Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial.

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.

Sub-acute effects of psilocybin on EEG correlates of neural plasticity in major depression: Relationship to symptoms.

BACKGROUND: Evidence suggests that serotonergic psychedelics (e.g. psilocybin), have rapid-acting and long-lasting antidepressant effects after a single dose. However, the mechanism underlying these effects remain unclear. One proposed mechanism is that these drugs promote neuroplasticity. However, this has not been conclusively demonstrated in humans. AIMS: We hypothesized that relative to placebo, psilocybin would: (1) increase electroencephalographic (EEG) correlates of neuroplasticity, (2) reduce depression symptoms, and (3) changes in EEG would correlate with improvements in depression. METHODS: In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder (MDD; n = 19) were administered placebo followed by psilocybin (0.3 mg/kg) in a fixed order (placebo, followed by psilocybin 4 weeks later). EEG indices of neuroplasticity (tetanus-induced long-term potentiation) as assessed via auditory evoked theta (4-8 Hz) power and measures of depression (GRID Hamilton Rating Scale for Depression-17 (GRID-HAM-D-17)) were measured at several time-points after placebo and psilocybin (24 h and 2 weeks after each session). RESULTS: EEG theta power doubled in amplitude 2 weeks after a single psychedelic dose of psilocybin but not after placebo. Further, improvements in depression symptoms 2 weeks after psilocybin were correlated with increases in theta power. CONCLUSIONS: The increased theta power observed represents evidence of sustained changes in the brain following psilocybin. Given the correlation with enhancement in depressive symptoms, changes in theta may represent an EEG biomarker of the sustained effects of psilocybin, and may shed light on potential mechanisms of psilocybin's antidepressant effect. Taken together, these results complement the emerging notion that psilocybin, and perhaps other psychedelics, can produce long-term alterations in neuroplasticity.

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial.

BACKGROUND: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. METHODS: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. RESULTS: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin (d' = 1.02-2.27) than after placebo (d' = 0.65-0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. CONCLUSIONS: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.

Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder.

There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic, and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured using the HAMD-17 in MDD participants 1 day after each dosing session. DMT was tolerated by both HC (n = 3) and MDD participants (n = 7) studied; there were no dropouts. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference -4.5 points, 95% CI: -7.80 to -1.20, Hedge's g = 0.75). Adverse events were mostly mild with one self-limited serious event. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects, which resolved within 20-30 min of injection. There were no dose-related differences in measures of drug reinforcement and abuse liability. In this small exploratory pilot study, intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next-day (rapid) antidepressant effects in patients with treatment-resistant MDD. Further rigorous trials are warranted to replicate these findings and to determine the durability of antidepressant effects.

Long-Term Effects of Chemical Warfare on Post-traumatic Stress Disorder, Depression, and Chronic Medical Conditions in Veterans.

We investigated the association between exposure to chemical warfare and chronic mental/physical conditions. This was a secondary analysis of data from a case-control study on Iranian male veterans. Participants with neuropsychiatric disorders other than depressive/anxiety disorders, anatomical defects, or malignancies were excluded. Compared to non-exposed veterans, exposed veterans demonstrated significantly higher odds of PTSD [OR (95% CI) = 5.23 (1.98-13.85)], hypertension [OR (95% CI) = 5.57 (1.68-18.48)], coronary heart disease [OR (95% CI) = 6.8 (1.62-28.49)], and diabetes [OR (95% CI) = 3.88 (1.35-11.16)], and marginally higher odds of moderate to severe depressive symptoms [OR (95% CI) = 2.21 (0.93-5.28)]. This study provides preliminary evidence on association of exposure to chemical warfare with long-term mental disorders as well as chronic medical conditions.

Effects of Saffron on Cognition, Anxiety, and Depression in Patients Undergoing Coronary Artery Bypass Grafting: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVES: Cognitive decline, depression, and anxiety are among the major concerns in patients undergoing coronary artery bypass grafting (CABG). Crocus sativus L. (saffron) seems to be a promising candidate for treatment of these conditions. DESIGN: In this 12-week, randomized, double-blind, placebo-controlled clinical trial, men and women with on-pump CABG, who had Wechsler Memory Scale (WMS) score >70 and age <70 years, received either saffron capsules (15 mg/twice daily) or placebo. Patients were excluded if they had history of treatment with saffron or acetylcholinesterase inhibitors, comorbid neuropsychiatric disorders, serious medical conditions other than cardiovascular diseases, and hypersensitivity to herbal compounds. The primary outcome was defined as the difference in mean total score changes for WMS-Revised from the baseline to week 12 between the saffron and placebo groups. Secondary outcomes included difference in mean score changes from baseline to endpoint between the two treatment groups for Mini Mental Status Examination and subscales of Hospital Anxiety and Depression Scale ( www.irct.ir ; IRCT201408071556N63). RESULTS: No significant difference was detected in primary or secondary outcomes between the saffron and placebo groups. Also, no significant time × treatment interaction effect was found for any of the scales. CONCLUSIONS: The results of this trial do not support the hypothesis of potential benefits of saffron in treatment of CABG-related neuropsychiatric conditions.

Pexacerfont as a CRF1 antagonist for the treatment of withdrawal symptoms in men with heroin/methamphetamine dependence: a randomized, double-blind, placebo-controlled clinical trial.

We assessed the efficacy of pexacerfont, a CRF1 antagonist, for the treatment of withdrawal symptoms. In this randomized, double-blind, placebo-controlled clinical trial, male patients with amphetamine or opioid dependence, on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR), in the age range 18-55 years, received either pexacerfont or placebo (300, 200, and 100 mg/day in the first, second, and third week, respectively). No antidepressants, behavioral interventions, or substitution therapy were administered. Candidates were excluded if they had DSM-IV-TR axis I or II disorders (other than depressive/anxiety disorders). The primary outcomes were difference in the distribution of positive urine test results for heroin and methamphetamine at the end of the trial, and the mean difference in the change in the Visual Analog Scale (VAS) score for craving from the baseline to the endpoint between the two groups. No significant difference was detected for urine test results, but a significant difference was observed for craving scores. Also, significant time×treatment interactions were found for all the scales including VAS craving, VAS temptation severity, frequency of temptation, Clinical Opiate Withdrawal Scale, Amphetamine Withdrawal Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory II. Our findings favor pexacerfont as a potential treatment for withdrawal from drug dependence; however, further comprehensive studies are warranted.