A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence.

BACKGROUND: Previous studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. METHOD: Our sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. RESULTS: There were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. CONCLUSION: Cannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study.

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

The effects of cannabis abstinence on cognition and resting state network activity in people with multiple sclerosis: A preliminary study.

We previously reported that people with multiple sclerosis (pwMS) who have been using cannabis frequently over many years can have significant cognitive improvements accompanied by concomitant task-specific changes in brain activation following 28 days of cannabis abstinence. We now hypothesize that the default Mode Network (DMN), known to modulate cognition, would also show an improved pattern of activation align with cognitive improvement following 28 days of drug abstinence. Thirty three cognitively impaired pwMS who were frequent cannabis users underwent a neuropsychological assessment and fMRI at baseline. Individuals were then assigned to a cannabis continuation (CC, n = 15) or withdrawal (CW, n = 18) group and the cognitive and imaging assessments were repeated after 28 days. Compliance with cannabis withdrawal was checked with regular urine monitoring. Following acquisition of resting state fMRI (rs-fMRI), data were processed using independent component analysis (ICA) to identify the DMN spatial map. Between and within group analyses were carried out using dual regression for voxel-wise comparisons of the DMN. Clusters of voxels were considered statistically significant if they survived threshold-free cluster enhancement (TFCE) correction at p < 0.05. The two groups were well matched demographically and neurologically at baseline. The dual regression analysis revealed no between group differences at baseline in the DMN. By day 28, the CW group in comparison to the CC group had increased activation in the left posterior cingulate, and right, angular gyrus (p < 0.05 for both, TFCE). A within group analysis for the CC group revealed no changes in resting state (RS) networks. Within group analysis of the CW group revealed increased activation at day 28 versus baseline in the left posterior cingulate, right angular gyrus, left hippocampus (BA 36), and the right medial prefrontal cortex (p < 0.05). The CW group showed significant improvements in multiple cognitive domains. In summary, our study revealed that abstaining from cannabis for 28 days reverses activation of DMN activity in pwMS in association with improved cognition across several domains.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Carfentanil structural analogs found in street drugs by paper spray mass spectrometry and their characterization by high-resolution mass spectrometry.

Carfentanil is one of the most potent synthetic opioids ever developed, with an estimated analgesic potency approximately 20-100 times that of fentanyl and 10,000 times that of morphine. Carfentanil has been appearing in the illicit drug supply in many regions and has been linked to fatal overdose events. A subset of 59 street drug samples obtained in Victoria, B.C., that were confirmed to contain carfentanil were analyzed by mass spectrometry for this study. Carfentanil quantitation by paper spray mass spectrometry ranged from 0.05 to 2.95 w/w% (median = 0.32%) in the original drug sample. Paper spray mass spectrometry analysis also detected two unknown peaks at m/z 380.2 and 381.2 in 31 of these 59 samples (53%). Initial tandem mass spectrometry experiments revealed structural similarities between these unknown compounds and carfentanil, suggesting they were potential structural analogs, possibly arising from incomplete purification during synthesis. High-resolution mass spectrometry determined the chemical formulas of these compounds as C23 H29 N3 O2 (m/z 380.2333) and C23 H29 N2 O3 (m/z 381.2137). Literature and tandem mass spectrometry results were used to determine the identity of these potential new psychoactive substances, C23 H29 N3 O2 as desmethylcarfentanil amide and C23 H29 N2 O3 as desmethylcarfentanil acid. µ-Opioid receptor binding modeling determined that the binding poses of these analogs were nearly identical to that of carfentanil with relative binding energy calculations of 0.544 kJ/mol (desmethylcarfentanil amide) and -0.171 kJ/mol (desmethylcarfentanil acid); these data suggest they may share the toxic effects of carfentanil and have similar potencies.

Drug checking services as a surveillance tool for clinical laboratories: Examining trends in the unregulated fentanyl supply.

OBJECTIVES: Timely assessment and understanding of drug trends is essential for clinical laboratories to effectively respond to the overdose epidemic. In this proof-of-concept study, we sought to determine whether information obtained through Toronto's Drug Checking Services (DCS) and cross-provincial urine drug testing (UDT) data can be used as a surveillance tool for clinical laboratories and discuss the value of collaboration between the clinical laboratory, clinicians, and community partners to optimize patient care. DESIGN & METHODS: Mass spectrometry-based UDT data from LifeLabs Ontario (n = 127,529) and British Columbia (n = 14,848), and drug checking data from Toronto DCS (n = 3,308 drugs or used paraphernalia) was collected between August 2020 and October 2021. Fentanyl co-positivity with toxic adulterants such as benzodiazepine-related drugs and fentanyl analogues were examined. RESULTS: The percent co-positivity of fentanyl with etizolam, flualprazolam, flubromazolam, carfentanil, and acetylfentanyl in both Ontario UDT and DCS drugs/used paraphernalia showed similar trends. Regional differences in co-positivity with etizolam and fentanyl analogues were noted between Ontario and British Columbia UDT with patterns consistent over the entire 15-month collection period. CONCLUSIONS: Clinical laboratories should connect with their local DCS, if available, to understand and monitor unregulated drug trends. These data can be used as an important tool to help clinical laboratories tailor their UDT menus and thereby provide a community-focused service to improve patient care.

Diverse psychotropic substances detected in drug and drug administration equipment samples submitted to drug checking services in Toronto, Ontario, Canada, October 2019-April 2020.

BACKGROUND: The overdose crisis has generated innovative harm reduction and drug market monitoring strategies. In Toronto, Ontario, Canada, a multi-site drug checking service (DCS) pilot project was launched in October 2019. The project provides people who use drugs with information on the chemical composition of their substances, thereby increasing their capacity to make more informed decisions about their drug use and avoid overdose. DCS also provides real-time market monitoring to identify trends in the unregulated drug supply. METHODS: Sample data were obtained through analyses of drug and used drug administration equipment samples submitted anonymously and free of charge to DCS in downtown Toronto from October 10, 2019, to April 9, 2020, representing the first six months of DCS implementation. Analyses were conducted in clinical laboratories using liquid chromatography- and/or gas chromatography-mass spectrometry (LC-MS, GC-MS) techniques. RESULTS: Overall, 555 samples were submitted, with 49% (271) of samples that were found to contain high-potency opioids, of which 87% (235) also contained stimulants. Benzodiazepine-type drugs were found in 21% (116) of all samples, and synthetic cannabinoids in 1% (7) of all samples. Negative effects (including overdose, adverse health events, and extreme sedation) were reported for 11% (59) of samples submitted for analysis. CONCLUSIONS: Toronto's DCS identified a range of high-potency opioids with stimulants, benzodiazepine-type drugs, and a synthetic cannabinoid, AMB-FUBINACA. This information can inform a range of evidence-informed overdose prevention efforts.

Combined effect of alcohol and cannabis on simulated driving.

RATIONALE: With alcohol and cannabis remaining the most commonly detected drugs in seriously and fatally injured drivers, there is a need to understand their combined effects on driving. OBJECTIVES: The present study examined the effects of combinations of smoked cannabis (12.5% THC) and alcohol (target BrAC 0.08%) on simulated driving performance, subjective drug effects, cardiovascular measures, and self-reported perception of driving ability. METHODS: In this within-subjects, double-blind, double-dummy, placebo-controlled, randomized clinical trial, cannabis users (1-7 days/week) aged 19-29 years attended four drug administration sessions in which simulated driving, subjective effects, cardiovascular measures, and whole blood THC and metabolite concentrations were assessed following placebo alcohol and placebo cannabis (<0.1% THC), alcohol and placebo cannabis, placebo alcohol and active cannabis, and alcohol and active cannabis. RESULTS: Standard deviation of lateral position in the combined condition was significantly different from the placebo condition (p < 0.001). Standard deviation of lateral position was also significantly different from alcohol and cannabis alone conditions in the single task overall drive (p = 0.029 and p = 0.032, respectively), from the alcohol alone condition in the dual task overall drive (p = 0.022) and the cannabis alone condition in the dual task straightaway drive (p = 0.002). Compared to the placebo condition, the combined and alcohol conditions significantly increased reaction time. Subjective effects in the combined condition were significantly greater than with either of the drugs alone at some time points, particularly later in the session. A driving ability questionnaire showed that participants seemed unaware of their level of impairment. CONCLUSION: Combinations of alcohol and cannabis increased weaving and reaction time, and tended to produce greater subjective effects compared to placebo and the single drug conditions suggesting a potential additive effect. The fact that participants were unaware of this increased effect has important implications for driving safety.

Xylazine detected in unregulated opioids and drug administration equipment in Toronto, Canada: clinical and social implications.

BACKGROUND: The North American opioid overdose crisis is driven in large part by the presence of unknown psychoactive adulterants in the dynamic, unregulated drug supply. We herein report the first detection of the psychoactive veterinary compound xylazine in Toronto, the largest urban center in Canada, by the city's drug checking service. METHODS: Toronto's Drug Checking Service launched in October 2019. Between then and February 2021, 2263 samples were submitted for analysis. The service is offered voluntarily at harm reduction agencies that include supervised consumption services. Samples were analyzed using gas chromatography-mass spectrometry or liquid chromatography-high resolution mass spectrometry. Targeted and/or untargeted screens for psychoactive substances were undertaken. RESULTS: In September 2020, xylazine was first detected by Toronto's Drug Checking Service. Among samples analyzed from September 2020 to February 2021 expected to contain fentanyl in isolation (610) or in combination with methamphetamine (16), xylazine was detected in 46 samples (7.2% and 12.5% of samples, respectively). Samples were predominantly drawn from used drug equipment. Three of the samples containing xylazine (6.5%) were associated with an overdose. CONCLUSION: We present the first detection of xylazine in Toronto, North America's fourth-largest metropolitan area. The increased risk of overdose associated with use of xylazine and its detection within our setting highlights the importance of drug checking services in supporting rapid responses to the emergence of potentially harmful adulterants. These data also highlight the clinical challenges presented by the dynamic nature of unregulated drug markets and the concomitant need to establish regulatory structures to reduce their contribution to overdose morbidity and mortality.

Impaired awareness: Why people with multiple sclerosis continue using cannabis despite evidence to the contrary.

BACKGROUND: With widespread moves toward legalization of cannabis, increasing numbers of people with multiple sclerosis (pwMS) are using the drug. Emerging MS-related data show that cannabis can cause or exacerbate cognitive dysfunction. OBJECTIVE: To understand why people with MS continue using cannabis despite adverse cognitive consequences. It was hypothesized that lack of awareness, a component of metacognition, could explain this decision, in part. METHOD: Forty pwMS who smoked cannabis almost daily were assigned by odd-even case number selection to either a cannabis continuation (CC) or cannabis withdrawal (CW) group. Both groups were followed for 28 days. All participants completed, at baseline and day 28, the brief repeatable battery of neuropsychological tests (BRNB) in MS for measures of processing speed, memory and executive function; Modified fatigue impact scale (mFIS) for self-report indices of cognitive functioning. RESULTS: No significant baseline differences between the groups on the BRNB and mFIS. At day 28, significant improvement within group was seen on all measures of the BRNB, but only in the CW group (p = .0001 for all indices). A repeat measure ANOVA did not find any significant group (CC vs. CW) × time (baseline and day 28) interactions for the self-report cognitive measures on the mFIS. Cannabis abstainers did report less ability to function away from home. All 19 participants in the CW group reverted to using cannabis on study completion despite being informed individually of their cognitive improvement. CONCLUSIONS AND RELEVANCE: The inability of pwMS to accurately appraise their memory and executive function can help explain, in part, why they continue to smoke cannabis despite objective evidence of the deleterious cognitive side effects of this behavior.

Detection of synthetic cannabinoid adulteration in the unregulated drug supply in three Canadian settings.

INTRODUCTION: Novel psychoactive substances (NPS) are increasingly being consumed worldwide, with synthetic cannabinoids and synthetic opioids being the second and third most commonly used NPS, respectively. Certain synthetic cannabinoids can produce significant harms, particularly when used with opioids. The objective of this study was to characterise the presence of synthetic cannabinoids in the unregulated drug supply in three Canadian settings METHODS: In the British Columbia setting, all samples were first analysed at point-of-care using combination Fourier-transform infrared (FTIR) spectroscopy and fentanyl immunoassay strips prior to confirmatory testing using quantitative nuclear magnetic resonance spectroscopy, gas chromatography/mass spectrometry (GC/MS) and/or liquid chromatography/mass spectrometry (LC/MS). In the Toronto, Ontario setting, the samples were analysed directly by GC/MS, LC/MS liquid chromatography-high resolution/mass spectrometry. RESULTS: Between January 2018 and December 2019, 38 (2.8%) synthetic cannabinoid samples were detected in the unregulated drug supply (25/909 in British Columbia and 13/440 in Ontario). In British Columbia and Ontario, 76% and 85% of samples, respectively, were expected by individuals to be an opioid. Synthetic cannabinoids detected included AMB-FUBINACA, AB-FUBINACA, 5-fluoro-MDMB-PINACA, and 5-fluoro-MDMB-PICA, and largely co-occurred with fentanyl. In the British Columbia context, Fourier-transform infrared spectroscopy failed to detect synthetic cannabinoid compounds in almost half (48%) of the samples at point-of-care. DISCUSSION AND CONCLUSIONS: As point-of-care technologies failed to detect these compounds in many occasions, our findings demonstrate the importance of laboratory confirmatory analysis to identify NPS. Given the high risk of harm associated with the consumption of synthetic cannabinoids, further research should investigate the reasons for adulteration.

Discontinuing cannabis improves depression in people with multiple sclerosis: A short report.

To assess whether symptoms of depression change when people with multiple sclerosis (pwMS) discontinue cannabis use, 40 cognitively impaired pwMS who smoked cannabis almost daily were randomly assigned to either a cannabis continuation (CC) or cannabis withdrawal (CW) group. Both groups were followed for 28 days. All participants completed the Hospital Anxiety and Depression Scale. At day 28 the 11-nor-9-carboxy-Δ9-tetrahydro-cannabinol (THCCOOH)/creatinine ratio in the CW group declined to zero (p = 0.0001), but remained unchanged in the CC group (p = 0.709). Depression scores in those pwMS who were using cannabis to manage their depression remained statistically unchanged in the CC group, but declined in the CW group (p = 0.006). Despite pwMS using cannabis to help their mood, depression improved significantly off the drug. Our finding provides a cautionary note in relation to cannabis use in pwMS, at least with respect to depression.

The Effect of Venlafaxine on Electrocardiogram Intervals During Treatment for Depression in Older Adults.

PURPOSE/BACKGROUND: Venlafaxine is a commonly used antidepressant with both serotonergic and noradrenergic activity. There are concerns that it may prolong the corrected QT interval (QTc), and older adults may be at higher risk for this adverse effect, especially at higher dosages of the medication. METHODS/PROCEDURES: In this secondary analysis of a prospective clinical trial, we measured changes in QTc and other electrocardiogram (ECG) parameters in 169 adults 60 years or older with a major depressive disorder treated acutely with venlafaxine extended release up to 300 mg daily. We examined the relationship of venlafaxine dosage and ECG parameters, as well as the relationship between serum levels of venlafaxine and ECG parameters. FINDINGS/RESULTS: Venlafaxine exposure was not associated with an increase in QTc. Heart rate increased with venlafaxine treatment, whereas the PR interval shortened, and QRS width did not change significantly. The QTc change from baseline was not associated with venlafaxine dosages or serum concentrations. Age, sex, cardiovascular comorbidities, and depression remission status did not predict changes in QTc with venlafaxine. IMPLICATIONS/CONCLUSIONS: Venlafaxine treatment did not prolong QTc or other ECG parameters, even in high dosages in older depressed adults. These findings indicate that venlafaxine does not significantly affect cardiac conduction in most older patients.

Acute and residual effects of smoked cannabis: Impact on driving speed and lateral control, heart rate, and self-reported drug effects.

BACKGROUND: Although driving under the influence of cannabis is increasingly common among young adults, little is known about residual effects on driver behavior. This study examined acute and residual effects of smoked cannabis on simulated driving performance of young cannabis users. METHODS: In this double-blind, placebo-controlled, parallel-group randomized clinical trial, cannabis users (1-4 days/week) aged 19-25 years were randomized with a 2:1 allocation ratio to receive active (12.5% THC) or placebo (0.009% THC) cannabis in a single 750 mg cigarette. A median split (based on whole-blood THC concentrations at the time of driving) was used to divide the active group into low and high THC groups. Our primary outcome was simulated driving performance, assessed 30 min and 24 and 48 h after smoking. Secondary outcomes included blood THC concentrations, subjective drug effects, and heart rate. RESULTS: Ninety-six participants were randomized, and 91 were included in the final analysis (30 high THC, 31 low THC, 30 placebo). Mean speed (but not lateral control) significantly differed between groups 30 min after smoking cannabis (p ≤ 0.02); low and high THC groups decreased their speed compared to placebo. Heart rate, VAS drug effect and drug high increased significantly immediately after smoking cannabis and declined steadily after that. There was little evidence of residual effects in any of the measures. CONCLUSION: Acutely, cannabis caused decreased speed, increased heart rate, and increases in VAS drug effect and drug high. There was no evidence of residual effects on these measures over the two days following cannabis administration.

Coming off cannabis: a cognitive and magnetic resonance imaging study in patients with multiple sclerosis.

Cognitive dysfunction affects 40-80% of patients with multiple sclerosis. Smoking cannabis may add to these deficits. It is unclear whether coming off cannabis results in cognitive improvement. To address this question, 40 patients with multiple sclerosis who started using cannabis after the onset of multiple sclerosis and who used it for at least 4 days a week over many years were divided by odd-even number selection into two groups: cannabis continuation and cannabis withdrawal. Assessments took place at baseline and after 28 days and included serial versions of the Brief Repeatable Neuropsychological Battery for multiple sclerosis containing tests of verbal and visual memory, processing speed and executive function; structural and functional MRI, the latter entailing a compatible version of the Symbol Digit Modalities Test; urine for cannabinoid metabolites to detect compliance with abstinence. Only those participants deemed globally impaired at baseline (failure on at least two cognitive domains) were enrolled. The results revealed that the two groups were well matched demographically and neurologically. One subject was removed from the withdrawal group because of failed abstinence. Urine analysis revealed the cannabinoid consumed was predominantly tetrahydrocannabinol (THC). There were no baseline between group cognitive differences, but by Day 28 the withdrawal group performed significantly better on every cognitive index (P < 0.0001 for all). Significant within group differences were present for every test over time, but only in the abstinent group (P < 0.0001 for all tests). There were no between group baseline or Day 28 differences in structural MRI indices (global atrophy, total T1 and T2 lesion volume). At index assessment the two groups had a similar performance on the functional MRI-compatible Symbol Digit Modalities Test and there were no group differences in brain activation. However, by Day 28, the withdrawal group completed more trials correctly (P < 0.012) and had a faster reaction time (P < 0.002), associated with significantly increased activation in brain regions known to be associated with performance of the test (bilateral inferior frontal gyri, caudate and declive/cerebellum, P < 0.001 for all regions). These results reveal that patients with multiple sclerosis who are frequent, long-term cannabis users can show significant improvements in memory, processing speed and executive function after 28 days of drug abstinence. The absence of similar improvements in a matched multiple sclerosis group that remained on cannabis shows that beneficial cognitive change after stopping cannabis is not solely attributable to the effects of practice.

Predicting Escitalopram Exposure to Breastfeeding Infants: Integrating Analytical and In Silico Techniques.

BACKGROUND: Escitalopram is used for post-partum depression; however, there are limited pharmacokinetic data of escitalopram in milk and plasma of infants breastfed by women taking the drug. OBJECTIVE: The objective of this study was to apply physiologically-based pharmacokinetic (PBPK) modelling to predict infant drug exposure (plasma area under the curve from time zero to infinity [AUC∞]) based on drug monitoring data of escitalopram in breast milk. METHODS: Using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we quantified escitalopram concentrations in milk samples of 18 breastfeeding women with escitalopram therapy at steady state, collected at three to five time points. The escitalopram concentrations in breast milk were used with infant feeding parameters from the literature to simulate infant daily dose. We used PK-Sim® to develop an adult PBPK model for escitalopram and extrapolated it to a population of 1600 infants up to 12 months of age. An integration of the simulated infant daily dose and the virtual infants with variable physiological-pharmacological parameters was used to predict drug exposure (plasma AUC∞) distribution in the population of infants breastfed by women receiving escitalopram 20 mg/day. RESULTS: Escitalopram concentrations in milk were 50 ± 17 ng/mL (mean ± standard deviation). The simulated infant plasma AUC∞ following escitalopram exposure through breast milk was low, with a median of 1.7% (range 0.5-5.9%) of the corresponding maternal plasma AUC∞, indicating no substantial exposure. CONCLUSIONS: Infant exposure levels to escitalopram in breast milk are low. A PBPK modeling approach can be used to translate data on drug monitoring in milk into a population distribution of infant plasma levels for drug safety assessment.

A method to achieve extended cannabis abstinence in cannabis dependent patients with schizophrenia and non-psychiatric controls.

BACKGROUND: Cannabis use disorders (CUD) are common in schizophrenia (~25%) compared to the general population (~3%). Tetrahydrocannabinol (THC), the principal psychoactive component in cannabis is fat-soluble, resulting in an extended period for cannabinoid elimination. While detection of cannabinoids in urine is indicative of prior cannabis exposure, time of last use is difficult to verify sustained abstinence for extended periods (e.g., 28-days) in chronic cannabis users. Therefore, we evaluated the utility of a sustained cannabis abstinence paradigm in patients with schizophrenia and non-psychiatric controls. METHODS: Cannabis dependent patients (n=19) and controls (n=20) underwent 28-days of monitored cannabis abstinence facilitated with contingency management. Urine samples were taken twice weekly. Abstinence was evaluated using 1) Self-report; 2) Qualitative biochemical confirmation using MEDTOX; and 3) in a subset of participants (schizophrenia, n=13; controls, n=13) gas chromatography-mass spectrometry (GC-MS) was performed to obtain quantitative creatinine-normalized carboxy-THC (THC-COOH) metabolite levels <20ng/mL). Subjective assessments were used to assess behavioral correlates of cannabis abstinence and further supported time-dependent abstinence trajectories. RESULTS: Abstinence rates of 42.1% (8/19) in patients and 55% (11/19) in controls (p=0.53) were observed. Increased cannabis withdrawal symptoms in both patients and controls supported abstinence. DISCUSSION: Our results suggest a feasible method for identification of short-term cannabis abstinence in individuals with schizophrenia at rates comparable to controls. Monitoring sustained abstinence may have implications for potential interventions for CUDs in schizophrenia.