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Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and d-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and d-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), d-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than d-amphetamine, and d-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and d-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and d-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and d-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with d-amphetamine. d-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or d-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and d-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744

The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy. Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT 2A ) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT 2A receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured. LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy. These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT 2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT 2A receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning.

Children in institutional care have a high risk to experience childhood adversities (CAs), with consequences for physical and mental well-being. The long-term effects of CAs on the brain, including consequences for neuronal plasticity and sleep, are poorly understood. This study examined the interplay between stress (including CAs), sleep, and brain-derived neurotrophic factor (BDNF), a prominent marker for neuronal plasticity. Participants ( N  = 131, mean age = 26.3±3.4 years, 40 females) with residential youth-care history completed questionnaires measuring CAs (Childhood Trauma Questionnaire, CTQ), psychological well-being (World Health Organization-Five Well-Being Index, WHO-5), and sleep disturbances (Pittsburgh Sleep Quality Inventory, PSQI). Hair cortisol and serum BDNF concentration were measured using enzyme-linked immunosorbent assays. The analyses were conducted by using bootstrap regression models. There was no association of stress parameters or sleep with BDNF concentration. However, we found a significant association of CAs and well-being with sleep disturbances. Last, we found an association between CAs and BDNF in sleep-healthy but not sleep-disturbed participants. Our findings indicated a role of sleep disturbance in the association between stress and BDNF. Still, further studies are warranted using vulnerable groups at-risk to understand long-term effects on mental health and sleep.

Recently, nutritional interventions have received attention as promising approaches to promote human health during a lifespan. The Mediterranean and Okinawan diets have been associated with longevity and decreasing risk for age-related diseases in contrast to the Western diet. The effect might be due to several antioxidative bioactive compounds highly consumed in both diets, namely, resveratrol, hydroxytyrosol, oleuropein, curcumin, and spermidine. This review aims to address the underlying mechanisms of these compounds to enhance mental fitness throughout life with a focus on brain mitophagy. Mitophagy is the autophagic clearance of dysfunctional, redundant, and aged mitochondria. In aging and neurodegenerative disorders, mitophagy is crucial to preserve the autophagy mechanism of the whole cell, especially during oxidative stress. Growing evidence indicates that curcumin, astaxanthin, resveratrol, hydroxytyrosol, oleuropein, and spermidine might exert protective functions via antioxidative properties and as well the enhanced induction of mitophagy mediators. The compounds seem to upregulate mitophagy and thereby alleviate the clearance of dysfunctional and aged mitochondria as well as mitogenesis. Thus, the Mediterranean or Okinawan diet could represent a feasible nutritional approach to reduce the risk of developing age-related cognitive impairment and corresponding disorders via the stimulation of mitophagy and thereby ensure a balanced redox state of brain cells.

N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant’s lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t1/2α) of 5.0–5.8 min, followed by longer late elimination (t1/2β = 14–16 min) after 15–20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions.Trial registration: ClinicalTrials.gov identifier: NCT04353024

Chronic stress is associated with accelerated biological aging as indexed by short age-adjusted leukocyte telomere length (LTL). Exploring links of biological stress responses with LTL has proved challenging due to the lack of biological measures of chronic psychological stress. Hair cortisol concentration (HCC) has emerged as a measure of chronic hypothalamic pituitary adrenal (HPA) axis activation, allowing the examination of relationships between aggregate cortisol concentrations over time and LTL. Our sample includes 92 participants (38% women, M age  = 26 ± 3.7 years) from a high-risk sample of young adults with previous residential care placements. Two cm hair was collected for HCC, reflecting approximately eight weeks of cortisol secretion. LTL was measured with quantitative polymerase chain reaction (qPCR) in whole blood samples. All samples for LTL were run in triplicate and assayed twice. Linear and polynomial regression models were used to describe the association between HCC and LTL, adjusting for age and sex. HCC and LTL showed negative associations (std. ß  = − 0.67, 95% CI [− 0.83, − 0.52], p < .001) in age- and sex-adjusted analyses, indicating that higher HCCs are associated with shorter LTL. Using polynomial regression, we found a curvilinear relationship indicating a stronger negative association at lower cortisol concentrations. Higher HCCs were associated with shorter LTL, supporting the hypothesized involvement of prolonged cortisol secretion in telomere attrition. Thus, HCC may prove useful as a biological indicator of chronic stress associated with aging-related processes in samples exposed to high levels of stress.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall. Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics. Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes. Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy. Clinical Trial registration: clinicaltrials.gov identifier: NCT03527316

Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in patients with hypopituitarism and hypothalamic damage (HHD), that might be associated with neuropsychological deficits and sexual dysfunction, leading to worse quality of life (QoL). Therefore, identifying a provocative test to diagnose an OXT-D will be important. Corticotropin-releasing hormone (CRH) is a candidate for such a test as it increases oxytocin secretion in animal models. This study aimed to examine the effects of CRH on oxytocin release in HHD compared to healthy controls (HC) and to describe the psychopathology, sexual function and QoL and their associations with oxytocin. This is a single-blind, randomized, placebo-controlled, proof-of-concept study (NCT 04902235) with crossover assignment (CRH vs. placebo). Nineteen HHD patients (10 females) and 20 HC (11 females) completed two visits, receiving CRH or placebo in random order and completed validated questionnaires to assess psychopathology, sexual function and QoL. Samples were collected over 120 min to assess oxytocin. Linear mixed-effects regression model evaluated the change in oxytocin after CRH/placebo in HHD vs. HC. CRH administration did not impact oxytocin concentrations across groups over time (p = 0.97). HHD had greater psychopathology (most ps < 0.05), sexual dysfunction (p < 0.03) and worse QoL (p < 0.001) compared to HC, nevertheless, baseline oxytocin concentrations and area under the curve of oxytocin were not significantly associated with psychopathology, sexual function or QoL, neither in HHD or HC. In conclusion, CRH administration does not appear to be a suitable provocative test for diagnosing OXT-D in HHD. Identifying a reliable diagnostic test for OXT-D remains crucial. Alternative provocative tests or biomarkers should be explored.