Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review.

RATIONALE & OBJECTIVES: ± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration's phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin. RESULTS: Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions. CONCLUSIONS: As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.

Serotonin toxicity of serotonergic psychedelics.

RATIONALE: In recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents. OBJECTIVES: A critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies. RESULTS: True ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity. CONCLUSIONS: Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.

Persistent Tinnitus after Inhaled N,N-dimethyltryptamine (DMT).

This case report describes a 39-year-old male with remote history of polysubstance use disorder and depression who developed tinnitus after use of inhaled N,N-dimethyltryptamine (DMT). Although development of ear ringing was attributed to use on a single occasion, tinnitus occurred within the context of a larger self-experiment involving weekly microdoses of lysergic acid diethylamide (LSD). Distress and anxiety over the ear ringing prompted evaluation by an audiologist, primary care physician, and consultant psychopharmacologist. Tinnitus persisted for several months, although intensity and ability to cope with symptoms improved over time. A microdose of psilocybin mushrooms exacerbated tinnitus on two separate occasions, after which psychedelics were discontinued. Psychedelics are associated with a range of acute sensory changes including auditory phenomenon, although have not previously been associated with tinnitus in medical literature. Here, we present a probable case of tinnitus associated with DMT use and review potential underlying mechanisms connecting psychedelics and tinnitus.

Assessing Outcomes Between Risperidone Microspheres and Paliperidone Palmitate Long-Acting Injectable Antipsychotics Among Veterans.

BACKGROUND: Long-acting injectable antipsychotics (LAIAs) are integral for managing schizophrenia, schizoaffective disorder, and bipolar I disorder among veterans. Studies comparing LAIAs, such as risperidone microspheres and paliperidone palmitate, are limited. The primary objective of our study was to compare the number of psychiatric hospitalizations among veterans initiated on risperidone microspheres and those taking paliperidone palmitate pre- and post-LAIA initiation. METHODS: We included veterans who had received ≥ 2 injections of risperidone microspheres or paliperidone palmitate between January 1, 2016 and December 31, 2018. Nonadherence was defined as missing an injection by > 3 days for risperidone microspheres and > 7 days for paliperidone palmitate. Pre-LAIA and post-LAIA hospitalizations and rehospitalizations were assessed using a pre-post design with equivalent periods. Descriptive statistics were used for demographics and diagnoses. Nonparametric tests were used to analyze primary and secondary outcomes. RESULTS: The study included 97 veterans; 44 took risperidone microspheres and 53 received paliperidone palmitate. Participants' average mean (SD) age was 46 (13.8) years, 92% were male, and 94% were diagnosed with schizophrenia or schizoaffective disorder. Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02), were less likely to be rehospitalized (22.7% vs 47.2%; P = .013) and had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04) compared with paliperidone palmitate. CONCLUSION: Veterans receiving risperidone microspheres had fewer posttreatment psychiatric hospitalizations and were less likely to be rehospitalized.

Development of an innovative adult attention-deficit hyperactivity disorder clinic.

Pharmacist-psychiatrist collaborative clinic models in specialty mental health clinics are limited, and there has been only 1 report of a clinic focused on adult attention-deficit hyperactivity disorder (ADHD). In this article, we describe the successful implementation of a pharmacist-psychiatrist collaborative practice agreement in an adult ADHD clinic at an academic medical center. Adult patients diagnosed with ADHD after a comprehensive assessment, including a full neuropsychological evaluation, were enrolled in the collaborative treatment clinic. The collaboration was a partnership between a psychiatry department and a school of pharmacy at a public university. We report the details of 58 patients and 774 patient encounters at the collaborative pharmacist-psychiatrist practice from March 2015 through June 2018. The visits were billed using traditional medical billing codes for follow-up visits. Pharmacist practice opportunities included psychiatric evaluation, medication management, counseling, and referral to auxiliary services. Challenges to the clinic's success included limited pharmacist time, prescriptive authority, and reimbursement for services from payors. A collaborative practice model targeted at adult ADHD patients may be a unique clinic setting for psychiatric pharmacists.

Effect of long-acting aripiprazole monohydrate on inpatient encounters: A retrospective mirror image study.

INTRODUCTION: Antipsychotics improve symptoms associated with schizophrenia and bipolar disorder. To improve medication adherence and decrease the need for hospitalization, many antipsychotics have been developed into long-acting injectable (LAI) formulations. Though mirror-image studies have demonstrated significantly decreased hospitalization rates with LAI use, there is limited data when suboptimal use parameters are present. METHODS: A retrospective chart review was conducted on patients who were administered aripiprazole monohydrate long-acting injectable (AM-LAI) in an adult mental health unit. Demographics and AM-LAI use parameters were analyzed descriptively. Endpoints compared the days between encounters pre and post AM-LAI administration and number of inpatient encounters between the 180 days pre and post AM-LAI administration. Effects of AM-LAI on inpatient encounters were analyzed using a Wilcoxon signed rank test with an alpha set to <0.05 for significance. RESULTS: Fifty-eight patients met inclusion criteria. Mean (± SD) age was 39.4 (11.4) years with 55.2% of the sample male. Most patients were diagnosed with schizophrenia or unspecified psychotic disorder and admitted involuntarily. The mean number of days from last admission to the date of initial AM-LAI administration was 109.3 (75.2), compared with 131.3 (69.8) days to next encounter (P = .044) post AM-LAI. Total inpatient encounters were also reduced (P = .004), although no differences in encounters for psychiatric reasons were detected. DISCUSSION: Use of AM-LAI was associated with a prolonged time to next inpatient encounter and reduced total inpatient encounters, however its use failed to demonstrate reductions in psychiatric encounters.

A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder.

Ibogaine is a plant-derived alkaloid and dissociative psychedelic that demonstrates anti-addictive properties with several substances of abuse, including alcohol. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring psychedelic known to occasion potent mystical-type experiences and also demonstrates anti-addictive properties. The potential therapeutic effects of both compounds in treating alcohol use disorder require further investigation and there are no published human neuroimaging findings of either treatment to date. We present the case of a 31-year-old male military veteran with moderate alcohol use disorder who sought treatment at an inpatient clinic in Mexico that utilized a sequential protocol with ibogaine hydrochloride (1550mg, 17.9mg/kg) on day 1, followed by vaporized 5-MeO-DMT (bufotoxin source 50mg, estimated 5-MeO-DMT content, 5-7mg) on day 3. The patient received SPECT neuroimaging that included a resting-state protocol before, and 3 days after completion of the program. During the patient's ibogaine treatment, he experienced dream-like visions that included content pertaining to his alcohol use and resolution of past developmental traumas. He described his treatment with 5-MeO-DMT as a peak transformational and spiritual breakthrough. On post-treatment SPECT neuroimaging, increases in brain perfusion were noted in bilateral caudate nuclei, left putamen, right insula, as well as temporal, occipital, and cerebellar regions compared to the patient's baseline scan. The patient reported improvement in mood, cessation of alcohol use, and reduced cravings at 5 days post-treatment, effects which were sustained at 1 month, with a partial return to mild alcohol use at 2 months. In this case, serial administration of ibogaine and 5-MeO-DMT resulted in increased perfusion in multiple brain regions broadly associated with alcohol use disorders and known pharmacology of both compounds, which coincided with a short-term therapeutic outcome. We present theoretical considerations regarding the potential of both psychedelic medicines in treating alcohol use disorders in the context of these isolated findings, and areas for future investigation.

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine.

Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting.

BACKGROUND: Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system. METHODS: The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD). RESULTS: Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion. LIMITATIONS: Retrospective nature of this study, lack of control group and use of self-report depression ratings scales. CONCLUSIONS: This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders.

Recent research suggests that functional connectivity changes may be involved in the pathophysiology of psychiatric disorders. Hyperconnectivity in the default mode network has been associated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric disorders. We have reviewed the current literature to investigate the efficacy and safety of psilocybin-assisted therapy for the treatment of psychiatric disorders. There were seven clinical trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related to anxiety, depression, and substance use. All trials demonstrated reductions in psychiatric rating scale scores or increased response and remission rates. There were large effect sizes related to improved depression and anxiety symptoms. Psilocybin may also potentially reduce alcohol or tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were less clear due to open-label study designs without statistical analysis. Psilocybin-assisted therapy efficacy and safety appear promising, but more robust clinical trials will be required to support FDA approval and identify the potential role in clinical psychiatry.

Ayahuasca: An ancient sacrament for treatment of contemporary psychiatric illness?

Ayahuasca is a traditional psychoactive sacrament that's been used in Amazonian shamanic rituals for hundreds of years. Ayahuasca is notorious for its psychedelic properties produced from the combination of monoamine oxidase inhibitors (MAOIs) found in the Banisteriopsis caapi vine and N-N-dimethyltryptamine from Psychotria viridis or Diplopterys cabrerana. Recently, ritual use of ayahuasca has increased and garnered attention for its potential in treating mental illnesses, such as substance use and depressive disorders. Due to its MAOI properties, there are serious drug interactions that may be of concern among patients who participate in ayahuasca use. The objectives of this paper are to describe ayahuasca's pharmacology, potential drug interactions, and clinical data for its treatment potential in psychiatric illness.

Essential oil of lavender in anxiety disorders: Ready for prime time?

Anxiety disorders are some of the most common psychiatric disorders, with potentially debilitating consequences on individual function. Existing pharmacotherapies for anxiety disorders are limited by delay to therapeutic effect, dependence, tolerance, withdrawal, and abuse potential. Therefore, safe and evidence-based complementary or alternative therapies may be important allies in the care of patients with anxiety disorders. Essential oils are lipophilic and concentrated botanical extracts that exhibit many properties of drugs, although they are not Food and Drug Administration approved and have limitations characteristic of herbal preparations. Lavender essential oil has an extensive anecdotal history of anxiolytic benefit that has recently been supported by clinical efficacy studies. The 2 primary terpenoid constituents of lavender essential oil, linalool and linalyl acetate, may produce an anxiolytic effect in combination via inhibition of voltage-gated calcium channels, reduction of 5HT1A receptor activity, and increased parasympathetic tone. The objectives of this article are to provide a brief overview of lavender oil in aromatherapy, explore variability in the constituents of lavender oil, summarize its pharmacology and safety profile, as well as describe its body of research that has been conducted for anxiety.

Effects of a student pharmacist consultation on patient knowledge and attitudes about vaccines.

OBJECTIVE To measure the impact of student pharmacists' consultation on participant knowledge and attitudes about influenza and tetanus-diphtheria-acellular pertussis (Tdap) vaccines. DESIGN Pre- and post-consultation surveys. SETTING Free health care service and immunization clinics in Vallejo and Martinez, CA. PARTICIPANTS Children and adults 13 years of age or older. INTERVENTION A convenience sample of participants completed a preintervention survey (PrIs) on basic vaccine knowledge and attitudes. Student pharmacists then delivered the intervention, which consisted of a 5-minute consultation on vaccines. A postintervention (PoIs) survey was administered immediately after the intervention. MAIN OUTCOME MEASURES Cumulative scores for eight knowledge-based questions and four attitude-based questions. RESULTS 198 participants completed both PrIs and PoIs. Compared with the PrI scores, the PoI scores showed significant improvement in basic vaccine knowledge and attitudes toward receiving vaccinations. Participants also were more likely to view pharmacists as a source of information about vaccines after the intervention. Student pharmacists administered 109 total vaccinations during the study, including 68 influenza vaccinations and 41 Tdap vaccinations. CONCLUSION A short, 5-minute consultation by a student pharmacist may increase vaccination rates and help serve as a vehicle to change the public's view of vaccines as well as pharmacists and their role in primary and preventive care.