Commentary: Evidence-Informed Recommendation to Achieve Approximate Parity in the Allowed Number of Doses for Common Psychedelics.

In recent years, policymakers have proposed and implemented regulatory changes promoting the deprioritization, decriminalization, or state-level legalization of one or more psychedelic substances, usually referencing data from clinical trials as reasons to support liberalizing drug control policies. As psychedelic policies continue to be drafted, personal possession limits may be considered for inclusion in those regulations. If "allowable amount" limits are to be written into law to set personal possession limits, then such amounts should be more consistently related to psychedelic doses found to be safe and efficacious in clinical trials, existing data on moderate-high doses commonly used in various naturalistic settings, and the few studies that estimate psychedelic dose equivalence based on the intensity of subjective effects. In this commentary, we provide an evidence-informed table of typical moderate-high doses for seven commonly used psychedelic substances. These estimates of comparable moderate-high doses can be used to inform "allowable amount" values for psychedelic substances. When such limits are written into legislation, the adoption of evidence-informed comparable limits akin to those presented here would be an important first step toward ensuring greater parity and consistency in drug policy, relative to limits that have little or no scientific basis.

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.

Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database.

3,4-Methylenedioxymethamphetamine (MDMA) is currently being evaluated by the Food and Drug Administration (FDA) for the treatment of post-traumatic stress disorder (PTSD). If MDMA is FDA-approved it will be important to understand what medications may pose a risk of drug-drug interactions. The goal of this study was to evaluate the risks due to MDMA ingestion alone or in combination with other common medications and drugs of abuse using the FDA drug safety surveillance data. To date, nearly one thousand reports of MDMA use have been reported to the FDA. The majority of these reports include covariates such as co-ingested substances and demographic parameters. Univariate and multivariate logistic regression was employed to uncover the contributing factors to the reported risk of death among MDMA users. Several drug classes (MDMA metabolites or analogs, anesthetics, muscle relaxants, amphetamines and stimulants, benzodiazepines, ethanol, opioids), four antidepressants (bupropion, sertraline, venlafaxine and citalopram) and olanzapine demonstrated increased odds ratios for the reported risk of death. Future drug-drug interaction clinical trials should evaluate if any of the other drug-drug interactions described in our results actually pose a risk of morbidity or mortality in controlled medical settings.

Surveys of substance use disorders education in US pharmacy programs.

INTRODUCTION: Substance use disorders (SUDs) are a significant US health problem affecting roughly 20 million Americans, but there continues to be limited access to SUD treatment and inadequate addiction medicine training. Therefore, it is important to understand how SUD education is being delivered to US health professionals, including pharmacists. METHODS: A recent survey of US pharmacy programs' neuropsychiatry curricula was evaluated to identify any progress made toward increasing SUD education since the last national survey in 2004 and determine any remaining gaps between what is currently being taught and American Association of Colleges of Pharmacy (AACP) curricular guidelines for SUD education updated in 2010. A survey of psychiatric pharmacists, regarding what they thought should be taught, was also evaluated and compared with the 2010 AACP curricular guidelines. RESULTS: Our survey of US pharmacy programs demonstrated that 94% of programs reported teaching SUD content in 2014-15, which has increased from 81% reported in a survey study from 2004. There was also an increase for average hours of SUD didactic instruction, which increased from 2.2 hours in 2004 to 2.7 hours in 2015. The majority of members (84%) recommended at least 2 hours of SUD instruction, and 27% recommended teaching ≥4 hours. DISCUSSION: There was an overall increase in SUD instruction, but the average hours taught still falls short of 2010 AACP curricular guideline recommendation suggesting ≥4 hours. Furthermore, a majority of the psychiatric pharmacists we surveyed did not agree with the AACP curricular guideline recommendation because only 27% of members recommended ≥4 hours of SUD instruction, and the average hours recommended was only 2.7 hours.

Concomitant calcium channel blocker and antipsychotic therapy in patients with schizophrenia: Efficacy analysis of the CATIE-Sz phase 1 data.

BACKGROUND: This study evaluated the influence of concomitant calcium channel blocker (CCB) and antipsychotic (AP) therapy on efficacy measures in patients with schizophrenia. METHODS: Data from the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study were used to evaluate the effect of concomitant CCB therapy on the Clinical Global Impression-Severity (CGI-S) score, Positive and Negative Syndrome Scale (PANSS) score, and time to all-cause discontinuation of AP treatment. Concomitant treatment participants (CCB plus AP) were matched with controls (AP alone) by propensity scores using a 3:1 greedy match algorithm, then analyzed using a mixed linear effects model adjusted for fixed covariates. RESULTS: The least squares mean change in CGI-S scores revealed a significant time-by-treatment interaction term, with greater improvements for the concomitant treatment group (P = .03). Total PANSS score showed no significant difference between groups at various time periods (1, 3, 6, 9, 12, 15, and 18 months) and time to all-cause discontinuation was also similar (hazard ratio 0.94, P = .73). CONCLUSIONS: Improvements in CGI-S scores over time suggest that concomitant CCB plus AP treatment may reduce severity of illness more than AP treatment alone. However, PANSS score and time to all-cause discontinuation of AP treatment did not demonstrate improved outcomes.

Curriculum in Psychiatry and Neurology for Pharmacy Programs.

Objective. To describe pharmacy curricula in psychiatry and neurology and to report on neuropsychiatric pharmacy specialists' views on optimal curriculum. Methods. Design and administer one electronic survey to accredited pharmacy programs asking them to report information on curricula in psychiatry and neurology for the 2014-2015 academic year. Design and administer a separate electronic survey to board certified pharmacists with an academic affiliation who are members of the College of Psychiatric and Neurologic Pharmacists (CPNP) asking about their teaching activities and their opinion on optimal curricula. Results. Fifty-six percent of pharmacy programs and 65% of CPNP members responded to the surveys. The program survey revealed greater than 80% of topics were taught by full-time faculty. Didactic lecturing, team-based learning, and case studies were the most common teaching methods. Programs dedicated the most didactics (3 to 5+ hours) to epilepsy, depression, schizophrenia, substance use disorders, and pain. Autism, traumatic brain injury, personality, and eating disorders were either not taught or given ≤ 1 hour of didactics in most programs. Inpatient psychiatry had the most APPE placements with a mean of 19.6, range 0-83. APPE electives in psychiatry outnumbered those in neurology 5 to 1. CPNP member survey results showed 2 out of 3 members agreed that curriculum could be improved with additional APPEs in psychiatry and neurology. Conclusion. Didactic hour distribution in psychiatry and neurology could be improved to better align with board certification in psychiatric pharmacy (BCPP) recommendations and disorder prevalence and complexity. Specialists recommend an experiential component in neurology and psychiatry to combat stigma and improve pharmacist knowledge and skills.

Substance use education in US schools of pharmacy: A systematic review of the literature.

BACKGROUND: The authors sought to systematically review the quantity and quality of literature describing substance use disorders (SUDs) education in US schools of pharmacy and determine the effectiveness of the educational interventions employed. METHODS: The authors conducted a systematic review of SUDs education studies in US pharmacy schools. All literature database searches were performed on April 30, 2016, in 5 databases: Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Embase.com, ERIC via FirstSearch, and CINAHL via EBSCOhost. The study authors conducted this systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-analyses guidelines and registered it with PROSPERO, which is an international prospective register of systematic reviews. The PROSPERO registration number is CRD42016037443. The study authors created a modified data extraction sheet based on the Best Evidence in Medical Education coding sheet. A Medical Education Research Study Quality Instrument (MERSQI) score was calculated for included articles. Results: From the 1626 retrieved records, 7 were included in the present review. The studies assessed students' impressions and abilities regarding SUDs pre- and post-intervention. The mean ± SD MERSQI score of the 7 studies was 9.86 ± 1.21 (range: 8-11.5). The included articles assessed pharmacy students at various academic years, with the majority students in either their first or second year of pharmacy school, and described both required and elective courses. The educational interventions varied in design and outcomes measured. Education included nicotine, alcoholism, and SUDs in general. None of the included articles reported on education regarding opioid use disorders. Conclusions: The studies included in this systematic review demonstrate that teaching pharmacy students about SUDs produces a positive impact in their attitudes and knowledge on this subject.

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.

Driving performance comparing older versus younger drivers.

OBJECTIVES: A cross-sectional study was conducted at the Touro University California campus to compare differences in reaction times and driving performance of younger adult drivers (18-40 years) and older adult drivers (60 years and older). Each test group consisted of 38 participants. METHODS: A Simple Visual Reaction Test (SVRT) tool was used to measure reaction times. The STISIM Drive M100 driving simulator was used to assess driving parameters. Driving performance parameters included mean lane position, standard deviation of mean lane position measured, mean speed, standard deviation of mean speed, car-following delay, car-following modulus, car-following coherence, off-road accidents, collisions, pedestrians hit, and traffic light tickets. RESULTS: Compared to younger participants, older drivers experienced significantly slower reaction times (510.0 ± 208.8 vs. 372.4 ± 96.1 ms, P =.0004), had more collisions (0.18 ± 0.39 vs. none, P =.0044), drove slower (44.6 ± 6.6 vs. 54.9 ± 11.7 mph, P <.0001), deviated less in speed (12.6 ± 4.3 vs. 16.8 ± 6.3, P =.0011), and were less able to maintain a constant distance behind a pace car (0.42 ± 0.23 vs. 0.59 ± 0.24; P =.0025). CONCLUSIONS: Differences exist in driving patterns of older and younger drivers as measured by reaction times and driving simulator outcomes. These results are the first to compare these 2 specific adult age groups' driving performance as measured by a standardized driving simulator scenario. Identifying these differences is essential in addressing them and preventing future traffic injuries.

Effects of valerian on subjective sedation, field sobriety testing and driving simulator performance.

INTRODUCTION: The availability of herbal medicines over-the-counter (OTC) has increased the use of natural products for self-treatment. Valerian has been used to effectively treat generalized anxiety disorder and insomnia. Studies suggest that valerenic acid may increase gamma-aminobutyric acid (GABA) modulation in the brain. Benzodiazepines have a similar mechanism of action and have been linked to an increased risk of hospitalizations due to traffic accidents. Despite the risk of somnolence, the safety of driving while under the influence of valerian remains unknown. PURPOSE: The purpose of the study was to determine the effects of a one-time valerian 1600mg dose on subjective sedation effects, standardized field sobriety testing (SFST) and driving simulator performance parameters. METHODS: The study design was a randomized, placebo-controlled, double-blind, cross-over trial. For each session, participants received either a dose of valerian or placebo. The outcome measures included a simple visual reaction test (SVRT), subjective sleepiness scales, SFST performance scores, and driving simulator performance parameters. RESULTS: There were no significant differences in the SVRT or sleepiness scales between placebo and valerian exposures, but the study may have been underpowered. SFST total and individual test failure rates were not significantly different between the two exposures. The driving simulator performance parameters were equivalent between the two exposure conditions. CONCLUSIONS: A one-time valerian 1600mg dose, often used to treat insomnia, does not appear to impair driving simulator performance after acute ingestion.

Valproic acid-induced hyperammonemia and minimal hepatic encephalopathy prevalence among psychiatric inpatients.

BACKGROUND: Our purpose was to evaluate the relationship between valproic acid (VPA)-induced hyperammonemia (HA) and the prevalence of minimal hepatic encephalopathy (MHE) cognitive impairment among psychiatric inpatients. METHODS: Fifty-two psychiatric inpatients prescribed VPA were tested for MHE impairment after achieving steady-state VPA and ammonia concentrations during hospitalization between December 2013 and June 2014. The relationship between steady-state VPA and ammonia concentration was tested by correlation coefficient. Patients completed a battery of 5 psychometric tests that determined a Psychometric Hepatic Encephalopathy Score (PHES), which was used to test the association between a PHES <-4 cutoff for MHE impairment and HA exposure (ammonia >50 µmol/L) by chi-square testing. RESULTS: Steady-state VPA plasma concentration was not correlated significantly with ammonia concentration (r = 0.24, P = .093). The patients with HA did not have a higher proportion of MHE cognitive impairment than patients with normal ammonia exposure (43.8% vs 66.7% respectively, P = .806). CONCLUSIONS: Steady-state VPA concentration was not correlated with ammonia concentration and VPA-induced HA was not associated with a greater prevalence of MHE impairment. This suggests that the MHE impairment PHES cutoff might not detect VHE in psychiatric inpatients without cirrhosis, especially because inpatients could experience cognitive impairment related to acute mental illness.

Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders.

Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders.

The Effects of Dextromethorphan on Driving Performance and the Standardized Field Sobriety Test.

Dextromethorphan (DXM) is abused most commonly among adolescents as a recreational drug to generate a dissociative experience. The objective of the study was to assess driving with and without DXM ingestion. The effects of one-time maximum daily doses of DXM 120 mg versus a guaifenesin 400 mg dose were compared among 40 healthy subjects using a crossover design. Subjects' ability to drive was assessed by their performance in a driving simulator (STISIM® Drive driving simulator software) and by conducting a standardized field sobriety test (SFST) administered 1-h postdrug administration. The one-time dose of DXM 120 mg did not demonstrate driving impairment on the STISIM® Drive driving simulator or increase SFST failures compared to guaifenesin 400 mg. Doses greater than the currently recommended maximum daily dose of 120 mg are necessary to perturb driving behavior.

Clozapine revisited: Impact of clozapine vs olanzapine on health care use by schizophrenia patients on Medicaid.

BACKGROUND: Our purpose was to evaluate health care use and cost patterns for clozapine compared with olanzapine in the treatment of schizophrenia. METHODS: Health care outcomes were measured over a 1-year posttreatment period for episodes of antipsychotic therapy initiated between 1997 and 2002. Four episode categories were defined: restart after lapse in therapy, switch after break, switch without break, and augmentation. We estimated the impact of clozapine or olanzapine using mixed model regression for costs by type of service and days of uninterrupted drug therapy. Time to admission in an acute hospital, psychiatric hospital, or longterm care facility, and time to suicide attempt were compared using Cox proportional hazards models. RESULTS: Clozapine increased duration of therapy and decreased risk of psychiatric hospitalization or suicide attempts compared to olanzapine. However, increased drug costs and use of community mental health centers (CMHC) for complete blood count (CBC) monitoring overwhelmed any offsetting savings. CONCLUSIONS: Clozapine is more expensive than olanzapine over the first year of treatment, primarily due to frequent CMHC visits required for CBC monitoring. However, fewer psychiatric hospitalizations, reduced suicide attempts, and longer duration of treatment should generate more benefits over time, which could eventually outweigh clozapine's higher first-year costs.

Use of translational pharmacodynamic biomarkers in early-phase clinical studies for schizophrenia.

Schizophrenia is a severe mental disorder characterized by cognitive deficits, and positive and negative symptoms. The development of effective pharmacological compounds for the treatment of schizophrenia has proven challenging and costly, with many compounds failing during clinical trials. Many failures occur due to disease heterogeneity and lack of predictive preclinical models and biomarkers that readily translate to humans during early characterization of novel antipsychotic compounds. Traditional early-phase trials consist of single- or multiple-dose designs aimed at determining the safety and tolerability of an investigational compound in healthy volunteers. However, by incorporating a translational approach employing methodologies derived from preclinical studies, such as EEG measures and imaging, into the traditional Phase I program, critical information regarding a compound's dose-response effects on pharmacodynamic biomarkers can be acquired. Furthermore, combined with the use of patients with stable schizophrenia in early-phase clinical trials, significant 'de-risking' and more confident 'go/no-go' decisions are possible.

P-glycoprotein (PGP) polymorphisms and sexual dysfunction in female patients with depression and SSRI-associated sexual side effects.

Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.

A pilot study of the pharmacodynamic impact of SSRI drug selection and beta-1 receptor genotype (ADRB1) on cardiac vital signs in depressed patients: a novel pharmacogenetic approach.

OBJECTIVE: The adrenergic beta-1 receptor gene (ADRB1) Ser49Gly and Arg389Gly variants differentially affect blood pressure response to beta-blocker therapy. Binding site prediction results for fluoxetine and paroxetine in a bioinformatics model estimated that each of these particular selective serotonin reuptake inhibitors (SSRIs) have high receptor affinity as an "Adrenergic (beta) Blocker," which was confirmed in vitro. This pilot study was conducted to understand the relationship between these "beta-blocking" SSRIs (fluoxetine and paroxetine) and cardiac vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)), when subjects are stratified by ADRB1 genotype. Previously ascertained DNA and clinical data was examined from 122 subjects recruited for a cross-sectional study of health and well being during SSRI pharmacotherapy. A multivariate linear regression analysis was used to determine which variables affected cardiac vital signs. There was a significant interaction between Arg389Gly variant status and "beta-blocking" SSRIs [p = 0.0353] in relation to SBP. Specifically in homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs had significantly lower SBP (mean 104 mmHg) compared to the group taking other SSRIs (mean 122 mmHg) [p = 0.0437]. In these same homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs also had lower HR (mean 60 bpm) compared to the other SSRIs (mean 79 bpm) [p = 0.00877]. Future prospective studies of this phenomenon are necessary to identify all genetic markers that can predict SSRI-associated cardiovascular effects that may be related to the SSRI discontinuation syndrome and potentially influence pharmacotherapy decisions.

Predicting new molecular targets for known drugs.

Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.

Pharmacogenetics of selective serotonin reuptake inhibitors and associated adverse drug reactions.

The selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely prescribed classes of drugs. They are relatively safe for the pharmacologic treatment of various psychiatric disorders; however, certain patients cannot tolerate some adverse drug reactions associated with this drug class. In addition, clinicians currently have no way to predict who will respond appropriately to a given SSRI, and the paradigm of trial and error is especially distressing for patients with mental illness. Pharmacogenetic association studies may provide insight into which genetic polymorphisms might be clinically relevant for individualizing pharmacotherapeutic regimens. Thus, we reviewed and summarized the literature regarding the pharmacogenomics of SSRI-associated adverse drug reactions. This growing body of knowledge may inform subsequent design of pharmacogenetic studies with respect to adverse drug reactions. As we appreciate the many pharmacologic mechanisms related to adverse drug reactions and gain polymorphic functional data, we will have opportunities to refine hypotheses for future pharmacogenetic association analyses.