Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms.

We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls).

Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (−1019, −1007, −681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF.

Recent stress correlated positively with blood monocyte methylation at the −681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the −1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD.

These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Anxiety disorders are a major public health burden with limited treatment options.

We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness.

This study was an a priori-planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 μg) or placebo per period. Participants (n = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger's State-Trait Anxiety Inventory–Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO-Five-Factor Inventory.

Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = −21.6 (−32.7, −10.4), d = 1.04, P < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and −16.5 (−26.2, −6.8), d = 1.02, P < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of −8.1 (−13.2, −3.1), d = 0.71, P < 0.01, and −8.9 (−12.9, −4.9), d = 1.21, P < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased (P < 0.0001) and trait extraversion increased (P < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience.

Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.