Use of Guanfacine for Cannabis Use Disorder and Related Symptomology.

BACKGROUND AND OBJECTIVES: No medication has Food and Drug Administration approval for cannabis use disorder (CUD), and most medication development focuses on the withdrawal syndrome. We evaluated the effects of short-term treatment using the α-2A-adrenergic receptor agonist, guanfacine, on withdrawal symptoms in volunteers with CUD and a history of early onset of cannabis use. METHODS: Non-treatment-seeking healthy volunteers (n = 7) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for CUD participated in a two-phase, within-subjects study. Volunteers received placebo or guanfacine (3 mg/day) for the first 8-day inpatient study and the alternative medication for the second 8-day inpatient study. On day 1 of both treatment periods, participants received 30 mg of synthetic Δ9 -tetrahydrocannabinol for standardization of abstinence onset. On days 2 to 7, participants received study medication. Cannabis withdrawal symptoms, sleep, craving, and physiology were assessed on all inpatient days. RESULTS: Compared with placebo, guanfacine did not show significant effects on withdrawal, craving, or sleep, although there were trends for guanfacine to increase positive mood symptoms and decrease craving-associated compulsivity. DISCUSSION AND CONCLUSIONS: Compared with former studies, we could not prove significant improvement in sleep or decrease of negative symptoms, but we found trends for increased positive mood symptoms. Our data did not show significant effects of guanfacine on withdrawal symptoms or craving. Due to early and longer cannabis use, our subjects indicate a great severity of illness increasing the likelihood of treatment resistance. SCIENTIFIC SIGNIFICANCE: On the basis of trends demonstrated here and other lines of evidence, further investigation is warranted regarding the utility of guanfacine as a potential treatment for CUD. (Am J Addict 2019;00:1-10).

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

"Just one bad high:" considering synthetic cannabinoid outcome expectancies in adolescents.

BACKGROUND/OBJECTIVES: Certain medical consequences seem unique to synthetic cannabinoid (SC) and not cannabis use. We report the case of an adolescent, whose drug expectancies appear to minimize the severity of SC-related adverse events. METHODS/RESULTS: An 18-year-old male presented with altered mental status and seizure, complicated by respiratory failure. He was stabilized and on discharge, despite counseling on the harms of SC usage, the patient planned to resume use, insisting that the hospitalization was "just one bad high". DISCUSSION/CONCLUSIONS/SCIENTIFIC SIGNIFICANCE: Diminished negative expectancies related to SC use among adolescents may reflect generalizations from cannabis. Effective interventions should counter cannabis-related expectancies of minimal harm. (Am J Addict 2016;XX:1-3).

At-home, telehealth-supported ketamine treatment for depression: Findings from longitudinal, machine learning and symptom network analysis of real-world data.

BACKGROUND: Improving safe and effective access to ketamine therapy is of high priority given the growing burden of mental illness. Telehealth-supported administration of sublingual ketamine is being explored toward this goal. METHODS: In this longitudinal study, moderately-to-severely depressed patients received four doses of ketamine at home over four weeks within a supportive digital health context. Treatment was structured to resemble methods of therapeutic psychedelic trials. Patients receiving a second course of treatment were also examined. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression. We conducted preregistered machine learning and symptom network analyses to investigate outcomes (osf.io/v2rpx). RESULTS: A sample of 11,441 patients was analyzed, demonstrating a modal antidepressant response from both non-severe (n = 6384, 55.8 %) and severe (n = 2070, 18.1 %) baseline depression levels. Adverse events were detected in 3.0-4.8 % of participants and predominantly neurologic or psychiatric in nature. A second course of treatment helped extend improvements in patients who responded favorably to initial treatment. Improvement was most strongly predicted by lower depression scores and age at baseline. Symptoms of Depressed mood and Anhedonia sustained depression despite ongoing treatment. LIMITATIONS: This study was limited by the absence of comparison or control groups and lack of a fixed-dose procedure for ketamine administration. CONCLUSIONS: At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement in patients with depression. Strategies for combining psychedelic-oriented therapies with rigorous telehealth models, as explored here, may uniquely address barriers to mental health treatment.

Reconsidering "dissociation" as a predictor of antidepressant efficacy for esketamine.

RATIONALE: The relationship between subjective drug experience and antidepressant outcomes for ketamine derivatives is poorly understood but of high clinical relevance. Esketamine is the patented (S)-enantiomer of ketamine and has regulatory approval for psychiatric applications. OBJECTIVES: We examined the relationship between acute dissociation, as measured by the Clinician-Administered Dissociative States Scale (CADSS), and antidepressant efficacy, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), for esketamine across the 4-week induction phase of treatment. METHODS: This post hoc analysis combined data (N = 576) from the TRANSFORM-1 and TRANSFORM-2 clinical trials of esketamine for treatment-resistant depression. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables: baseline MADRS score, treatment condition × time interaction, and CADSS × time interaction. To assess whether initial dissociation predicted rapid antidepressant benefit with esketamine, a separately planned regression was performed with day 2 MADRS as the outcome variable with the following dependent variables: baseline MADRS, treatment condition, and day 1 CADSS. RESULTS: The linear mixed model did not show any effect of a CADSS × time interaction (p = 0.7). Looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a - .04 [95% CI - .08, - .002] (p = .04) decrease in MADRS score. CONCLUSIONS: We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine. Our findings suggest that subsequent inquiry in this area will benefit from improved characterization of drug experiences relevant to therapeutic outcomes.

Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers.

Rationale: N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being. Objective: The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials. Methods: Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration. Results: High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM. Conclusions: This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences. This study was registered with ClinicalTrials.gov (NCT02033707).

Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: results from a prospective, longitudinal survey.

Introduction: The classic psychedelic psilocybin, found in some mushroom species, has received renewed interest in clinical research, showing potential mental health benefits in preliminary trials. Naturalistic use of psilocybin outside of research settings has increased in recent years, though data on the public health impact of such use remain limited. Methods: This prospective, longitudinal study comprised six sequential automated web-based surveys that collected data from adults planning to take psilocybin outside clinical research: at time of consent, 2 weeks before, the day before, 1-3 days after, 2-4 weeks after, and 2-3 months after psilocybin use. Results: A sample of 2,833 respondents completed all baseline assessments approximately 2 weeks before psilocybin use, 1,182 completed the 2-4 week post-use survey, and 657 completed the final follow-up survey 2-3 months after psilocybin use. Participants were primarily college-educated White men residing in the United States with a prior history of psychedelic use; mean age = 40 years. Participants primarily used dried psilocybin mushrooms (mean dose = 3.1 grams) for "self-exploration" purposes. Prospective longitudinal data collected before and after a planned psilocybin experience on average showed persisting reductions in anxiety, depression, and alcohol misuse, increased cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and reduced neuroticism and burnout after psilocybin use. However, a minority of participants (11% at 2-4 weeks and 7% at 2-3 months) reported persisting negative effects after psilocybin use (e.g., mood fluctuations, depressive symptoms). Discussion: Results from this study, the largest prospective survey of naturalistic psilocybin use to date, support the potential for psilocybin to produce lasting improvements in mental health symptoms and general wellbeing.

Toward Synergies of Ketamine and Psychotherapy.

Ketamine is a dissociative drug that has been used medically since the 1970s primarily as an anesthetic agent but also for various psychiatric applications. Anecdotal reports and clinical research suggest substantial potential for ketamine as a treatment in conjunction with psychological interventions. Here, we review historical and modern approaches to the use of ketamine with psychotherapy, discuss the clinical relevance of ketamine's acute psychoactive effects, propose a unique model for using esketamine (one isomeric form of ketamine) with Acceptance and Commitment Therapy (ACT), and suggest considerations for moving medication-assisted psychotherapy forward as a field.

Mapping consent practices for outpatient psychiatric use of ketamine.

BACKGROUND: Given increasing community-based and off-label use of ketamine for psychiatric indications, we examined current informed consent processes from a convenience sample of outpatient ketamine clinics to identify areas of congruence with current evidence and opportunities for growth. METHODS: Using a rubric developed from existing practice guidelines, we conducted an exploratory analysis of informed consent documents (IC-Docs) from 23 American clinics offering ketamine as a psychiatric treatment. Domains assessed included clinical content, procedures, and syntax. RESULTS: Participating clinics (23/288) varied widely in their constitution, training, and services provided. We found that IC-Docs addressed a majority of consent elements, though did so variably on an item-level. Areas for improvement included communication around long-term adverse effects, treatment alternatives, medical/psychiatric evaluation prior to treatment, medical/psychological support during treatment, adjunctive psychological interventions, and subjective/dissociative-type effects. All forms were limited by poor readability. LIMITATIONS: Our study was limited by convenience sampling along with possible underestimation of verbal consent processes. CONCLUSIONS: As ketamine continues to emerge as a psychiatric intervention, both patients and providers will benefit from a deliberate consent process informed by scientific, ethical, and pragmatic factors toward the goal of shared decision-making regarding treatment.

Parental Attitudes Toward Use of Ketamine in Adolescent Mood Disorders and Suicidality.

Objectives: Investigation into parental decision-making processes involving ketamine is of high priority, given the necessary role of parents in consenting to treatment. In this study, we examined parental attitudes toward the emerging use of ketamine in adolescent mood disorders and suicidality. Methods: Two hundred eighty-three English-speaking parents completed an online survey using Amazon Mechanical Turk on psychiatric use of ketamine, acceptability of treatment, and their perceptions of ketamine treatment. Data quality control measures were used to mitigate invalid reporting. Results: Parents reported high acceptability toward use of ketamine for suicidality, major depressive disorder, and bipolar disorder in adolescents. Primary concerns around ketamine involved its potential side effects and lack of United States Food and Drug Administration (FDA) approval. Responses indicated a preference for short-term applications and less invasive routes of administration for ketamine. Parent history of mental illness, familiarity with psychological treatments, and comfort using other mental health interventions in their children predicted greater acceptability of ketamine. Conclusion: Although ketamine is not currently approved by the FDA for psychiatric use in children nor recommended outside of research protocols, these findings suggest that parents have interest in the application of ketamine as a treatment for pediatric mood disorders and point to future directions for research and clinical orientation.

Recovery from impaired working memory performance during chronic Δ-9-tetrahydrocannabinol administration to adolescent rhesus monkeys.

BACKGROUND: The relationship between adolescent cannabis use and susceptibility to persistent cognitive impairments is poorly understood. AIMS: We examined the effects of repeated exposure to Δ-9-tetrahydrocannabinol (THC) on reinforcement-related learning and performance of spatial working memory (WM) tasks of varying difficulty in adolescent monkeys. METHODS: Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 12 months. Performance on 4-item spatial WM trials was assessed throughout the 12-month study period. At the 6-month time point, more difficult novel and distractor 8-item spatial WM trials were added. Residual effects on performance were determined 23 or 71 h after THC or vehicle administration throughout the study. RESULTS/OUTCOMES: Relative to vehicle-exposed animals, repeated THC exposure was initially associated with significantly slower improvement in performance accuracy on 4-item spatial WM trials; however, this performance difference gradually diminished such that by month 12, accuracy did not significantly differ between vehicle and THC groups. Similarly, for the novel and distractor 8-item trials introduced at month 6, performance accuracy improved more slowly in the THC than in the vehicle group, despite comparable performance between groups on the 4-item task during this same period. CONCLUSIONS/INTERPRETATION: These findings suggest that compared to vehicle exposure, THC exposure during adolescence impairs the reinforcement-related learning process required for improved performance on spatial WM tasks, but this impairment might be overcome with continued training, even in the face of ongoing THC exposure.

The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review.

OBJECTIVE: The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD). METHODS: Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports. RESULTS: Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS. CONCLUSIONS: Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.

Deep transcranial magnetic stimulation for obsessive compulsive disorder.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that can be chronic and debilitating if not properly treated. Current first-line treatments for OCD include cognitive-behavioral therapy with exposure and response prevention and serotonin uptake inhibitor medications; however, these therapies are not effective for all individuals. AREAS COVERED: Deep transcranial magnetic stimulation (dTMS) has been hypothesized to be an effective alternative for individuals with treatment-resistant OCD. dTMS has thought to be favorable due to its low side effect profile and its minimally invasive nature. EXPERT OPINION: This review evaluates the current research on effectiveness of dTMS therapy for individuals with treatment-resistant OCD. This review also investigates shortcomings in current dTMS research and the hypothesized future of dTMS therapy.