA during bupropion therapy may result in higher plasma concentrations and enhanced mood effects but also lower cardiac stimulation. Genetic polymorphisms of the norepinephrine SLC6A2 gene weakly moderates the cardiovascular response to MDMA and may play a minor role in adverse cardiovascular eventsCompletedClinicalTrials.gov identifier: NCT01771874 (Schmid et al., 2015b; Steuer et al., 2015; Vizeli et al., 2018)
    MDMAHealthy volunteers125 mg, orally, onceMDMA increases oxytocin but not BDNF plasma levels. No association between interindividual variations in the acute effects of MDMA in humans and DA system gene variantsCompletedClinicalTrials.gov identifier: NCT03019822 (Vizeli and Liechti, 2019; Holze et al., 2020)
    MDMAHealthy volunteers125 mg, orally, onceMDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic actionCompletedClinicalTrials.gov identifier: NCT00886886 (Hysek and Liechti, 2012)
    MDMAHealthy volunteers125 mg, orally, onceα1-Adrenergic receptor contributes to the acute cardiostimulant effects of MDMACompletedClinicalTrials.gov identifier: NCT01386177 (Hysek et al., 2013)
    MDMAHealthy volunteers125 mg, orally, onceThe combined use of methylphenidate and MDMA enhances cardiovascular and adverse effectsCompletedClinicalTrials.gov identifier: NCT01465685 (Hysek et al., 2014)
    MDMAHealthy volunteers125 mg, orally, onceThe 5-HT and NE transporter inhibitor duloxetine inhibits MDMA effects (may be useful in the treatment of psychostimulant dependence). MDMA increases copeptin, a marker for arginine vasopressin hormone secretion, in women but not in men. This may explain higher hyponatremia frequency in femalesCompletedClinicalTrials.gov identifier: NCT00990067 (Simmler et al., 2011; Hysek et al., 2012b)
    MDMAHealthy volunteers125 mg, orally, onceMDMA produces pupil dilation, subjective good drug effects, drug liking, happiness, and trust. MDMA reduces subjective anxiety and fear. MDMA produces sexual arousal-like effects. MDMA increases cortisol, prolactin, and oxytocinCompletedClinicalTrials.gov identifier: NCT01951508 (Dolder et al., 2018)
    MDMAHealthy volunteers1.5 mg/kg, orally, onceInvestigate the effects of serotonin release in the subjective effects of MDMACompletedClinicalTrials.gov identifier: NCT00838305
    MDMAHealthy volunteers1.6 mg/kg, orally, onceInvestigated the interactive effects of the β-blocker pindolol with MDMA on heart rate, blood pressure, body temperature, and adverse effectsCompletedClinicalTrials.gov identifier: NCT00895804
    MDMAHealthy volunteers1 mg/kg, orally, onceAssess the effects of MDMA on encoding and retrieval of emotional and social memories when the drug is administered before encoding and before retrievalCompletedClinicalTrials.gov identifier: NCT03050541
    MDMAHealthy volunteers100 mg, orally, onceAssess the effects of MDMA on startle response and fear conditioning. Measurement of blood BDNF, oxytocin, and cortisol. Assess the effects of MDMA on sleepRecruitingClinicalTrials.gov identifier: NCT03181763
    MDMAHealthy volunteers125 mg, orally, onceAssess the role of MDMA-induced acute serotonin release in the effects of fear extinctionRecruitingClinicalTrials.gov identifier: NCT03527316
    MDMAHealthy volunteers125 mg, orally, followed by a supplemental half dose 1.25–2.5 h later, onceAssess the effects of MDMA on therapists trained to perform MDMA-assisted psychotherapy researchEnrolling by invitationClinicalTrials.gov identifier: NCT01404754
    MDMAHealthy volunteers0.75–1.5 mg/kg, orally, onceAssess the effects of MDMA on the functioning of reward-related brain circuits (fMRI)Not yet recruitingClinicalTrials.gov identifier: NCT04060108
    MDMAHealthy volunteersN/AEffects of MDMA on mood and cognitive performanceCompletedClinicalTrials.gov identifier: NCT02033707
    MDMAHealthy volunteers120 mg, orally, followed by a supplemental half dose 1.5–2 h later, onceCollect information to support the safety profile of MDMA-assisted psychotherapy. Understand acute effects for use in therapyNot yet recruitingClinicalTrials.gov identifier: NCT04073433
    • AUD, alcohol use disorder; CBCT, cognitive behavioral conjoint therapy; COMT, catechol O-methyltransferase; fMRI, functional magnetic resonance imaging; N/A, not available; NCT, ClinicalTrials.gov identifier; SLC6A2, sodium-dependent noradrenaline transporter; 5-HTTLPR, serotonin transporter-linked polymorphic region.

    • View popup
    TABLE 2

    Clinical trials available on ClinicalTrials.gov investigating the use of psilocybin as a potential therapeutic approach for MDD and other psychiatric disorders

    For completed trials, the references of the published work were added if available either from the ClinicalTrials.gov web site or PubMed upon searching the NCT identifier. If information was available on the main findings of the study, it was added. If the trial was not completed or it was completed but no information was available in the form of a published original manuscript, we reported the main research question(s) the study aims to address.

    CompoundCohortRegimenResearch Question/Main FindingsStatusReference
    PsilocybinMajor depressive disorderFirst session: 0.3 mg/kg, orally; second session (after 2 wk from first): 0.45 mg/kg, orally; third session (after 4 wk from second): 0.6 mg/kg, orallyPharmacokinetics study. No physical or psychological adverse events within 30 days of any dose. The dose of 0.6 mg/kg might be in excess of therapeutic dose. No psilocybin found in plasma or urine. Renal clearance of intact psilocin 2%. No dose reduction needed for subjects with mild to moderate renal impairment. High-dose psilocybin is associated with positive subjective effects in healthy volunteersCompletedClinicalTrials.gov identifier: NCT02163707 (Brown et al., 2017b; Nicholas et al., 2018)
    PsilocybinTreatment-resistant depressionFirst session: 10 mg; second session: 25 mg (7 days apart)Treatment is well tolerated. No major adverse events. Transient anxiety, confusion, mild nausea, and headache. Psychological support recommended before, during, and after the session. Depressive symptoms reduced 1 wk, 5 wk, and 3 mo after psilocybin. Marked improvements in anxiety and anhedonia. Quality of the acute experience predicts the reduction in depressive scoresCompletedCarhart-Harris et al., 2016a, 2018
    PsilocybinTreatment-resistant depressionFirst session: 10 mg; second session: 25 mg (7 days apart)Psilocybin (post-treatment) decreases cerebral blood flow in the temporal cortex and amygdala. Decreased amygdala activity correlates with the antidepressant effect of psilocybin. Increased functional connectivity between ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex and decreased functional connectivity between parahippocampus-PFC predicts treatment response at 5 wkCompletedCarhart-Harris et al., 2017
    PsilocybinTreatment-resistant depressionFirst session: 10 mg; second session: 25 mg (7 days apart)Increased emotional responses to happy and fearful faces in the right amygdala after treatment. Psilocybin revives emotional responsiveness in patients with TRDCompletedRoseman et al., 2018
    PsilocybinTreatment-resistant depressionFirst session: 10 mg; second session: 25 mg (7 days apart)Psilocybin treatment decreases authoritarianism and increases nature relatednessCompletedLyons and Carhart-Harris, 2018
    PsilocybinMajor depressive disorder0.215 mg/kg, orally, onceEffects on depressive symptoms and brain functioning (fMRI)RecruitingClinicalTrials.gov identifier: NCT03715127
    PsilocybinMajor depressive disorder25 mg, orally, oncePotential efficacy of a single 25-mg oral dose of psilocybin for MDDRecruitingClinicalTrials.gov identifier: NCT03866174
    PsilocybinMajor depressive disorder0.1 and 0.3 mg/kg, orally, twiceAssess whether psilocybin enhances neuroplasticity in MDD patients (EEG + long-term potentiation task)RecruitingClinicalTrials.gov identifier: NCT03554174
    PsilocybinMajor depressive disorder25 mg, orally, onceLong-term (up to 24 mo) follow-up study of patients with MDD who previously received psilocybinEnrolling by invitationClinicalTrials.gov identifier: NCT04353921
    PsilocybinMajor depressive disorderModerate/high dose (dose N/A)Acute and persisting effects of psilocybin on depressive symptoms and other moods, attitudes, and behaviorActive, not recruitingClinicalTrials.gov identifier: NCT03181529
    PsilocybinMajor depressive disorderMultiple dosing days (dose and frequency N/A)Comparing antidepressant action and mechanisms of action of psilocybin and the SSRI escitalopram (fMRI)Active, not recruitingClinicalTrials.gov identifier: NCT03429075
    PsilocybinMajor depressive disorder25 mg, orally, onceLong-term therapeutic effects of psilocybin (fMRI, peripheral gene expression and molecules as predictor biomarkers of treatment outcome)Not yet recruitingClinicalTrials.gov identifier: NCT03380442
    PsilocybinMDD with mild cognitive impairment or early Alzheimer diseaseFirst session: 15 mg/70 kg; second session (2 wk after): 15 or 25 mg/70 kgSafety and efficacy of psilocybin given under supportive conditions in depressed people with MCI or early AD. Follow-up assessment of long-term therapeutic effectsRecruitingClinicalTrials.gov identifier: NCT04123314
    Treatment-Resistant Depression
    PsilocybinTreatment-resistant depressionLow, medium, high dose (dose and frequency N/A)Safety and efficacy of psilocybin in patients with TRDRecruitingClinicalTrials.gov identifier: NCT03775200
    Alcohol, Tobacco, and Substance Use Disorder
    PsilocybinAlcohol use disorder0.3–0.4 mg/kg, orally, twiceAbstinence increased after psilocybin. Gains maintained at 36 wk. Experience intensity in the first psilocybin session predicts decreases in drinking and craving and increases in abstinence. No significant treatment-related adverse eventsActive, not recruitingClinicalTrials.gov identifier: NCT02061293 (Bogenschutz et al., 2015; Nielson et al., 2018)
    PsilocybinAlcohol use disorder25 mg, orally, onceClinical and mechanistic effects of psilocybin in patients with alcohol addiction (3- and 6-mo follow-up)Not yet recruitingClinicalTrials.gov identifier: NCT04141501
    PsilocybinOpioid use disorderTwo doses 4 wk apart, orally (dose N/A)Psilocybin augmentation of buprenorphine/naloxone maintenance therapy for OUD with guided counseling. Assess changes in pain and life qualityNot yet recruitingClinicalTrials.gov identifier: NCT04161066
    PsilocybinTobacco use disorder20 and 30 mg/70 kg, onceComparing psilocybin to transdermal nicotine patch in individuals seeking to quit smoking (3-, 6-, and 12-mo follow-up). Previous trial: 80% abstinence after 7 days, 67% abstinence at 12- mo follow-up. Psilocybin experiences among the five most personally meaningful and spiritually significant experiences of participants’ livesRecruitingClinicalTrials.gov identifier: NCT01943994 (Garcia-Romeu et al., 2014; Johnson et al., 2014, 2017)
    PsilocybinCocaine use disorder0.36 mg/kg, orally, onceFeasibility and efficacy of psilocybin-facilitated treatment of cocaine use. Impact of psilocybin-facilitated treatment on other drug use and outcomes relevant to cocaine involvement (such as criminal involvement). Default mode network changes investigated by fMRIRecruitingClinicalTrials.gov identifier: NCT02037126
    Obsessive-Compulsive Disorder
    PsilocybinObsessive-compulsive disorder0.25 mg/kg, orally, onceInvestigate neural mechanisms underpinning OCD symptom improvements by psilocybin (fMRI)RecruitingClinicalTrials.gov identifier: NCT03356483
    PsilocybinObsessive-compulsive disorder0.1 and 0.3 mg/kg, orally, once weekly for 8 wkSafety, tolerability, and mechanism of action of psilocybin (and the anxiolytic lorazepam) as OCD treatments. Functional connectivity changes between the caudate nucleus and orbital frontal cortexRecruitingClinicalTrials.gov identifier: NCT03300947 (Moreno et al., 2006)
    Patients with Cancer
    PsilocybinPotentially life-threatening cancer1–3 or 22–30 mg/kg, orally, twicePsilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. Improved quality of life, life meaning, and optimism and decreases in death anxiety. Changes sustained at 6-mo follow-up in 80% of participants. Improvements in attitudes about life/self, mood, relationships, and spirituality. Increased well-being/life satisfactionCompletedClinicalTrials.gov identifier: NCT00465595 (Griffiths et al., 2016)
    PsilocybinPotentially life-threatening cancer0.2 mg/kg, orally, onceReduction in anxiety scores at 1 and 3 mo and improvements in depression scores at 6 moCompletedClinicalTrials.gov identifier: NCT00302744 (Grob et al., 2011)
    PsilocybinPotentially life-threatening cancer0.3 mg/kg, orally, onceImmediate, substantial, and sustained improvements in anxiety and depression. Decreases in cancer-related demoralization and hopelessness, improved spiritual well-being, and increased quality of life. Enduring anxiolytic and antidepressant effects and reductions in depression and anxiety at 6-mo follow-up in 60%–80% of patients. Sustained benefits in existential distress and quality of life and improved attitudes toward death. Psilocybin-occasioned mystical experiences mediate the therapeutic effects on anxiety and depressionActive, not recruitingClinicalTrials.gov identifier: NCT00957359 (Ross et al., 2016)
    Others
    PsilocybinAnorexia nervosaFirst session: the lesser of 20 mg or 0.6 mg/kg; second session: the lesser of 25 mg or 0.6 mg/kg.Assess the safety and efficacy of moderate- to high-dose psilocybin in people suffering from AN. Assess whether long-term positive behavioral changes (eating habits, anxiety, and depression) can be elicited in a supportive setting with close follow-up. Assess whether psilocybin decreases eating disorder pathophysiologyRecruitingClinicalTrials.gov identifier: NCT04052568
    PsilocybinAIDS survivorsOnce, orally (dose N/A)Safety, tolerability, and feasibility of psilocybin-assisted group therapy for demoralization in long-term AIDS survivors. Effects on demoralization, complicated grief, anxiety, life quality, functional social support, post-traumatic growth, openness to experience, mindfulness, social connection, nature relatedness, and medication adherenceCompletedClinicalTrials.gov identifier: NCT02950467
    PsilocybinLong-term meditatorsOnce or twice, dose manipulation (dose N/A)Characterize performance of tasks, brain functioning, and the effects of psilocybin in long-term meditators. Psychological function, behavioral and cognitive tasks, brain resting-state functional connectivityCompletedClinicalTrials.gov identifier: NCT01988311
    PsilocybinLong-term meditatorsVery low dose, moderately low dose, moderately high dose (dose N/A)Acute and persisting effects of psilocybin on meditation, spirituality, health, well-being, prosocial attitudes, and brain functioning (fMRI)CompletedClinicalTrials.gov identifier: NCT02145091
    Religious Professional Leaders
    PsilocybinReligious professional leadersFirst session: 20 mg/70 kg, orally; second session: 20 or 30 mg/70 kg, orallyUtility of psilocybin for professional religious leaders. Further understanding of mystical-type experiences. Changes in psychological functioning, spirituality, health, well-being, and prosocial attitudesRecruitingClinicalTrials.gov identifier: NCT02421263
    PsilocybinReligious professional leadersFirst session: 20 mg/70 kg, orally; second session: 20 or 30 mg/70 kg, orallyEffects and utility of psilocybin-facilitated experiences for professional religious leadersRecruitingClinicalTrials.gov identifier: NCT02243813
    Healthy Volunteers
    PsilocybinHealthy volunteers25 mg/70 kg, orally, onceReduction of negative affect and amygdala response to facial affect stimuli at 1 wk postpsilocybin. Increase in positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally conflicting stimuli after 1 wk. Negative affective and amygdala response to facial affect stimuli back to baseline after 1 mo, whereas positive affect remains elevated, and trait anxiety reduced. Increased resting-state functional connectivity at 1 wk and 1 mo postpsilocybin. Psilocybin may increase emotional and brain plasticity, and negative affect may be targeted with psilocybinCompletedClinicalTrials.gov identifier: NCT02971605 (Barrett et al., 2020)
    PsilocybinHealthy volunteers2 mg by i.v. infusion, onceProfound changes in consciousness. Decreased BOLD fMRI signals in thalamus, anterior and posterior cingulate cortex, and mPFC. Decrease in positive coupling between the mPFC and PCC. Psychedelics may induce a state of “unrestrained cognition”CompletedCarhart-Harris et al., 2012
    PsilocybinHealthy volunteers2 mg by i.v. infusion, oncePsilocybin increases DMN-TPN functional connectivity, as observed in psychosis and meditative states. Thalamocortical functional connectivity not affectedCompletedCarhart-Harris et al., 2013
    PsilocybinHealthy volunteers2 mg by i.v. infusion, onceDuring the psychedelic state, the brain biases a mode of whole-brain functional integration at the expense of local networksCompletedBioRxiv 10.1101/376491v1
    PsilocybinHealthy volunteers2 mg by i.v. infusion, onceThe subjective effects of psilocybin might arise as a result of cortical oscillatory rhythm desynchronization, potentially arising from the stimulation of deep-layer 5-HT2A receptors on pyramidal neuronsCompletedMuthukumaraswamy et al., 2013
    PsilocybinHealthy volunteers2 mg by i.v. infusion, onceAssociation between ego dissolution and decreased functional connectivity between medial temporal lobe and high-level cortical regions. Ego dissolution also associated with “disintegration” of the salience network and reduced interhemispheric communicationCompletedLebedev et al., 2015
    PsilocybinHealthy volunteers2 mg by i.v. infusion, onceIncreased between-network resting-state functional connectivityCompletedRoseman et al., 2014
    PsilocybinHealthy volunteers30 mg/70 kg, oncePsilocybin increases measures of mystical experience. Psilocybin experience has substantial personal meaning and spiritual significance. Sustained positive changes in attitudes and behavior attributed to the experience. Around 60% of participants rate their psilocybin experience among the most significant and spiritual in their livesCompletedClinicalTrials.gov identifier: NCT00802282 (Griffiths et al., 2006, 2008)
    PsilocybinHealthy volunteers10–20–30 mg/70 kg (low, moderate, and high dose, respectively)Dose-dependent effects of psilocybin on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. No delirium or global cognitive impairment observedCompletedClinicalTrials.gov identifier: NCT02033707 Barrett et al., 2018
    PsilocybinHealthy volunteers15–20–30 mg, orally, onceCompare altered states of consciousness induced by psilocybin, LSD, and mescalineRecruitingClinicalTrials.gov identifier: NCT03604744, NCT04227756
    PsilocybinHealthy volunteers25 mg, orally, onceEffects of SERT inhibition (escitalopram) on the subjective response to psilocybin in healthy subjectsRecruitingClinicalTrials.gov identifier: NCT03912974
    PsilocybinHealthy volunteersN/AApplication of PCI based on IIT. Combination of transcranial magnetic stimulation and high-density electroencephalography to measure electrocortical responses as distributed cerebral interactions (integration) and spatiotemporal pattern (information)RecruitingClinicalTrials.gov identifier: NCT03853577
    PsilocybinHealthy volunteers0.2–0.215–0.315 mg/kg, orally, onceNeuropharmacological mechanisms underlying ego dissolution. Integration of functional connectivity in sensory regions and disintegration in associative regions may underlie the psychedelic stateActive, not recruitingClinicalTrials.gov identifier: NCT03736980 (Preller et al., 2020)
    • AD, Alzheimer’s disease; AIDS, acquired immunodeficiency syndrome; AN, anorexia BOLD, blood oxygen level–dependent; EEG, electroencephalogram; fMRI, functional magnetic resonance imaging; IIT, integrated information theory; MCI, mild cognitive impairment; NCT, ClinicalTrials.gov identifier; N/A, not available; OUD, opioid use disorder; PCI, perturbational complexity index; TPN, task-positive network; TRD, treatment-resistant depression.

    • View popup
    TABLE 3

    Clinical trials available on ClinicalTrials.gov investigating the use of LSD as a potential therapeutic approach for MDD, anxiety, and other psychiatric disorders

    For completed trials, the references of published work were added if available either from the ClinicalTrials.gov web site or PubMed upon searching the NCT identifier. If information was available on the main findings of the study, it was added. If the trial was not completed or it was completed but no information was available in the form of a published original manuscript, we reported the main research question(s) the study aims to address.

    CompoundCohortRegimenResearch Question/Main FindingsStatusReference
    LSDMajor depressive disorderFirst session: 25 or 100 μg, orally; second session: 25, 100, or 200 μg, orallyAssess the benefits of LSD-assisted psychotherapy in patients with MDDRecruitingClinicalTrials.gov identifier: NCT03866252
    LSDMajor depressive disorderFirst session: 25 or 100 μg, orally; second session: 25, 100, or 200 μg, orallyAssess antidepressant and anxiolytic effects of LSD in patients with MDDRecruitingClinicalTrials.gov identifier: NCT03866252
    LSDIllness-related anxiety20 or 200 μg, orally, onceLSD reduces anxiety. Sustained anxiolytic effects and increased quality of life over a 12-mo period. Facilitated access to emotions and confrontation with previously unknown anxieties. The experience leads to a restructuring of the person’s emotional trust, situational understanding, habits, and world view. No adverse reactions. LSD can be safe and generate lasting benefits in patients with a life-threatening diseaseCompletedClinicalTrials.gov identifier: NCT00920387 (Gasser et al., 2014, 2015)
    LSDHealthy volunteers100–200 µg, orally, onceLSD induces visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Increased subjective well-being, happiness, closeness to others, and openness. LSD breaks down hippocampal-prefrontal cortex–mediated inhibitory processing, which might be involved in the formation of LSD-induced visual imageries. LSD increases blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. No severe acute adverse effects. LSD detected in all subjects up to 12 h after administration. Maximal LSD plasma concentrations reached 0.5–4 h after administration. Half-life of 2.5–4.5 h up to 12 h and slower elimination after. No sex differences in pharmacokinetics. Acute effects up to 12 h. LSD induces fewer mystical experiences than psilocybin. LSD produced higher ratings of blissful state, insightfulness, and changed meaning of percepts after 200 µg compared with 100 µg. Feelings of ego dissolution at 100 µg correlated to LSD plasma levelsCompletedClinicalTrials.gov identifier: NCT01878942 (Dolder et al., 2015; Schmid et al., 2015a; Strajhar et al., 2016)
    LSDHealthy volunteers100–200 µg, orally, onceLSD impairs fear recognition and enhances emotional empathy and sociality. Maximum mean plasma concentration of 1.3 and 3.1 ng/ml reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. Mean plasma half-life 2.6 h. Subjective effects last 8.2 ± 2.1 h for the 100-µg and 11.6 ± 1.7 h for the 200-µg dose, respectively. Subjective peak effects reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. LSD reduces left amygdala and right medial prefrontal cortex activity during the presentation of fearful faces. Negative correlation between LSD-induced amygdala response to fearful stimuli and LSD-induced subjective drug effectsCompletedClinicalTrials.gov identifier: NCT02308969 (Dolder et al., 2016, 2017b; Liechti et al., 2017; Mueller et al., 2017)
    LSDHealthy volunteers100 µg, orally, onceChanges in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to 5-HT2A. LSD impairs working memory, executive functions, and cognitive flexibility but not risk-based decision-making. 5-HT2A signaling underlies LSD-induced alteration of the neural response to dynamic changes in music. LSD decreases striatothalamic functional connectivity independently of 5-HT2A and increases thalamo-PCC connectivity in a 5-HT2A–dependent fashionCompletedClinicalTrials.gov identifier: NCT02451072 (Preller et al., 2018, 2019; Holze et al., 2019; Pokorny et al., 2019)
    LSDHealthy volunteers100 µg, orally, onceLSD compared with MDMA produces greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity. LSD produces greater impairments in concentration, sense of time, and speed of thinking. LSD does not increase oxytocin levels. Acute LSD does not affect circulating BDNFCompletedClinicalTrials.gov identifier: NCT03019822 (Holze et al., 2020)
    LSDHealthy volunteers75 µg by i.v. injection, onceLSD enhances suggestibility, and this effect could be harnessed in psychotherapeutic settingsCompletedCarhart-Harris et al., 2015
    LSDHealthy volunteers75 µg by i.v. injection, onceLSD administration modulates learning adaptive mechanisms and attenuates top-down suppression of prediction errorCompletedTimmermann et al., 2018
    LSDHealthy volunteers40–80 µg by i.v. injection, onceLSD enhances the emotional response to music. Increased functional connectivity between parahippocampal-visual cortex and increased parahippocampal-visual cortex information flow in the interaction between music and LSDCompletedKaelen et al., 2015
    LSDHealthy volunteers75 µg by i.v. injection, onceLSD increases blood flow to the visual cortex and decreases alpha power, and these effects predict the magnitude of visual hallucinations. LSD decreases DMN integrity and delta and alpha power in the PCC, and these effects correlate with ego dissolutionCompletedCarhart-Harris et al., 2016c
    LSDHealthy volunteers75 µg by i.v. injection, onceLSD increases brain entropy. Entropy increases are greatest while listening to music and experiencing ego dissolutionCompletedLebedev et al., 2016
    LSDHealthy volunteers25–50–100–200 µg, orally, once per dose5-HT2A receptor involvement in LSD consciousness-altering effects (using the 5-HT2A antagonist ketanserin before LSD)CompletedClinicalTrials.gov identifier: NCT03321136
    LSDHealthy volunteers100–200 µg, orally, once per doseCompare the acute effects of LSD and psilocybinRecruitingClinicalTrials.gov identifier: NCT03604744
    LSDHealthy volunteers6.5–13–26 µg, orally, once per doseLSD microdosing produces dose-related subjective effects across the three doses. Microdoses increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content at 26 µg. Other mood, cognition, and physiological measures were unaffected. Low-dose LSD (13 µg) increases amygdala connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum and decreases amygdala connectivity with the superior temporal gyrus. Effects on mood positively correlated with the increase in amygdala-middle frontal gyrus connectivityRecruitingClinicalTrials.gov identifier: NCT03790358 (Bershad et al., 2019, 2020)
    LSDHealthy volunteers13 µg, orally, onceAssess the effects of repeated very low doses of LSD on mood in individuals with negative moodRecruitingClinicalTrials.gov identifier: NCT03934710
    LSDHealthy volunteers100 µg, orally, onceComparative acute effects of LSD, psilocybin, and mescaline (Five Dimensions of Altered States of Consciousness and resting state fMRI)Not yet recruitingClinicalTrials.gov identifier: NCT04227756
    • NCT, ClinicalTrials.gov identifier.

    • View popup
    TABLE 4

    Clinical trials available on ClinicalTrials.gov investigating the use of ayahuasca and DMT for treatment-resistant depression and in healthy individuals

    For completed trials, the references of published work were added if available either from the ClinicalTrials.gov web site or PubMed upon searching the NCT identifier. If information was available on the main findings of the study, it was added. If the trial was not completed or it was completed but no information was available in the form of a published original manuscript, we reported the main research question(s) the study aims to address.

    CompoundCohortRegimenResearch Question/Main FindingsStatusReference
    AyahuascaTreatment-resistant depression2.2 ml/kg, orally, once. Composition: 0.8 mg/ml DMT, 0.21 mg/ml harmine. No harmaline at detection threshold of 0.02 mg/ml (Osório et al., 2015; Sanches et al., 2016) 1 ml/kg, orally, once. Composition: 0.36 mg/ml DMT, 1.86 mg/ml harmine, 0.24 mg/ml harmaline, 1.20 mg/ml tetrahydroharmine (Galvao et al., 2018; de Almeida et al., 2019; Palhano-Fontes et al., 2019; Zeifman et al., 2019; Pasquini et al., 2020)Ayahuasca is a safe and well tolerated approach for TRD. Decreases in up to 80% of patients in depression-related scales from 80 min to day 21. Increased blood perfusion in the left nucleus accumbens, right insula, and left subgenual area. Vomiting in 47% of participants. Ayahuasca elicits fast-acting and sustained antidepressant effects. Ayahuasca decreases suicidality scores and might be useful for suicidality. Increased BDNF levels in patients with TRD and healthy controls 48 h after administration. Ayahuasca acutely increases salivary cortisol but does not affect awakening salivary cortisol response at 48 h in patients with TRD. At 24 h after ayahuasca, increased anterior cingulate cortex connectivity within the salience network, together with decreased PCC connectivity within the DMN, and increased connectivity between the salience and DMN. No effect on the connectivity of primary sensory networksCompletedClinicalTrials.gov Identifier: NCT02914769 (Osório et al., 2015; Sanches et al., 2016; Palhano-Fontes et al., 2019; Galvao et al., 2018; de Almeida et al., 2019; Zeifman et al., 2019; Pasquini et al., 2020)
    DMTHealthy volunteers15–25 mg by i.v. bolus + 0.6 to 1 mg/min by i.v. infusion over 90 min (total 69–115 mg)Psychological and physical tolerability of different intravenous DMT administration schedules to investigate the subjective and autonomic effects of prolonged DMT infusion in healthy subjectsNot yet recruitingClinicalTrials.gov Identifier: NCT04353024
    • NCT, ClinicalTrials.gov identifier; TRD, treatment-resistant depression.

    • View popup
    TABLE 5

    Main receptor interactions and downstream effects of psychedelic compounds on pathways involved in synaptic and neuronal plasticity, neuroimmunomodulation, and modulation of neurotransmitter systems of relevance to psychiatry

    For each compound (column 1), the receptors involved in signal transduction are reported with decreasing Ki (column 2). The transcription factors, enzymes, hormones, and cytokines up/downregulated by each compound are reported in terms of acute and chronic responses (where data are available, column 3). The main outcomes on modulation of neurotransmitter systems are reported in column 4. Systemic and psychological effects elicited are reported for each compound (column 5). Referenced articles are reported in column 6.

    CompoundReceptors (>Ki)Transcription Factors/Enzymes/Hormones/CytokinesNeurotransmitter EffectsCentral Effects/Systemic Effects/Psychological EffectsReferences
    LSD5-HT1B, 5-HT7, 5-HT6, 5-HT1A, 5-HT1D, 5-HT5A, 5-HT2A, D3, 5-HT2B, 5-HT2C, adrenoreceptor (ADRA) 2, 5-HT1E, D2, D4, D1, D5, ADRA1A, histamine receptor (H1), ADRB1, ADRB2, ADRA1BAcute: ↑mTOR, ↑cFOS, ↑Egr-1, ↑Egr-2, ↑Cebpb, ↑IKB, ↑SGK, ↑Nor1, ↑ANIA3, ↑MKP1, ↑DHEA, ↑CORT, ↓IL2, ↓IL4, ↓IL6, Chronic: ↑GABRB1, ↑GABRB2, ↑GABRG3, ↑NR2A, ↑NR2B, ↑BDNF, ↑KROX20, ↓D1, ↓D2, ↓5-HT2C, ↓SLC6A13 (GABA transporter)↑(Prolonged) glutamate release in layer V pyramidal neurons, ↓5-HT firing in DRN via 5-HT2A (low doses), ↓DA firing via 5-HT1A (high doses), ↓DA neurotransmission in VTA (high doses)↑Neurogenesis, ↑axon, branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxietyHouse et al., 1994; Watts et al., 1995; Egan et al., 1998; González-Maeso et al., 2003, 2007; Nichols and Sanders-Bush, 2004; Lambe and Aghajanian, 2006; Ray, 2010; Marona-Lewicka et al., 2011; Barrot, 2012; Martin et al., 2014; De Gregorio et al., 2016a,b; Ly et al., 2018; Rickli et al., 2015; Strajhar et al., 2016;
    Psilocybin5-HT2B, 5-HT1D, D1, 5-HT1E, 5-HT1A, 5-HT5A, 5-HT7, 5-HT6, D3, 5-HT2C, 5-HT1B, 5-HT2A, I1, SERT, ADRA2B, ADRA2A, ADRA2C↑ACTH, ↑CORT, ↑TSH↑Striatal DA release (caudate/putamen)↑Neurogenesis, ↑axon branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxietyMcKenna et al., 1990; Vollenweider et al., 1999b; Ray, 2010; Hasler et al., 2004; Carhart-Harris et al., 2016a
    Ayahuasca5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, 5-HT7R, TAAR1, S1R↑5-HT2A, ↑SERT, ↑CORT (acute only), ↓CORT (awakening response), ↑GH↑Hippocampal GABA (dose-independently); ↑amygdalar GABA (low doses); ↓amygdalar GABA (higher doses); ↑amygdalar 5-HT, DA, and noradrenaline; ↑hippocampal 5-HT (highest doses); ↑5-HT, DA, and noradrenaline turnover↑Neurogenesis, ↑neuronal differentiation, ↓inflammation, ↓depression, ↓anxietyCallaway et al., 1999; de Castro-Neto et al., 2013; Morales-Garcia et al., 2017; Galvao et al., 2018; Palhano-Fontes et al., 2019
    DMT5-HT7, 5-HT1D, 5-HT2B, ADRA2B, ADRA2C, D1, 5-HT2C, 5-HT1E, 5-HT6, 5-HT5A, I1, ADRA1B, ADRA2A, ADRA1A, 5-HT2A, SERT, S1R↑IL10, ↓IDO, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-αN/A↑Neurogenesis, ↑dendritic spines formation, ↓inflammationFontanilla et al., 2009; Keiser et al., 2009; Ray, 2010; Tourino et al., 2013; Szabo et al., 2014;
    5-MeO-DMT5-HT1A, 5-HT7, 5-HT1D, 5-HT6, 5-HT1B, D1, 5-HT5A, 5-HT1E, D3, ADRA2C, 5-HT2C, ADRA2A, 5-HT2A, SERT, I1, ADRA2B, NET1, D4, D2, 5-HT2B↑NMDAR, ↑ERK 1/2, ↑CREB, ↑CAMK2, ↓NF-ĸB, ↓NFAT, ↓TLR, ↓mGluR5, ↓PKC, ↓PLC, ↓IP3R, ↓EPAC1, ↓PKA, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-α, ↑IL10N/A↑Neurogenesis, ↑dendritic spines formation, ↑long-term potentiation, ↓neurodegeneration, ↑cytoskeletal reorganization, ↓inflammation, ↑T lymphocytes differentiation, ↓cell death, ↓depression, ↓anxietyRay, 2010; Szabo et al., 2014; Dakic et al., 2017; Lima da Cruz et al., 2018; Ly et al., 2018; Davis et al., 2019; Szabo et al., 2014
    DOI5-HT2C, ADRA2A, ADRB2, 5-HT2A, ADRA2B, 5-HT2BR, 5-HT1D, CHRM4, ADRB1, ADRA2C, SERT, 5-HT1E, CHRM3, H1, CHRM2, 5-HT6, CHRM5, 5-HT1A, CHRM1, 5-HT7, S1R, S2R, D1↑Egr-1, ↑Egr-2, ↑cFOS, ↑IKBA, ↓Egr-3, ↓TNF-α, ↓ILB, ↓IL6, ↓iNOS, ↓ICAM1, ↓VCAM1, ↓MCP1, ↓CX3CL1N/A↓InflammationGonzález-Maeso et al., 2003; Yu et al., 2008; Ray, 2010; Nau et al., 2013; Lima da Cruz et al., 2018
    KetamineNMDAR, D1, D2, 5-HT2A, 5-HT3, S1R, S2R, OPRM1, OPRK1, OPRD1Acute: ↑mTOR, ↑BDNF, ↑IL1β, ↑IL6, ↑TNF-α, ↓EEAT2, Chronic: ↓TNF-α↑DA activity via DR1 in the NA, ↑DA neurotransmission in VTA after amphetamine withdrawal↑Neurogenesis, ↑dendritic spines growth, ↑synapse formation, ↑dopaminergic activity, ↓depression, ↓anxietyLi et al., 2010, 2017; Murrough et al., 2013b; Belujon and Grace, 2014; Belujon et al., 2016; Choi et al., 2017; Lisek et al., 2017;
    MDMATAAR1, NMDAR, VMAT2, 5-HT1A, SERT, I1, 5-HT2B, CACNA1A, ADRA2C, ADRA2B, CHRM3, ALPHA2A, CHRM5, CHRM4↑Cortisol, ↑prolactin, ↑oxytocin, ↑IL10, ↓IL1β, ↓IL6, ↓IL12, ↓IL15, ↓TNF-α, ↓CXCL10, ↓CCL5↑5-HT, DA, and NE neurotransmission; ↓5-HT and DA reuptake; oxytocin-dependent reopening of long-term depression in the NA↓PTSD symptoms, ↑long-term depression in the NA, ↓inflammationGouzoulis-Mayfrank et al., 1999; Ray, 2010; Boyle and Connor, 2010; Yuan et al., 2016; Mithoefer et al., 2018; Nardou et al., 2019
    • ADRA, alpha adrenergic receptor; ADRB, beta adrenergic receptor; ALPHA2A, alpha 2 adrenergic receptor; ANIA3, activity and neurotransmitter-induced early gene 3; CACNA1A, voltage-dependent P/Q-type calcium channel subunit alpha-1A; CAMK2, calcium/calmodulin-dependent protein kinase 2; CCL5, C-C motif chemokine 5; CHRM, muscarinic acetylcholine receptor M2; Cebpb, CCAAT/enhancer-binding protein beta; CORT, cortisol; CX3CL1, fractalkine; CXCL10, C-X-C motif chemokine 10; EEAT2, excitatory amino acid transporter 2; EPAC1, rap guanine nucleotide exchange factor 3; GABR, gamma-aminobutyric acid type B receptor; GH, growth hormone; I1, imidazoline receptor 1; ICAM, intercellular adhesion molecule; IP3R, inositol trisphosphate receptor; KROX20, early growth response protein 2; MAPK1, mitogen-activated protein kinase 1; N/A, not available; NET1, norepinephrine transporter 1; NFAT, nuclear factor o activated T-cells; NMDAR, N-methyl-D-aspartic acid receptor; Nor1, neuron-derived orphan receptor-1; OPRM1, mu-type opioid receptor; OPRK1, kappa-type opioid receptor; OPRD1, delta-type opioid receptor; IKB, inhibitor of kB kinases; PLC, pospholipase C; PKA, protein kinase A; PKC, protein kinase C; SGK, serine/threonine-protein kinase Sgk1; SLC6A13, sodium- and chloride-dependent GABA transporter 2; TLR, toll-like receptor; TSH, thyroid stimulating hormone; VCAM, vascular cell adhesion protein.

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Table -

      Supplemental Table 1 -  Clinical trials available on ClinicalTrials.gov investigating the use of ketamine as a potential therapeutic approach for treatment-resistant depression and other psychiatric disorders.

PreviousNext
Back to top

In this issue

Pharmacological Reviews: 73 (1)
Pharmacological Reviews
Vol. 73, Issue 1
1 Jan 2021
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Pharmacological Reviews article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
(Your Name) has forwarded a page to you from Pharmacological Reviews
(Your Name) thought you would be interested in this article in Pharmacological Reviews.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Review ArticleReview Article

Psychedelics in Psychiatry: Therapeutic Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Pharmacological Reviews January 1, 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Review ArticleReview Article

Psychedelics in Psychiatry: Therapeutic Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Pharmacological Reviews January 1, 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • I. Introduction
    • II. Psychedelic Compounds as Neuroplastic Agents
    • III. Psychedelic Compounds as Immunomodulatory and Anti-Inflammatory Agents
    • IV. Psychedelic Compounds as Modulators of Neurotransmitter Systems
    • V. Biased Signaling, Biased Phosphoproteomics, and Psychedelic Compounds
    • VI. Going Beyond Receptors: Neuronal Circuits Activated by Psychedelic Drugs
    • VII. Effects of Psychedelics on Sleep
    • VIII. Long-Term Neurobiological and Psychological Effects of Psychedelic Compounds
    • IX. Side Effects of Psychedelic Compounds
    • X. Recommendations for Future Research
    • XI. Conclusion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Nanozymes for viral diagnosis and therapy
  • Structure and Inhibition of NLRP3 Inflammasome
  • Neural mechanisms of general anesthesia
Show more Review Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Pharmacological Reviews
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacology Research & Perspectives
ISSN 1521-0081 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics