Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

Antonio Inserra; Danilo De Gregorio; Gabriella Gobbi

doi:10.1124/pharmrev.120.000056

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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.
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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.
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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.

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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.

Compound	Cohort	Regimen	Research Question/Main Findings	Status	Reference
MDMA	Post-traumatic stress disorder	30, 75, or 125 mg, orally, followed by a supplemental half dose 1.5–2 h later, thrice	MDMA-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 treatment	Completed	ClinicalTrials.gov identifier: NCT03485287, NCT03282123, NCT01211405 (Mithoefer et al., 2018; Gorman et al., 2020)
MDMA	Post-traumatic stress disorder	125 mg, orally, followed by a supplemental half dose 1.5–2 h later, thrice	Decrease 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 session	Completed	ClinicalTrials.gov identifier: NCT00090064 (Mithoefer et al., 2011, 2013)
MDMA	Post-traumatic stress disorder	30, 75, or 125 mg, orally, followed by a supplemental half dose 1.5–2 h later, once	Identify psychotherapeutic processes in MDMA-assisted psychotherapy for PTSD	Completed	ClinicalTrials.gov identifier: NCT02102802
MDMA	Post-traumatic stress disorder	25 or 125 mg, orally, followed by a supplemental half dose 2 h later, thrice	Safety and efficacy of MDMA-assisted psychotherapy for PTSD	Completed	ClinicalTrials.gov identifier: NCT01958593, NCT01689740
MDMA	Post-traumatic stress disorder	62.5, 125, or 125 + 62.5 mg, orally	Additional MDMA psychotherapy for people who relapsed 1 yr after the first trial	Completed	ClinicalTrials.gov identifier: NCT01458327
MDMA	War- or terrorism-related PTSD	25 and 125 mg, orally, followed by a supplemental half dose 2–2.5 h later, twice	MDMA-assisted psychotherapy for people with war- or terrorism-related PTSD	Terminated due to staff turnover and its effects on data collection	ClinicalTrials.gov identifier: NCT00402298
MDMA	Post-traumatic stress disorder	1.5 mg/kg, orally, once	Effects of MDMA on prefrontal and amygdala activation. Relationship between neural changes and acute behavioral effects in patients with PTSD	Recruiting	ClinicalTrials.gov identifier: NCT03752918
MDMA	Post-traumatic stress disorder	80 and 120 mg, orally, followed by a supplemental half dose 1.5–2 h later, thrice	Multisite phase III study of MDMA-assisted psychotherapy for PTSD	Active, not recruiting	ClinicalTrials.gov identifier: NCT03537014
MDMA	Post-traumatic stress disorder	80 and 120 mg, orally, followed by a supplemental half dose 1.5–2 h later, twice	First 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 design	Not yet recruiting	ClinicalTrials.gov identifier: NCT04030169
MDMA	Combat-related post-traumatic stress disorder	First 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 later	Efficacy of MDMA-assisted psychotherapy in veterans with combat-related, refractory PTSD	Not yet recruiting	ClinicalTrials.gov identifier: NCT04264026
MDMA	CBCT in dyads with one member with post-traumatic stress disorder	First 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 later	Safety 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 psychotherapy	Completed	ClinicalTrials.gov identifier: NCT02876172
Autism Spectrum Disorder
MDMA	Autism spectrum disorder	First session: 75 or 100 mg, orally; second session: 100 or 125 mg	MDMA-assisted psychotherapy is safe and elicits rapid and durable therapeutic improvements in social anxiety symptoms in adults with ASD	Completed	ClinicalTrials.gov identifier: NCT02008396 (Danforth et al., 2018)
MDMA	Autism spectrum disorder	1.5 mg/kg, orally	Assess whether MDMA affects the response to affective touch in individuals with a range of autistic traits and healthy volunteers	Recruiting	ClinicalTrials.gov identifier: NCT04053036, NCT03790618
Substance, Alcohol, and Tobacco Abuse
MDMA	Alcohol use disorder	125 mg, orally, followed by a supplemental half dose 2 h later, twice	Feasibility of MDMA-assisted psychotherapy in patients with AUD who have recently undergone detoxification	Active, not recruiting	ClinicalTrials.gov identifier: NCT04158778
MDMA	Substance abuse disorder	125 mg, orally, once	Oxytocin 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 variants	Completed	ClinicalTrials.gov identifier: NCT01270672 (Vizeli and Liechti, 2018)
MDMA	Substance abuse disorder	125 mg, orally, once	Effects of MDMA on social and emotional processing	Completed	ClinicalTrials.gov identifier: NCT01465685 (Hysek et al., 2014; Vizeli and Liechti, 2018)
MDMA	Substance abuse disorder	1.6 mg/kg, orally, once	Evaluate the effects of MDMA on thinking and the relationship between plasma MDMA levels and brain function (fMRI)	Completed	ClinicalTrials.gov identifier: NCT01148342
Others
MDMA	Life-threatening illness	125 mg, orally, followed by a supplemental half dose 1.25–2.5 later, thrice	Safety 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 anxiety	Completed	ClinicalTrials.gov identifier: NCT02427568, NCT02954562
MDMA	Hepatic impairment	80 mg, orally, once	Assess 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 impairment	Recruiting	ClinicalTrials.gov identifier: NCT03606538
MDMA	Recreational users	Depending on self-administration	Ecstasy use is associated with tissue changes in the globus pallidus. Lower cortical postsynaptic 5-HT_2A in recent users. Higher 5-HT_2A 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 abusers	Completed	ClinicalTrials.gov identifier: NCT00235768 (Reneman et al., 2001a,b, 2002b; de Win et al., 2004)
MDMA	Recreational users	Depending on self-administration	MDMA users report somatic complaints on day 1, and symptoms of reduced energy, increased fatigue, and weakness persisted up to 4 days post–drug ingestion	Completed	ClinicalTrials.gov identifier: NCT01400204
Healthy Volunteers
MDMA	Healthy volunteers	1.5 mg/kg, orally, once	Female 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 days	Completed	ClinicalTrials.gov identifier: NCT01447472 (O’Mathuna et al., 2008; Yubero-Lahoz et al., 2011; Pardo-Lozano et al., 2012)
MDMA	Healthy volunteers	125 mg, orally, once	Dopamine 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 events	Completed	ClinicalTrials.gov identifier: NCT01771874 (Schmid et al., 2015b; Steuer et al., 2015; Vizeli et al., 2018)
MDMA	Healthy volunteers	125 mg, orally, once	MDMA increases oxytocin but not BDNF plasma levels. No association between interindividual variations in the acute effects of MDMA in humans and DA system gene variants	Completed	ClinicalTrials.gov identifier: NCT03019822 (Vizeli and Liechti, 2019; Holze et al., 2020)
MDMA	Healthy volunteers	125 mg, orally, once	MDMA-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 action	Completed	ClinicalTrials.gov identifier: NCT00886886 (Hysek and Liechti, 2012)
MDMA	Healthy volunteers	125 mg, orally, once	α1-Adrenergic receptor contributes to the acute cardiostimulant effects of MDMA	Completed	ClinicalTrials.gov identifier: NCT01386177 (Hysek et al., 2013)
MDMA	Healthy volunteers	125 mg, orally, once	The combined use of methylphenidate and MDMA enhances cardiovascular and adverse effects	Completed	ClinicalTrials.gov identifier: NCT01465685 (Hysek et al., 2014)
MDMA	Healthy volunteers	125 mg, orally, once	The 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 females	Completed	ClinicalTrials.gov identifier: NCT00990067 (Simmler et al., 2011; Hysek et al., 2012b)
MDMA	Healthy volunteers	125 mg, orally, once	MDMA 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 oxytocin	Completed	ClinicalTrials.gov identifier: NCT01951508 (Dolder et al., 2018)
MDMA	Healthy volunteers	1.5 mg/kg, orally, once	Investigate the effects of serotonin release in the subjective effects of MDMA	Completed	ClinicalTrials.gov identifier: NCT00838305
MDMA	Healthy volunteers	1.6 mg/kg, orally, once	Investigated the interactive effects of the β-blocker pindolol with MDMA on heart rate, blood pressure, body temperature, and adverse effects	Completed	ClinicalTrials.gov identifier: NCT00895804
MDMA	Healthy volunteers	1 mg/kg, orally, once	Assess the effects of MDMA on encoding and retrieval of emotional and social memories when the drug is administered before encoding and before retrieval	Completed	ClinicalTrials.gov identifier: NCT03050541
MDMA	Healthy volunteers	100 mg, orally, once	Assess the effects of MDMA on startle response and fear conditioning. Measurement of blood BDNF, oxytocin, and cortisol. Assess the effects of MDMA on sleep	Recruiting	ClinicalTrials.gov identifier: NCT03181763
MDMA	Healthy volunteers	125 mg, orally, once	Assess the role of MDMA-induced acute serotonin release in the effects of fear extinction	Recruiting	ClinicalTrials.gov identifier: NCT03527316
MDMA	Healthy volunteers	125 mg, orally, followed by a supplemental half dose 1.25–2.5 h later, once	Assess the effects of MDMA on therapists trained to perform MDMA-assisted psychotherapy research	Enrolling by invitation	ClinicalTrials.gov identifier: NCT01404754
MDMA	Healthy volunteers	0.75–1.5 mg/kg, orally, once	Assess the effects of MDMA on the functioning of reward-related brain circuits (fMRI)	Not yet recruiting	ClinicalTrials.gov identifier: NCT04060108
MDMA	Healthy volunteers	N/A	Effects of MDMA on mood and cognitive performance	Completed	ClinicalTrials.gov identifier: NCT02033707
MDMA	Healthy volunteers	120 mg, orally, followed by a supplemental half dose 1.5–2 h later, once	Collect information to support the safety profile of MDMA-assisted psychotherapy. Understand acute effects for use in therapy	Not yet recruiting	ClinicalTrials.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.

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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.

Compound	Cohort	Regimen	Research Question/Main Findings	Status	Reference
Psilocybin	Major depressive disorder	First 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, orally	Pharmacokinetics 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 volunteers	Completed	ClinicalTrials.gov identifier: NCT02163707 (Brown et al., 2017b; Nicholas et al., 2018)
Psilocybin	Treatment-resistant depression	First 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 scores	Completed	Carhart-Harris et al., 2016a, 2018
Psilocybin	Treatment-resistant depression	First 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 wk	Completed	Carhart-Harris et al., 2017
Psilocybin	Treatment-resistant depression	First 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 TRD	Completed	Roseman et al., 2018
Psilocybin	Treatment-resistant depression	First session: 10 mg; second session: 25 mg (7 days apart)	Psilocybin treatment decreases authoritarianism and increases nature relatedness	Completed	Lyons and Carhart-Harris, 2018
Psilocybin	Major depressive disorder	0.215 mg/kg, orally, once	Effects on depressive symptoms and brain functioning (fMRI)	Recruiting	ClinicalTrials.gov identifier: NCT03715127
Psilocybin	Major depressive disorder	25 mg, orally, once	Potential efficacy of a single 25-mg oral dose of psilocybin for MDD	Recruiting	ClinicalTrials.gov identifier: NCT03866174
Psilocybin	Major depressive disorder	0.1 and 0.3 mg/kg, orally, twice	Assess whether psilocybin enhances neuroplasticity in MDD patients (EEG + long-term potentiation task)	Recruiting	ClinicalTrials.gov identifier: NCT03554174
Psilocybin	Major depressive disorder	25 mg, orally, once	Long-term (up to 24 mo) follow-up study of patients with MDD who previously received psilocybin	Enrolling by invitation	ClinicalTrials.gov identifier: NCT04353921
Psilocybin	Major depressive disorder	Moderate/high dose (dose N/A)	Acute and persisting effects of psilocybin on depressive symptoms and other moods, attitudes, and behavior	Active, not recruiting	ClinicalTrials.gov identifier: NCT03181529
Psilocybin	Major depressive disorder	Multiple dosing days (dose and frequency N/A)	Comparing antidepressant action and mechanisms of action of psilocybin and the SSRI escitalopram (fMRI)	Active, not recruiting	ClinicalTrials.gov identifier: NCT03429075
Psilocybin	Major depressive disorder	25 mg, orally, once	Long-term therapeutic effects of psilocybin (fMRI, peripheral gene expression and molecules as predictor biomarkers of treatment outcome)	Not yet recruiting	ClinicalTrials.gov identifier: NCT03380442
Psilocybin	MDD with mild cognitive impairment or early Alzheimer disease	First session: 15 mg/70 kg; second session (2 wk after): 15 or 25 mg/70 kg	Safety and efficacy of psilocybin given under supportive conditions in depressed people with MCI or early AD. Follow-up assessment of long-term therapeutic effects	Recruiting	ClinicalTrials.gov identifier: NCT04123314
Treatment-Resistant Depression
Psilocybin	Treatment-resistant depression	Low, medium, high dose (dose and frequency N/A)	Safety and efficacy of psilocybin in patients with TRD	Recruiting	ClinicalTrials.gov identifier: NCT03775200
Alcohol, Tobacco, and Substance Use Disorder
Psilocybin	Alcohol use disorder	0.3–0.4 mg/kg, orally, twice	Abstinence 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 events	Active, not recruiting	ClinicalTrials.gov identifier: NCT02061293 (Bogenschutz et al., 2015; Nielson et al., 2018)
Psilocybin	Alcohol use disorder	25 mg, orally, once	Clinical and mechanistic effects of psilocybin in patients with alcohol addiction (3- and 6-mo follow-up)	Not yet recruiting	ClinicalTrials.gov identifier: NCT04141501
Psilocybin	Opioid use disorder	Two 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 quality	Not yet recruiting	ClinicalTrials.gov identifier: NCT04161066
Psilocybin	Tobacco use disorder	20 and 30 mg/70 kg, once	Comparing 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’ lives	Recruiting	ClinicalTrials.gov identifier: NCT01943994 (Garcia-Romeu et al., 2014; Johnson et al., 2014, 2017)
Psilocybin	Cocaine use disorder	0.36 mg/kg, orally, once	Feasibility 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 fMRI	Recruiting	ClinicalTrials.gov identifier: NCT02037126
Obsessive-Compulsive Disorder
Psilocybin	Obsessive-compulsive disorder	0.25 mg/kg, orally, once	Investigate neural mechanisms underpinning OCD symptom improvements by psilocybin (fMRI)	Recruiting	ClinicalTrials.gov identifier: NCT03356483
Psilocybin	Obsessive-compulsive disorder	0.1 and 0.3 mg/kg, orally, once weekly for 8 wk	Safety, tolerability, and mechanism of action of psilocybin (and the anxiolytic lorazepam) as OCD treatments. Functional connectivity changes between the caudate nucleus and orbital frontal cortex	Recruiting	ClinicalTrials.gov identifier: NCT03300947 (Moreno et al., 2006)
Patients with Cancer
Psilocybin	Potentially life-threatening cancer	1–3 or 22–30 mg/kg, orally, twice	Psilocybin 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 satisfaction	Completed	ClinicalTrials.gov identifier: NCT00465595 (Griffiths et al., 2016)
Psilocybin	Potentially life-threatening cancer	0.2 mg/kg, orally, once	Reduction in anxiety scores at 1 and 3 mo and improvements in depression scores at 6 mo	Completed	ClinicalTrials.gov identifier: NCT00302744 (Grob et al., 2011)
Psilocybin	Potentially life-threatening cancer	0.3 mg/kg, orally, once	Immediate, 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 depression	Active, not recruiting	ClinicalTrials.gov identifier: NCT00957359 (Ross et al., 2016)
Others
Psilocybin	Anorexia nervosa	First 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 pathophysiology	Recruiting	ClinicalTrials.gov identifier: NCT04052568
Psilocybin	AIDS survivors	Once, 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 adherence	Completed	ClinicalTrials.gov identifier: NCT02950467
Psilocybin	Long-term meditators	Once 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 connectivity	Completed	ClinicalTrials.gov identifier: NCT01988311
Psilocybin	Long-term meditators	Very 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)	Completed	ClinicalTrials.gov identifier: NCT02145091
Religious Professional Leaders
Psilocybin	Religious professional leaders	First session: 20 mg/70 kg, orally; second session: 20 or 30 mg/70 kg, orally	Utility of psilocybin for professional religious leaders. Further understanding of mystical-type experiences. Changes in psychological functioning, spirituality, health, well-being, and prosocial attitudes	Recruiting	ClinicalTrials.gov identifier: NCT02421263
Psilocybin	Religious professional leaders	First session: 20 mg/70 kg, orally; second session: 20 or 30 mg/70 kg, orally	Effects and utility of psilocybin-facilitated experiences for professional religious leaders	Recruiting	ClinicalTrials.gov identifier: NCT02243813
Healthy Volunteers
Psilocybin	Healthy volunteers	25 mg/70 kg, orally, once	Reduction 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 psilocybin	Completed	ClinicalTrials.gov identifier: NCT02971605 (Barrett et al., 2020)
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	Profound 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”	Completed	Carhart-Harris et al., 2012
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	Psilocybin increases DMN-TPN functional connectivity, as observed in psychosis and meditative states. Thalamocortical functional connectivity not affected	Completed	Carhart-Harris et al., 2013
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	During the psychedelic state, the brain biases a mode of whole-brain functional integration at the expense of local networks	Completed	BioRxiv 10.1101/376491v1
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	The subjective effects of psilocybin might arise as a result of cortical oscillatory rhythm desynchronization, potentially arising from the stimulation of deep-layer 5-HT_2A receptors on pyramidal neurons	Completed	Muthukumaraswamy et al., 2013
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	Association 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 communication	Completed	Lebedev et al., 2015
Psilocybin	Healthy volunteers	2 mg by i.v. infusion, once	Increased between-network resting-state functional connectivity	Completed	Roseman et al., 2014
Psilocybin	Healthy volunteers	30 mg/70 kg, once	Psilocybin 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 lives	Completed	ClinicalTrials.gov identifier: NCT00802282 (Griffiths et al., 2006, 2008)
Psilocybin	Healthy volunteers	10–20–30 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 observed	Completed	ClinicalTrials.gov identifier: NCT02033707 Barrett et al., 2018
Psilocybin	Healthy volunteers	15–20–30 mg, orally, once	Compare altered states of consciousness induced by psilocybin, LSD, and mescaline	Recruiting	ClinicalTrials.gov identifier: NCT03604744, NCT04227756
Psilocybin	Healthy volunteers	25 mg, orally, once	Effects of SERT inhibition (escitalopram) on the subjective response to psilocybin in healthy subjects	Recruiting	ClinicalTrials.gov identifier: NCT03912974
Psilocybin	Healthy volunteers	N/A	Application 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)	Recruiting	ClinicalTrials.gov identifier: NCT03853577
Psilocybin	Healthy volunteers	0.2–0.215–0.315 mg/kg, orally, once	Neuropharmacological mechanisms underlying ego dissolution. Integration of functional connectivity in sensory regions and disintegration in associative regions may underlie the psychedelic state	Active, not recruiting	ClinicalTrials.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.

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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

Compound	Cohort	Regimen	Research Question/Main Findings	Status	Reference
LSD	Major depressive disorder	First session: 25 or 100 μg, orally; second session: 25, 100, or 200 μg, orally	Assess the benefits of LSD-assisted psychotherapy in patients with MDD	Recruiting	ClinicalTrials.gov identifier: NCT03866252
LSD	Major depressive disorder	First session: 25 or 100 μg, orally; second session: 25, 100, or 200 μg, orally	Assess antidepressant and anxiolytic effects of LSD in patients with MDD	Recruiting	ClinicalTrials.gov identifier: NCT03866252
LSD	Illness-related anxiety	20 or 200 μg, orally, once	LSD 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 disease	Completed	ClinicalTrials.gov identifier: NCT00920387 (Gasser et al., 2014, 2015)
LSD	Healthy volunteers	100–200 µg, orally, once	LSD 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 levels	Completed	ClinicalTrials.gov identifier: NCT01878942 (Dolder et al., 2015; Schmid et al., 2015a; Strajhar et al., 2016)
LSD	Healthy volunteers	100–200 µg, orally, once	LSD 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 effects	Completed	ClinicalTrials.gov identifier: NCT02308969 (Dolder et al., 2016, 2017b; Liechti et al., 2017; Mueller et al., 2017)
LSD	Healthy volunteers	100 µg, orally, once	Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to 5-HT_2A. LSD impairs working memory, executive functions, and cognitive flexibility but not risk-based decision-making. 5-HT_2A signaling underlies LSD-induced alteration of the neural response to dynamic changes in music. LSD decreases striatothalamic functional connectivity independently of 5-HT_2A and increases thalamo-PCC connectivity in a 5-HT_2A–dependent fashion	Completed	ClinicalTrials.gov identifier: NCT02451072 (Preller et al., 2018, 2019; Holze et al., 2019; Pokorny et al., 2019)
LSD	Healthy volunteers	100 µg, orally, once	LSD 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 BDNF	Completed	ClinicalTrials.gov identifier: NCT03019822 (Holze et al., 2020)
LSD	Healthy volunteers	75 µg by i.v. injection, once	LSD enhances suggestibility, and this effect could be harnessed in psychotherapeutic settings	Completed	Carhart-Harris et al., 2015
LSD	Healthy volunteers	75 µg by i.v. injection, once	LSD administration modulates learning adaptive mechanisms and attenuates top-down suppression of prediction error	Completed	Timmermann et al., 2018
LSD	Healthy volunteers	40–80 µg by i.v. injection, once	LSD 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 LSD	Completed	Kaelen et al., 2015
LSD	Healthy volunteers	75 µg by i.v. injection, once	LSD 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 dissolution	Completed	Carhart-Harris et al., 2016c
LSD	Healthy volunteers	75 µg by i.v. injection, once	LSD increases brain entropy. Entropy increases are greatest while listening to music and experiencing ego dissolution	Completed	Lebedev et al., 2016
LSD	Healthy volunteers	25–50–100–200 µg, orally, once per dose	5-HT_2A receptor involvement in LSD consciousness-altering effects (using the 5-HT_2A antagonist ketanserin before LSD)	Completed	ClinicalTrials.gov identifier: NCT03321136
LSD	Healthy volunteers	100–200 µg, orally, once per dose	Compare the acute effects of LSD and psilocybin	Recruiting	ClinicalTrials.gov identifier: NCT03604744
LSD	Healthy volunteers	6.5–13–26 µg, orally, once per dose	LSD 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 connectivity	Recruiting	ClinicalTrials.gov identifier: NCT03790358 (Bershad et al., 2019, 2020)
LSD	Healthy volunteers	13 µg, orally, once	Assess the effects of repeated very low doses of LSD on mood in individuals with negative mood	Recruiting	ClinicalTrials.gov identifier: NCT03934710
LSD	Healthy volunteers	100 µg, orally, once	Comparative acute effects of LSD, psilocybin, and mescaline (Five Dimensions of Altered States of Consciousness and resting state fMRI)	Not yet recruiting	ClinicalTrials.gov identifier: NCT04227756

NCT, ClinicalTrials.gov identifier.

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TABLE 4

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

Compound	Cohort	Regimen	Research Question/Main Findings	Status	Reference
Ayahuasca	Treatment-resistant depression	2.2 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 networks	Completed	ClinicalTrials.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)
DMT	Healthy volunteers	15–25 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 subjects	Not yet recruiting	ClinicalTrials.gov Identifier: NCT04353024

NCT, ClinicalTrials.gov identifier; TRD, treatment-resistant depression.

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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 K_i (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.

Compound	Receptors (>K_i)	Transcription Factors/Enzymes/Hormones/Cytokines	Neurotransmitter Effects	Central Effects/Systemic Effects/Psychological Effects	References
LSD	5-HT_1B, 5-HT₇, 5-HT₆, 5-HT_1A, 5-HT_1D, 5-HT_5A, 5-HT_2A, D3, 5-HT_2B, 5-HT_2C, adrenoreceptor (ADRA) 2, 5-HT_1E, D2, D4, D1, D5, ADRA1A, histamine receptor (H1), ADRB1, ADRB2, ADRA1B	Acute: ↑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-HT_2C, ↓SLC6A13 (GABA transporter)	↑(Prolonged) glutamate release in layer V pyramidal neurons, ↓5-HT firing in DRN via 5-HT_2A (low doses), ↓DA firing via 5-HT_1A (high doses), ↓DA neurotransmission in VTA (high doses)	↑Neurogenesis, ↑axon, branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxiety	House 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;
Psilocybin	5-HT_2B, 5-HT_1D, D1, 5-HT_1E, 5-HT_1A, 5-HT_5A, 5-HT₇, 5-HT₆, D3, 5-HT_2C, 5-HT_1B, 5-HT_2A, I1, SERT, ADRA2B, ADRA2A, ADRA2C	↑ACTH, ↑CORT, ↑TSH	↑Striatal DA release (caudate/putamen)	↑Neurogenesis, ↑axon branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxiety	McKenna et al., 1990; Vollenweider et al., 1999b; Ray, 2010; Hasler et al., 2004; Carhart-Harris et al., 2016a
Ayahuasca	5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT_5A, 5-HT₆, 5-HT₇R, TAAR1, S1R	↑5-HT_2A, ↑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, ↓anxiety	Callaway et al., 1999; de Castro-Neto et al., 2013; Morales-Garcia et al., 2017; Galvao et al., 2018; Palhano-Fontes et al., 2019
DMT	5-HT₇, 5-HT_1D, 5-HT_2B, ADRA2B, ADRA2C, D1, 5-HT_2C, 5-HT_1E, 5-HT₆, 5-HT_5A, I1, ADRA1B, ADRA2A, ADRA1A, 5-HT_2A, SERT, S1R	↑IL10, ↓IDO, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-α	N/A	↑Neurogenesis, ↑dendritic spines formation, ↓inflammation	Fontanilla et al., 2009; Keiser et al., 2009; Ray, 2010; Tourino et al., 2013; Szabo et al., 2014;
5-MeO-DMT	5-HT_1A, 5-HT₇, 5-HT_1D, 5-HT₆, 5-HT_1B, D1, 5-HT_5A, 5-HT_1E, D3, ADRA2C, 5-HT_2C, ADRA2A, 5-HT_2A, SERT, I1, ADRA2B, NET1, D4, D2, 5-HT_2B	↑NMDAR, ↑ERK 1/2, ↑CREB, ↑CAMK2, ↓NF-ĸB, ↓NFAT, ↓TLR, ↓mGluR5, ↓PKC, ↓PLC, ↓IP3R, ↓EPAC1, ↓PKA, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-α, ↑IL10	N/A	↑Neurogenesis, ↑dendritic spines formation, ↑long-term potentiation, ↓neurodegeneration, ↑cytoskeletal reorganization, ↓inflammation, ↑T lymphocytes differentiation, ↓cell death, ↓depression, ↓anxiety	Ray, 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
DOI	5-HT_2C, ADRA2A, ADRB2, 5-HT_2A, ADRA2B, 5-HT2BR, 5-HT_1D, CHRM4, ADRB1, ADRA2C, SERT, 5-HT_1E, CHRM3, H1, CHRM2, 5-HT₆, CHRM5, 5-HT_1A, CHRM1, 5-HT₇, S1R, S2R, D1	↑Egr-1, ↑Egr-2, ↑cFOS, ↑IKBA, ↓Egr-3, ↓TNF-α, ↓ILB, ↓IL6, ↓iNOS, ↓ICAM1, ↓VCAM1, ↓MCP1, ↓CX3CL1	N/A	↓Inflammation	González-Maeso et al., 2003; Yu et al., 2008; Ray, 2010; Nau et al., 2013; Lima da Cruz et al., 2018
Ketamine	NMDAR, D1, D2, 5-HT_2A, 5-HT₃, S1R, S2R, OPRM1, OPRK1, OPRD1	Acute: ↑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, ↓anxiety	Li et al., 2010, 2017; Murrough et al., 2013b; Belujon and Grace, 2014; Belujon et al., 2016; Choi et al., 2017; Lisek et al., 2017;
MDMA	TAAR1, NMDAR, VMAT2, 5-HT_1A, SERT, I1, 5-HT_2B, 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, ↓inflammation	Gouzoulis-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.

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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.