Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Background Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss. Methods Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8–10 group therapy visits and one psilocybin administration visit (0·3–0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467) Findings From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], η p 2 = 0·47, 90% CI 0·21–0·60). Interpretation We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs. Funding Carey Turnbull, Heffter Research Institute, NIMH R25 MH060482, NIH UL1 TR001872, River Styx Foundation, Saisei Foundation, Sarlo Foundation, Stupski Foundation, Usona Institute, US Department of Veterans Affairs (Advanced Neurosciences Fellowship and IK2CX001495).

INTRODUCTIONSemantic dementia (SD) is a clinical syndrome characterized by a progressive loss of conceptual knowledge. Patients typically present in the presenium with difficulty in recalling and understanding words, and later show impairment in recognizing objects (Lambon Ralph et al., 1998Hodges et al., 1992). Surface dyslexia is also part of the SD clinical picture, as patients have greater difficulty reading words with irregular pronunciations (such as "yacht") compared to regularly spelled words (such as "context"). Within the language domain, speech, phonological and syntactic processing are usually spared. Spatial abilities, non-verbal reasoning and day-to-day episodic memory also remain relatively intact, while episodic memory is often impaired on formal testing (see Hodges and Miller, 2001). Current clinical research criteria list SD as one of the possible clinical presentations of frontotemporal lobar degeneration (FTLD) (Neary et al., 1998). Neuroimaging findings in SD indicate that the anterior temporal lobe is the site of most prominent atrophy and/or hypometabolism, providing a powerful model for studying this brain region rarely hit by other neurological diseases (Mummery et al., 2000;Galton et al., 2001;Chan et al., 2001;Rosen et al., 2002a). Voxel-based Morphometry studies (VBM) and region of interest analysis on MRI scans have shown that the hippocampal/amygdala structures and the infero-lateral temporal neocortex are both significantly atrophied in SD (Chan et al., 2001;Rosen et al., 2002aRosen et al., , 2002b. It has also been shown that the ventro-medial frontal lobe and the insula are involved (Rosen et al., 2002a). The finding that orbitofrontal cortex and amygdala are damaged in SD is consistent with reports that personality changes, disturbances in social behavior, and abnormalities in emotional processing can be part of the clinical syndrome.Most reported cases of semantic dementia have shown mainly left anterior temporal lobe atrophy. Thus, the classic clinical picture of SD with prominent semantic memory deficits has also been labeled as the "left temporal lobe variant"(LTLV) of FTLD (Edwards-Lee et al., 1997). Less evidence is available regarding the clinical presentation of cases with "right-temporal lobe variant" (RTLV) of FTLD. Only a few reports of RTLV cases have concentrated on describing early difficulties in processing information regarding familiar people, either as progressive disturbance in recognizing familiar faces, or as a more generalized semantic deficit for person-specific information (Gainotti et al., 2003;Barbarotto et al., 1995;Gentileschi et al., 1999;Tyrrell et al., 1990;Evans et al., 1995). In these cases, the presence of behavioral changes was sometimes mentioned, but its significance and the time of first manifestation was not reported (Gainotti et al., 2003 ABSTRACT Semantic dementia (SD) is a clinical variant of frontotemporal lobar degeneration (FTLD) characterized by progressive deterioration of semantic memory with relative sparing of other cognitive fun...

Summary Background Individuals with schizophrenia have functionally significant deficits in automatic and controlled social cognition, but no currently available pharmacologic treatments reduce these deficits. The neuropeptide oxytocin has multiple prosocial effects when administered intranasally in humans and there is growing interest in its therapeutic potential in schizophrenia. Methods We administered 40 IU of oxytocin and saline placebo intranasally to 29 male subjects with schizophrenia and 31 age-matched, healthy controls in a randomized, double-blind, placebo-controlled, cross-over study. Social cognition was assessed with The Awareness of Social Inference Test (TASIT) and the Reading the Mind in the Eyes Test (RMET). We examined the effects of oxytocin administration on automatic social cognition (the ability to rapidly interpret and understand emotional cues from the voice, face, and body); controlled social cognition (the ability to comprehend indirectly expressed emotions, thoughts, and intentions through complex deliberations over longer time periods); and a control task (the ability to comprehend truthful dialog and perform general task procedures) in individuals with and without schizophrenia using mixed factorial analysis of variance models. Results Patients with schizophrenia showed significant impairments in automatic and controlled social cognition compared to healthy controls, and administration of oxytocin significantly improved their controlled, but not automatic, social cognition, F(1, 58) = 8.75; p = 0.004. Conversely, oxytocin administration had limited effects on social cognition in healthy participants. Patients and controls performed equally well and there were no effects of oxytocin administration on the control task. Discussion Intact social cognitive abilities are associated with better functional outcomes in individuals with schizophrenia. Our data highlight the potentially complex effects of oxytocin on some but not all aspects of social cognition, and support the exploration of intranasal oxytocin as a potential adjunct treatment to improve controlled social cognition in schizophrenia. Published by Elsevier Ltd.

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