Cannabis Compounds Research Articles

THE HEART OF THE MATTER: CANNABIS EXPOSURE INITIATES CYCLIC ALTERATIONS IN HUMAN ENDOMETRIAL STROMAL CELLS AND DYSREGULATES PRENATAL CARDIAC DEVELOPMENT

Cannabis use prior to and during pregnancy has risen due to increasing legalization. We established a renewable and expandable source of human endometrial stromal cells (ESC) and immature cardiomyocytes (CM) to distill the paradoxical effects of Δ9-tetrahydrocannabinol (THC), the psychoactive compound in cannabis, on maternal and fetal health. This is imperative as animal models do not fully mimic the dynamic human endometrium, nor do primary CM expand well ex vivo.

Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells.

Simple SummaryOvarian cancer is the most lethal gynecological malignancy. Cancer stem cells have been implicated in tumor initiation, progression, and invasion, as well as tumor recurrence, metastasis, and drug resistance. Cannabis is used worldwide to alleviate numerous symptoms associated with various medical conditions. Phytocannabinoids, produced by cannabis, were shown to have anti-cancer activity in cell lines and animal models, but also the potential to increase other drugs’ adverse effects. Yet, very few studies have examined the effectiveness of cannabis compounds against ovarian cancer. Cannabis compounds have been shown to affect genetic pathways and biological processes related to development of ovarian cancer stem cells. Phytocannabinoid-based treatments might be used to disrupt cancer stem cell homeostasis and thereby to prevent chemotherapy resistance. The potential benefits of the combination of chemotherapy with phytocannabinoid treatment could be examined in ovarian cancer patients.Ovarian cancer (OC) is the most lethal gynecological malignancy, with about 70% of cases diagnosed only at an advanced stage. Cannabis sativa, which produces more than 150 phytocannabinoids, is used worldwide to alleviate numerous symptoms associated with various medical conditions. Recently, studies across a range of cancer types have demonstrated that the phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) have anti-cancer activity in vitro and in vivo, but also the potential to increase other drugs’ adverse effects. THC and CBD act via several different biological and signaling pathways, including receptor-dependent and receptor-independent pathways. However, very few studies have examined the effectiveness of cannabis compounds against OC. Moreover, little is known about the effectiveness of cannabis compounds against cancer stem cells (CSCs) in general and OC stem cells (OCSCs) in particular. CSCs have been implicated in tumor initiation, progression, and invasion, as well as tumor recurrence, metastasis, and drug resistance. Several hallmarks and concepts describe CSCs. OCSCs, too, are characterized by several markers and specific drug-resistance mechanisms. While there is no peer-reviewed information regarding the effect of cannabis and cannabis compounds on OCSC viability or development, cannabis compounds have been shown to affect genetic pathways and biological processes related to CSCs and OCSCs. Based on evidence from other cancer-type studies, the use of phytocannabinoid-based treatments to disrupt CSC homeostasis is suggested as a potential intervention to prevent chemotherapy resistance. The potential benefits of the combination of chemotherapy with phytocannabinoid treatment should be examined in ovarian cancer patients.

Effects of the Storage Conditions on the Stability of Natural and Synthetic Cannabis in Biological Matrices for Forensic Toxicology Analysis: An Update from the Literature

The use and abuse of cannabis, be it for medicinal or recreational purposes, is widely spread among the population. Consequently, a market for more potent and consequently more toxic synthetic cannabinoids has flourished, and with it, the need for accurate testing of these substances in intoxicated people. In this regard, one of the critical factors in forensic toxicology is the stability of these drugs in different biological matrices due to different storage conditions. This review aims to present the most updated and relevant literature of studies performed on the effects of different storage conditions on the stability of cannabis compounds present in various biological matrices, such as blood and plasma, urine, and oral fluids, as well as in alternative matrices, such as breath, bile fluid, hair, sweat, cerumen, and dried blood spots.

An efficient and simple SERS approach for trace analysis of tetrahydrocannabinol and cannabinol and multi-cannabinoid detection

Many countries have legalized cannabis and its derived products for multiple purposes. Consequently, it has become necessary to develop a rapid, effective, and reliable tool for detecting delta-9-tetrahydrocannabinol (THC) and cannabinol (CBN), which are important biologically active compounds in cannabis. Herein, we have fabricated SERS chips by using glancing angle deposition and tuned dimensions of silver nanorods (AgNRs) for detecting THC and CBN at low concentrations. Experimental and computational results showed that the AgNR substrate with film thickness (or nanorod length) of 150 nm, corresponding to nanorod diameter of 79 nm and gap between nanorods of 23 nm, can effectively sense trace THC and CBN with good reproducibility and sensitivity. Due to limited spectral studies of the cannabinoids in previous reports, this work also explored towards identifying characteristic Raman lines of THC and CBN. This information is critical to further reliable data analysis and interpretation. Moreover, multianalyte detection of THC and CBN in a mixture was successfully demonstrated by applying an open-source independent component analysis (ICA) model. The overall method is fast, sensitive, and reliable for sensing trace THC and CBN. The SERS chip-based method and spectral results here are useful for a variety of cannabis testing applications, such as product screening and forensic investigation.

(Almost) Everything You Always Wanted to Know About Cannabis Science, but Were Afraid to Ask!

Aim: It is estimated that approximately 25% of cancer patients are currently taking cannabis to alleviate symptoms of their disease and/or cope with the side effects of their treatment. Patients want to learn more about cannabis from their cancer healthcare team, but most Radiation Therapists (RTs) feel too uninformed to discuss this subject. The purpose of this abstract is to provide information about cannabis that is relevant and useful for RTs. Process: Cannabis is a broad term used to describe organic products derived from the Cannabis plant. The unique group of active chemical compounds found in cannabis are called cannabinoids. Among the more than 100 different types of cannabinoids, the most abundant and well-studied are delta9 tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the primary intoxicating compound of cannabis, which is responsible the euphoric “high”. CBD is a non-intoxicating constituent of cannabis. Terpenes are the third most prevalent compound in cannabis, these give cannabis its distinctive fragrance. Plants are selectively bred to produce particular THC/CBD ratios, and there are more than 200 medical strains currently available from licensed producers in Canada. Cannabis comes in many forms, including dried flower, processed oil, pharmaceutical grade pills and topical patches. Cannabis can be ingested by inhalation, orally, sublingually and topically. Each of these methods has its own rate of onset and duration of effects, and differences in the bioavailability of cannabinoids. Cannabinoids are absorbed into the blood, then rapidly distributed into the brain and other high perfusion tissues. They are then metabolized by CYP liver enzymes and eventually eliminated via feces or urine. All forms of cannabinoids work on the endocannabinoid system within the human body, which consists of a series of neuromodulators and their associated receptors located throughout the brain, peripheral nervous system and immune system. Benefits/Challenges: Cancer patients most frequently take cannabis to improve nausea and appetite, pain, stress and sleep, with 51% - 83% self-reporting a major benefit. The Canadian Cannabis Act (2018) provides access to cannabis for those over 18yrs via medical cannabis programs, prescription pharmaceuticals, pharmacies, provincial websites and retail storefronts. Despite widespread availability, there are multiple precautions and contraindications when considering taking cannabis. These include patient risk factors (e.g. schizophrenia, cardio-metabolic disorders, respiratory conditions), drug-on-drug interactions (e.g. anti-coagulants, statins, SSRIs), lifestyle risk factors (e.g. driving, working, travelling) and the development of a use disorder. Short term harms associated with cannabis use include impaired cognitive and motor function, tachycardia, anxiety and paranoia. Long term harms include impaired learning and memory and development of chronic bronchitis. Evidence-based guidelines are now available to lower the risks associated with taking cannabis. Impact/Outcomes Most RTs have little knowledge about the therapeutic use of cannabis by cancer patients, and <15% of patients receive any information about cannabis from their healthcare team. This leaves our patients exposed to cannabis myths and misrepresentations found during internet searches. Educational opportunities are urgently needed to provide RTs with information about the science of cannabis so they can support and advise their patients.

Cannabis edibles packaging: Communicative objects in a growing market.

Cannabis edibles were legalized for recreational use across Canada in October 2019. The Canadian Cannabis Act requires legally produced edibles to be sold in plain single-color packages with limited branded elements and prominent health warning labels, serving size and nutritional information, and product ingredients including amounts of cannabis compounds. Little research, however, assesses what consumers think of standardized packaging, and how product packaging influences perceptions of cannabis edibles. Eight focus groups with young adults (ages 18-24; n=57) were conducted in November 2018. Participants were recruited from a Canadian university, and asked to assess sample images of cannabis packaging approved by Health Canada. They then discussed the information they would like to see on packages. Focus group discussions were transcribed and analyzed using a descriptive, qualitative approach following methods of process evaluation and inductive coding. Discussions generally pertained to four main themes: dosage and consumption recommendations; food and nutritional information; concerns for children; and health warning labels. Participants suggested improvements for cannabis packaging, including standardized THC units, non-numerical consumption instructions, and unit-dose packaging. Instead of recommending packaging that deters consumption, participants requested packaging features that promote safe consumption by adults while also protecting children. Findings reveal how packages function as communicative objects that convey meanings about safety and risk, yet these meanings may not resonate with Canadian young adults' perceptions of cannabis as relatively safe. While the packaging regulated for use in Canada may be assumed, due to its plain, standardized format, to communicate "little", we highlight tensions in the meanings of such packaging to young adults-especially around competing ideas related to safety and risk.

Medicinal Cannabis and Central Nervous System Disorders.

Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.

Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities.

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.

Metabolomic Fingerprint of Behavioral Changes in Response to Full-Spectrum Cannabis Extracts.

Numerous existing full-spectrum cannabis extract products have been used in clinical trials for the treatment of various diseases. Despite their efficacy, the clinical use of some of these full-spectrum cannabis extracts is limited by behavioral side effects such as cognitive dysfunction and impaired motor skills. To better understand what constitutes cannabis-induced behavioral effects, our objective was to identify a novel panel of blood-based metabolites that are predictive, diagnostic, and/or prognostic of behavioral effects.At 8 weeks of age, male rats were randomly assigned to groups and were gavage fed with full-spectrum cannabis extract (tetrahydrocannabinol/cannabidiol (THC/CBD) along with all other cannabis compounds, 15 mg/kg), broad-spectrum cannabis extract (CBD along with all other cannabis compounds, 15 mg/kg), or vehicle oil. Four hours after being gavage fed, behavioral assessments were determined using the open field test and the elevated plus maze. Following these assessments, serum was collected from all rats and the serum metabolites were identified and quantified by LC–MS/MS and 1H NMR spectroscopy.We found that only rats treated with full-spectrum cannabis extract exhibited behavioral changes. Compared to vehicle-treated and broad-spectrum extract–treated rats, full-spectrum extract–treated rats demonstrated higher serum concentrations of the amino acid phenylalanine and long-chain acylcarnitines, as well as lower serum concentrations of butyric acid and lysophosphatidylcholines. This unique metabolomic fingerprint in response to cannabis extract administration is linked to behavioral effects and may represent a biomarker profile of cannabis-induced behavioral changes. If validated, this work may allow a metabolomics-based decision tree that would aid in the rapid diagnosis of cannabis-induced behavioral changes including cognitive impairment.

A Comprehensive Review on the Techniques for Extraction of Bioactive Compounds from Medicinal Cannabis.

Cannabis is well-known for its numerous therapeutic activities, as demonstrated in pre-clinical and clinical studies primarily due to its bioactive compounds. The Cannabis industry is rapidly growing; therefore, product development and extraction methods have become crucial aspects of Cannabis research. The evaluation of the current extraction methods implemented in the Cannabis industry and scientific literature to produce consistent, reliable, and potent medicinal Cannabis extracts is prudent. Furthermore, these processes must be subjected to higher levels of scientific stringency, as Cannabis has been increasingly used for various ailments, and the Cannabis industry is receiving acceptance in different countries. We comprehensively analysed the current literature and drew a critical summary of the extraction methods implemented thus far to recover bioactive compounds from medicinal Cannabis. Moreover, this review outlines the major bioactive compounds in Cannabis, discusses critical factors affecting extraction yields, and proposes future considerations for the effective extraction of bioactive compounds from Cannabis. Overall, research on medicinal marijuana is limited, with most reports on the industrial hemp variety of Cannabis or pure isolates. We also propose the development of sustainable Cannabis extraction methods through the implementation of mathematical prediction models in future studies.

Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats.

Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood. The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours. We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats. We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states. These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.

Antimicrobial and Antiviral (SARS-CoV-2) Potential of Cannabinoids and Cannabis sativa: A Comprehensive Review.

Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coronavirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO’s current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the Mpro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.

Chronic exposure to ∆ 9-tetrahydrocannabinol in adolescence decreases social play behaviours.

Background: Cannabis use remains a major public health concern, and its use typically begins in adolescence. Chronic administration of ∆ 9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, during adolescence can produce deficits in adult learning and memory, stress reactivity and anxiety. One possible mechanism behind the disruptions in adulthood from adolescent exposure to THC includes changes in social behaviours, such as social play, which has been shown to be critical to socio-cognitive development. Methods: Here, using an established animal model of adolescent THC exposure in male and female Long-Evans rats, we explored the effects of THC on play behaviour during the chronic administration period. Following puberty onset, as indicated by external changes to the genitalia, THC (5mg/kg) was administered for 14 days. Play behaviour was assessed seven days following the onset of the injection period at approximately 1 hour post treatment. The frequency of nape attacks, the likelihood and tactics of defensive behaviour, and pins were scored and analyzed. Results: THC exposure decreased playfulness in adolescent rats including the number of attacks, likelihood of defense and pins compared to control and vehicle treated rats. Conclusion: This suggests that THC suppresses both the attack and defense components of social play. This is an important finding because there is evidence that attack and defense may be mediated by different mechanisms. Furthermore, the effect of THC exposure decreasing playfulness occurred similarly in males and females.

Biological activity of Cannabis compounds: a modern approach to the therapy of multiple diseases

Biological activity of Cannabis compounds: a modern approach to the therapy of multiple diseases

Analgesic Potential of Terpenes Derived from Cannabis sativa.

Pain prevalence among adults in the United States has increased 25% over the past two decades, resulting in high health-care costs and impacts to patient quality of life. In the last 30 years, our understanding of pain circuits and (intra)cellular mechanisms has grown exponentially, but this understanding has not yet resulted in improved therapies. Options for pain management are limited. Many analgesics have poor efficacy and are accompanied by severe side effects such as addiction, resulting in a devastating opioid abuse and overdose epidemic. These problems have encouraged scientists to identify novel molecular targets and develop alternative pain therapeutics. Increasing preclinical and clinical evidence suggests that cannabis has several beneficial pharmacological activities, including pain relief. Cannabis sativa contains more than 500 chemical compounds, with two principle phytocannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Beyond phytocannabinoids, more than 150 terpenes have been identified in different cannabis chemovars. Although the predominant cannabinoids, Δ9-THC and CBD, are thought to be the primary medicinal compounds, terpenes including the monoterpenes β-myrcene, α-pinene, limonene, and linalool, as well as the sesquiterpenes β-caryophyllene and α-humulene may contribute to many pharmacological properties of cannabis, including anti-inflammatory and antinociceptive effects. The aim of this review is to summarize our current knowledge about terpene compounds in cannabis and to analyze the available scientific evidence for a role of cannabis-derived terpenes in modern pain management. SIGNIFICANCE STATEMENT: Decades of research have improved our knowledge of cannabis polypharmacy and contributing phytochemicals, including terpenes. Reform of the legal status for cannabis possession and increased availability (medicinal and recreational) have resulted in cannabis use to combat the increasing prevalence of pain and may help to address the opioid crisis. Better understanding of the pharmacological effects of cannabis and its active components, including terpenes, may assist in identifying new therapeutic approaches and optimizing the use of cannabis and/or terpenes as analgesic agents.

A Review of the Potential Use of Pinene and Linalool as Terpene-Based Medicines for Brain Health: Discovering Novel Therapeutics in the Flavours and Fragrances of Cannabis.

“Medicinal cannabis” is defined as the use of cannabis-based products for the treatment of an illness. Investigations of cannabis compounds in psychiatric and neurological illnesses primarily focus on the major cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), which are hypothesised to benefit multiple illnesses manifesting cognitive impairment, neurodegeneration and neuro-inflammation, as well as chronic pain, epilepsy and post-traumatic stress disorder, respectively. The cannabis plant contains >500 compounds, including terpenes responsible for the flavour and fragrance profiles of plants. Recently, research has begun providing evidence on the potential use of certain plant-derived terpenes in modern medicine, demonstrating anti-oxidant, anti-inflammatory, and neuroprotective effects of these compounds. This review examined the effects of two key terpenes, pinene and linalool, on parameters relevant to neurological and psychiatric disorders, highlighting gaps in the literature and recommendations for future research into terpene therapeutics. Overall, evidence is mostly limited to preclinical studies and well-designed clinical trials are lacking. Nevertheless, existing data suggests that pinene and linalool are relevant candidates for further investigation as novel medicines for illnesses, including stroke, ischemia, inflammatory and neuropathic pain (including migraine), cognitive impairment (relevant to Alzheimer's disease and ageing), insomnia, anxiety, and depression. Linalool and pinene influence multiple neurotransmitter, inflammatory and neurotrophic signals as well as behaviour, demonstrating psycho-activity (albeit non-intoxicating). Optimising the phytochemical profile of cannabis chemovars to yield therapeutic levels of beneficial terpenes and cannabinoids, such as linalool, pinene and CBD, could present a unique opportunity to discover novel medicines to treat psychiatric and neurological illnesses; however, further research is needed.

Molecular basis for ligand modulation of the cannabinoid CB1 receptor

The cannabinoid CB1 receptor is the most abundant G protein coupled receptor (GPCR) in the central nervous system, which mediates the functional response to endocannabinoids and Cannabis compounds. A variety of ligands for CB1 receptors have been developed as promising drug candidates for the treatment of neurological disorders. New high-resolution structures of CB1 receptor in different functional states have significantly improved our molecular understanding of CB1 ligand interactions, selectivity, receptor activation and allosteric modulation. These advances have paved the way for development of novel ligands for different therapeutic applications. In this review, we describe the structural determinants for modulation of CB1 receptors by different types of ligands, as well as the differences between CB1 and its homologous, the CB2 receptor. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

Physiologically-based pharmacokinetic model for predicting blood and tissue tetrahydrocannabinol concentrations

Background and ObjectiveThe introduction of cannabis as a legalized recreational drug in Canada has led to significant changes in public health policy. Tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and its absorption, distribution, metabolism, and elimination are poorly understood. The use of THC can impair an individual's ability to operate a motor vehicle, leading to an increased risk of accidents. Thus, additional research must be conducted to gauge the inter-individual differences in effect and duration of THC's effect. MethodsIn this study, a comprehensive whole-body physiologically-based pharmacokinetic (PBPK) model for THC metabolism was developed to track blood THC concentrations accounting for interindividual variations such as age, sex, body composition, bioavailability and drug metabolizing enzyme (DME) polymorphisms after various dosages. This model was fitted and validated with clinical human cannabis smoking data. ResultsUsing this model, we found effects of various factors on THC concentrations in different tissue compartments, and that the wild-type form of Cytochrome P450 2C9 (CYP2C9) DME showed faster metabolism of THC than other isoforms. The nature of the our PBPK model allowed for the investigation of non-blood compartments as well. To gauge the effects on driving, we compared the Standard Deviation of Lateral Position under the effects of THC and ethanol, and found that ethanol has a stronger but shorter-lasting effect. ConclusionWe anticipate that this model can be used to better predict the effects of a “standard THC unit” and help advise public health policies for safe cannabis usage.

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes.

Estimating Cannabis Involvement in Fatal Crashes in Washington State Before and After the Legalization of Recreational Cannabis Consumption Using Multiple Imputation of Missing Values.

The government of Washington state legalized recreational cannabis consumption in December 2012. We used data on all drivers involved in fatal crashes in Washington in the years 2008-2019 (n=8,282) to estimate prevalence in fatal crashes of drivers with ∆9-tetrahydrocannabinol (THC; the main psychoactive compound in cannabis) in their blood before and after legalization. However, nearly half of the drivers were not tested for drugs; we therefore used multiple imputation to estimate THC presence and concentration among them. We used logistic regression followed by marginal standardization to estimate the adjusted prevalence of THC-positive drivers after legalization relative to what would have been predicted without legalization. In the combined observed and imputed data, the proportion of drivers positive for THC was 9.3% before and 19.1% after legalization (adjusted prevalence ratio: 2.3, 95% confidence interval: 1.3, 4.1). The proportion of drivers with high THC concentrations increased substantially (adjusted prevalence ratio: 4.7, 95% confidence interval: 1.5, 15.1). Some of the increased prevalence of THC-positive drivers might have reflected cannabis use unassociated with driving; however, the increased prevalence of drivers with high THC concentrations suggests an increase in the prevalence of driving shortly after using cannabis. Other jurisdictions should compile quantitative data on drug test results of drivers to enable surveillance and evaluation.