ArticleLiterature Review

Ashton CH. Pharmacology and effects of cannabis: A brief review. Br J Psychiatry 178: 101-106

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Abstract

Increasing prevalence of recreational cannabis use among the young population has stimulated debate on the possible effects of acute and longterm use. To highlight recent knowledge of mechanisms of action, effects on psychomotor and cognitive performance, and health risks associated with cannabis consumption. A brief review of recent literature on the prevalence of recreational cannabis use, the potency of modern cannabis preparations and the pharmacological actions of cannabis. Cannabinoids derived from herbal cannabis interact with endogenous cannabinoid systems in the body. Actions on specific brain receptors cause dose-related impairments of psychomotor performance with implications for car and train driving, aeroplane piloting and academic performance. Other constituents of cannabis smoke carry respiratory and cardiovascular health risks similar to those of tobacco smoke. Cannabis is not, as widely perceived, a harmless drug but poses risks to the individual and to society.

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... Marijuana is prepared from the dried flowering tops and leaves of the plant. Hashish consists of dried cannabis resin and compressed flowers [1]. Cannabis preparations contains more than 70 cannabinoids [2]. ...
... Cannabis preparations contains more than 70 cannabinoids [2]. One of these, 9 -tetrahydrocannabinol ( 9 -THC) which is found in a resin that covers the flowering tops and upper leaves of the female plant, is believed to be responsible for the psychomimetic properties of marijuana or hashish [1,3,4]. Other cannabinoids include Cannabidiol (CBD), cannabinol, tetrahydrocannabivarin, and cannabichromene, with THC and cannabidiol accounting for 95% of marijuana's active ingredients [2,5]. ...
... Other cannabinoids include Cannabidiol (CBD), cannabinol, tetrahydrocannabivarin, and cannabichromene, with THC and cannabidiol accounting for 95% of marijuana's active ingredients [2,5]. 9 -THC acts at the cannabinoid CB1 receptor to produce a wide-range of biological and behavioral responses e.g., euphoria and relaxation, perceptual alterations, time distortion, intensification of ordinary sensory experiences and increased appetite [1,4]. Cannabinoids have been shown to mediate their effects by interacting with two subtypes of G-proteincoupled cannabinoid (CB1 and CB2) receptors with *Address correspondence to this author at the Department of Toxicology and Narcotics, National Research Centre, Tahrir St., Dokki, Cairo, Egypt; Fax: 202-33370931; E-mail: omasalam@hotmail.com ...
Article
The aim of this study was to investigate the effect of repeated administration of Cannabis sativa extract on some biochemical, immunological parameters, on DNA damage and on brain and liver histology in the rat. Rats received either saline or Cannabis sativa at 5, 10 or 20 mg/kg (expressed as ?9-tetrahydrocannabinol), intraperitoneally daily for 30 days. Cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total proteins, glucose were determined in serum. DNA fragmentation was measured in the liver. The level of DNA damage of peripheral blood mononuclear cells (PBMCs) was evaluated by alkaline single cell gel electrophoresis (comet assay). Brain and liver histopathology and caspase-3 immunohistochemistry were performed. Cannabis treatment resulted in increased cholesterol (41.2% by 20 mg/kg cannabis) and triglycerides (17.8-31.8% by 10-20 mg/kg cannabis). HDL-C decreased by 21.9-38.4% while LDL-C increased by 14.7-174.7% by 10-20 mg/kg cannabis. Total proteins were unaltered but glucose increased by 34.2-53.3% by 10-20 mg/kg of cannabis. CD4 increased by 16.6-19.5% by 10-20 mg/kg cannabis. Liver DNA fragmentation increased by 16.7% after cannabis at 20 mg/kg. The comet percentage of PBMCs was higher after 5, 10 and 20 mg/kg cannabis (7.0 ± 0.36, 9.0 ± 0.92 and 21.0 ± 0.97) than that in saline control group (5 ± 0.36). Cannabis caused dark neurons, decreased size of nuclei, cellular infiltration and increased caspase-3 immunoreactivity. In the liver, cannabis treatment was associated with fibrosis, vacuolar degeneration, cellular infiltration in the portal area, dilatation of portal vein and positive reaction to caspase-3 antibody. These effects of cannabis were dose-dependent.
... Cannabis induces pleasurable feelings such as euphoria, excitement and relaxation [2]. These psychoactive effects are mainly attributed to the main component of cannabis, ∆-9-tetrahydrocannabinol (THC) [3]. Various synthetic cannabinoids (SCBs) have been developed to mimic the effects of THC. ...
... The average number of infusions was significantly higher in the Mepirapim groups (0.003, 0.01 and 0.03 mg·kg −1 ·inf −1 ) compared with the vehicle group ( Figure 2B, F (3,16) = 5.57, p < 0.05). Two-way ANOVA results revealed statistically significant effects of drug treatment (F (3,16) = 5.57, p < 0.05) and day (F (6,96) = 17.35, p < 0.05), but there was no significant effect of their interaction (F (18,96) = 1.31, p = 0.2). ...
... Two-way ANOVA results revealed statistically significant effects of drug treatment (F (3,16) = 5.57, p < 0.05) and day (F (6,96) = 17.35, p < 0.05), but there was no significant effect of their interaction (F (18,96) = 1.31, p = 0.2). Similarly, the average number of active lever presses was significantly higher in the Mepirapim groups (0.003, 0.01 and 0.03 mg·kg −1 ·inf −1 ) compared with the vehicle group ( Figure 2C, F (3,16) = 4.05, p < 0.05). Two-way ANOVA revealed statistically significant effects of drug treatment (F (3,16) = 4.05, p < 0.05) and day (F (6,96) = 22.6, p < 0.05), but there was no significant effect of their interaction (F (18,96) = 1.01, p = 0.46). ...
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Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.
... Kannabinoidlerinin yağda kolay çözündüğü bilindiği için, vücudun yağlı dokularında birikmekte ve birkaç gün içerisinde vücuda tekrar salınımı gerçekleşmektedir. Vücuttan tamamen temizlenebilmesi ise yaklaşık 30 gün sürmektedir (Ashton, 2001). ...
... En göze çarpan etkisinin kişinin öznel iyi oluşunu arttırdığı olduğu görülmektedir. Kullanımıyla birlikte, kaygı, huzursuzluk ve depresif belirtilerde azalma görülür (Ashton, 2001). İrdelenen çalışmalara göre, esrar kullanımının sebebinin genellikle yalnızca keyif verme özelliğinden kaynaklandığı bildirilmektedir (Webb, Ashton, Kelly ve Kamali, 1996). ...
... Ek olarak, algıda ve bilişte bozulmalara ve psikomotor işlevlere etki etmektedir. Zararın sigaraya göre fazla olduğu durumlarda, esrar dumanının ciğerlere uzun ve derin soluklarla çekilmesi ve filtresiz içme gibi kullanım farklarının etkili olduğu düşünülmektedir (Ashton, 2001). Bronşit ve anfizem gibi hastalıklar için ise, kronik esrar kullanımında günde 3-4 kenevir sigarasının, günde 20 ya da daha fazla tütün sigarasına denk olduğu gösterilmiştir (Benson ve Bentley, 1995;aktaran Udum, 2018). ...
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İnsan yaşamını etkileyen savaş, göç, kaza, cinsel ve fiziksel istismar, ani beklenmedik ölümler ve ciddi hastalıklar gibi travmatik olayların birey ve toplum hayatı üzerinde önemli bir etkisinin olduğu açıktır. Yaşanan travmatik olayla birlikte biyo-psiko-sosyal gelişimi sekteye uğrayan çocuk ve bireyin yaşadığı dünyayla baş etmesi güçleşmektedir. Travmanın olumsuz etkilerinden kurtulamayan çoğu birey yeni psikiyatrik sorunlarla baş etmek zorunda kalmakta ve ikincil travmalara daha açık hale gelmektedirler. Sıradan yaşam akışını bozan ve bireyin dünyayı, kendini algılamasında sağlıksız duygu ve bilişler ortaya çıkaran travmatik deneyimlerin ardından en sık görülen psikiyatrik bozukluk Travma Sonrası Stres Bozukluğudur. Madde ve alkol kullanımının stresle başa çıkmada bir yol olduğu, başa çıkma tutumlarının madde kullanma eğilimi ile anlamlı ilişkilere sahip olduğu daha önceki çalışmalarda bildirilmiştir. İlgili kitap yalnızca dünya genelinde gittikçe büyüyen madde kullanım bozukluğunu ele almamaktadır. Travma ve madde kullanım bozukluğu arasındaki ilişkiyi ve bu ilişkiye yönelik tedavi yöntemlerini irdeleyen bu kitapta merak ettiklerinizi bulabilirsiniz.
... The reason for therapeutic purpose in ancient times lies in the chemical in cannabis and cannabinoids have been used for medicinal purposes [1]. Cannabis has psychoactive substance as THC and CBD where both of the chemicals act on endocannabinoid system [2]. ...
... However, with rapid introduction, this has led to misunderstanding and debate about cannabis. For example, 1) believing that every disease can be cured with cannabis, 2) the popularity of illegal cannabis over the social media, and, 3) the application of cannabis towards ineligible patients with little or no evidence supporting the treatment [2]. Nowadays, stores and shops are increasingly using cannabis in food and beverages. ...
Article
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Cannabis related products are frequently found in Thailand because Cannabis sativa had passed the law in 2018. This study used cross-sectional survey method aimed to investigate Thai people knowledge and perspectives towards the utilization of cannabidiol products. The survey was done by a set of online questionnaires constructed by the researcher and tested content validity by experts and reliability by Cronbach’s alpha. The results showed that there were 470 participants with female majority (57.9%) and aged between 41 – 60 years old (37.0%). 42.8% of them had experience of using cannabinol products, which were for only food and drinks (21.29%), cannabinol oil sublingually (18.32%), massage oil (3.96%), respectively. The mean knowledge regarding cannabinol product use and effects was 6.55 out of 13 (SD±2.95) and mean perspectives toward cannabinol product use was 8.82 out of 12 (SD±2.32). Moreover, I found significant correlation between perspective and experience of cannabinol product use (p<0.001) as well as gender (p<0.001). Thai people have knowledge on cannabis but with limited extent especially side effect and toxicity of cannabinol substances and observed to hold a positive attitude towards cannabidiol products usage.
... Synthetic cannabinoids Δ9-tetrahydrocannabinol (THC) and other cannabinoids are distributed differently in the brain, with high concentrations in the neocortical, limbic, sensory, and motor areas. Cannabis affects almost every system in the body; acts as anxiolytic, sedative, analgesic, and psychedelic agent; stimulates appetite; and has systemic effects [130,131]. ...
... Chronic marijuana smoking is associated with bronchitis and emphysema. At high doses, the effects can change and (i) lead to recent memory loss and difficulty performing tasks that require mental performance, (ii) cause anxiety, and (iii) trigger or aggravate a psychotic condition [130]. Synthetic cannabinoids comprise different products with chemical structures that resemble the structure of THC ( Figure 5), the primary psychoactive principle of natural cannabis. ...
Article
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Correct identification of substances is essential to understand drug use and trafficking trends and guide measures for harm reduction and treatment. Two steps are needed to verify the nature of a substance properly: a presumptive test and a confirmatory test. There are presumptive tests which presents deficiencies, such as providing false-positive and false-negative results. Confirmatory tests are more reliable, but they are more expensive. With the appearance of New Psychoactive Substances (NPS), identifying and characterizing illicit substances has become more challenging. This paper focuses on presenting information about NPS characteristics and analysis. For this purpose, we have reviewed the literature to address the main aspects of five groups of NPS: amphetamine-type stimulants, synthetic cannabinoids, N-methoxybenzyl-methoxyphenylethylamine (NBOMe), synthetic opioids, and benzodiazepines. We present the main characteristics of each group and certain aspects of presumptive and confirmatory tests regarding these groups. Our findings show obstacles in developing methodologies that can correctly identify these substances, and problems can increase as new structures appear. This information can be helpful to drive research into identifying NPS and inform law enforcement and law practitioners about the main characteristics of each group and the main questions involving their identification.
... Regarding the potency of cannabis, it has been steadily increasing decades before the enactment of any cannabis regulations, transitioning from an approximate 2% of delta-9-tetrahydrocannabinol ( 9 -THC) in 1970, to close to 15% in 2016 (55). Stronger potency of 9 -THC content in cannabis products is vital to monitor, as it is most likely the main component responsible for the psychological, cognitive and health harms of cannabis (78,79). We found no comparative and longitudinal study that has evaluated 9 -THC potency changes before, and subsequent to, RML implementation. ...
Article
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Background: Ineffective cannabis regulatory frameworks such as prohibition have sparked interest in alternative solutions to reduce individual and societal harms. While it has been suggested that the recreational legalization process has yielded early successes, the relatively recent implementation of the novel policies has provided a modest time frame for a truly thorough establishment and assessment of key population-level indicators. The following systematic review focuses on identifying the downstream public health sequelae of cannabis legalization policies, including parameters such as cannabis consumption rates, hospitalization rates, vehicular accidents and fatalities, criminal activity, and suicidal behaviours, as well as other substance use trends. Methods: An exhaustive search of the MEDLINE and Google Scholar databases were performed to identify high-quality (1) longitudinal studies, which (2) compared key public health outcomes between regions which had and had not implemented recreational cannabis legalization (RML) policies, (3) using distinct databases and/or time frames. Thirty-two original research articles were retained for review. Results: Adult past-month cannabis consumption (26+ years) seems to have significantly increased following RML, whereas young adult (18-26 years) and adolescent (12-17 years) populations do not show a significant rise in past-month cannabis use. RML shows preliminary trends in increasing service use (such as hospitalizations, emergency department visits, or poisonings) or vehicular traffic fatalities. Preliminary evidence suggests that RML is related to potential increases in serious/violent crimes, and heterogeneous effects on suicidal behaviours. While the research does not illustrate that RML is linked to changing consumptions patterns of cigarette, stimulant, or opioid use, alcohol use may be on the rise, and opioid prescribing patterns are shown to be significantly correlated with RML. Conclusion: The current data supports the notion that RML is correlated with altered cannabis consumption in adults, potentially increased criminal activity, and a decline in opioid quantities and prescriptions provided to patients. Future work should address additional knowledge gaps for vulnerable populations, such as individuals with mental health problems or persons consuming cannabis frequently/at higher THC doses. The effects of varying legalization models should also be evaluated for their potentially differing impacts on population-level outcomes.
... Cannabis contains approximately 400 distinct chemical compounds (phytochemicals), including over 100 cannabinoids, the most prominent being ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) [20]. THC exerts its pharmacological activity mainly by engaging with type-1 and type-2 cannabinoid receptors, namely CB1 and CB2 receptors. ...
Article
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Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits. The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that “no drugs have established efficacy in treating or managing EUPD”, and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers. Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist. Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.
... Several theories have been proposed regarding why cannabis may exert a positive effect on sexual function. Cannabis has been shown to decrease anxiety and inhibition and increase sociability [20]. A study by Sumnall et al. in 2007 found that the second most frequently reported association between drug use and sex was the facilitation of a sexual encounter [21]. ...
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Purpose of Review To evaluate the medical literature regarding the effects of cannabis use on female sexual function in order to provide healthcare professionals with a summary of the most recent data. Recent Findings Limited data has shown that there is a correlation between cannabis use and an improvement in female sexual function in some settings at moderate doses. Cannabis use at moderate doses may positively affect several domains of sexual function, such as orgasm, libido, and arousal, dissimilarly. Cannabis use at high doses may have negative effects on female sexual function. Summary Small studies of poor quality have determined that the use of moderate amounts of cannabis during the sexual experience may improve female sexual function. However, further research is needed, specifically randomized, placebo-controlled trials, to determine the effects of cannabis on different domains of sexual experiences as well as the sexual experience as a whole. Current data has shown that cannabis may have both positive and negative effects depending on the dosage, frequency of use, and domain of sexual experience in question. Nonetheless, with cannabis becoming legalized and used frequently in more states, it is imperative that we understand its effects on female sexuality.
... One of such insects is honey bees. positive effects of hemp extracts have been described many times in relation to diseases such as depression, epilepsy, Alzheimer's, appetite disorders, as an aid in the treatment of cancer and in multiple sclerosis [27][28][29][30][31]. There are also interesting studies in which the hemp extract helped to regenerate damaged brain tissues in rats, damaged as a result of the action of chemical agents [32]. ...
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We examined how CBD extract influences the activity of the immune system in the hemolymph of honey bees in the hive test. The bees were divided into 3 groups: (CSy) bees fed with CBD in sugar syrup with glycerin; (CSt) cotton strip with CBD placed in hive bees fed pure sugar syrup, (C) control bees fed sugar syrup with glycerin. CBD extract increased the total protein concentrations, proteases and their inhibitor activities in each age (the except for acidic protease activities in the 21st and 28th day and alkaline protease inhibitor activities in the 28th day in CSt group) in comparison with group C. In the groups with the extract there was also an increase in the enzymatic marker activities: ALP, AST (decrease on day 28 for CSt), ALT; and non-enzymatic marker concentrations: glucose; triglycerides; cholesterol and creatinine. The urea acid and albumin concentrations were lower in CSy and CSt groups compared to the C group (higher concentration of albumin was displayed by control bees). Higher activities/concentrations of most of biochemical parameters were obtained in the CSy compared to the CSt and C. CBD supplementation can positively influence workers’ immune system.
... In this regard, there is ample evidence that, in patients with pre-existing psychotic disorders, the use of SCs can worsen existing psychotic symptoms or facilitate the appearance of new ones [60][61][62][63]. Acute cannabinoid consumption affects cognitive integrity, inducing bizarre thinking, depersonalization [64], and psychotic symptoms [65]; similar effects result in disorders such as psychosis, depression, mania, and anxiety in prolonged consumption [66,67]. In acute intoxication, cognitive skills such as learning new information, prolonged attention, executive functions, and psychomotor integrity are also impaired [68,69]. ...
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Background. Synthetic cannabinoid-related acute kidney injury represents an increasingly important public health issue due to the diagnostic challenges given by low clinical suspicion of the disease and the frequent undetectability in routine drug tests. Methods. A systematic literature search on PubMed was carried out until 31 January 2022. Case reports, case series, retrospective and prospective studies, as well as reviews on acute kidney injury related to the consumption of synthetic cannabinoid were searched. Results. The systematic review process selected 21 studies for a total of 55 subjects with synthetic cannabinoid-induced acute kidney injury. Renal damage was demonstrated by elevated serum creatinine levels in 49 patients (89%). On renal ultrasound, the most frequent finding was an increase in cortical echogenicity. Renal biopsy, performed in 33% of cases, revealed acute tubular damage, acute tubulointerstitial nephritis, and acute interstitial nephritis, in decreasing order of frequency. Conclusion. Prompt identification and treatment of synthetic cannabinoid-related acute kidney injury represent a sensitive public health goal both for the acute management of damage from synthetic cannabinoids and for the prevention of chronic kidney disease.
... Adverse effects remain low at 4% in our study. Patients need to be informed of the dizzy, light-headed, and "funny" feeling of marijuana, which is similar to reported literature [13][14][15][16]. Only one patient had a severe adverse effect due to dizziness causing a fall. ...
Article
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Objectives: Medical marijuana is a symptom treatment option for palliative cancer patients; however, its useful applications remain limited. The goals of this study were to review the characteristics of patients who received medical marijuana under our ambulatory palliative care program and to determine barriers to access and use of medical marijuana in this population. Methods: This study was a retrospective analysis of patients who were enrolled in the medical marijuana registry through the ambulatory palliative care department at Upstate Cancer Center. Data from June 2017 to June 2020 were analyzed. Patients were included if they had a diagnosis of cancer, were certified by a qualified practitioner in the New York Medical Marijuana Program, and received care at Upstate Medical University. Patients were excluded if no marijuana certificate was found or if they transferred care. Results: The study population was 184 patients. Ninety-three patients (51.5%) received at least one prescription from a New York licensed marijuana dispensary while 72 (39.13%) were certified but never obtained any medical marijuana. For patients who took at least one dose of medical marijuana, 48.14% experienced an improvement in pain, 44.95% used fewer opioids, and 85.11% had an improvement in at least one symptom. Adverse effects were low at 3.72%. Conclusion: Medical marijuana has an important role in the palliation of symptoms in advanced cancers with few adverse effects. There are still many barriers to effective use. More prospective research is needed to optimize delivery and dosing.
... As a result, if the plant contains THC it has a high illicit use and interest, therefore its cultivation is prohibited by national laws [4]. Among the illicit cannabis preparations, we can mention the following: marijuana (a mixture of leaves, flowers and seeds of the hemp plant), hashish (obtained from unfertilized buds) and also oils that can be easily prepared [5]. ...
Article
The plant Cannabis sativa L., is a dioecious species belonging to the familie Cannabaceae, natived to Central Asia, with a long history. The first data on the use of this plant date from 2500 BC [1]. In Europe, the plant began to be cultivated between the 14th and 15th centuries, during which time it played an important role in agriculture, helping economic growth. In the Western world, it was increasingly used in nineteenth-century medicine [2]. It was cultivated worldwide in the 18th and 19th centuries as a source of fiber, food and oil. The main ingredients of hemp oils are phytocannabinoids such as cannabidiol (CBD) and terpenoids. The main active compound in the plant is d-9-tetrahydrocannabinol (D-9-THC), which is largely responsible for the psychoactive effects that made Indian hemp famous. While d9-THC has returned to the attention of researchers, other constituents of cannabis, such as CBD, have been studied in recent years for its therapeutic uses [3].Hemp has gained substantial attention in recent years due to the fact that an increasing number of countries legalized Cannabis for medicinal and recreational use. Taking into account the current legislation, there are small differences in the amounts of THC allowed in hemp preparations, ranging from 0.05 to 0.6%. As a result, if the plant contains THC it has a high illicit use and interest, therefore its cultivation is prohibited by national laws [4]. Among the illicit cannabis preparations, we can mention the following: marijuana (a mixture of leaves, flowers and seeds of the hemp plant), hashish (obtained from unfertilized buds) and also oils that can be easily prepared [5].Globally, the use of cannabis-derived preparations in the medical field has a long history. In the twentieth century, consumption became limited until March 30, 1961, when the Cannabis plant and cannabinoids were classified in the Single UN Convention as non-medical substances. In recent years, however, patients' interest in the use of cannabinoids has increased [6].CBD, the main phytocannabinoid obtained from Cannabis sativa, brings new hope to patients suffering from a wide range of conditions: pain, inflammation, epilepsy, sleep disorders, multiple sclerosis, anorexia, schizophrenia, cancer.
... Acute cannabis use can adversely affect cognitive integrity by inducing bizarre thoughts, feelings of depersonalization [47] and schizophrenia-like symptoms [48]. These acute effects are well demonstrated to hesitate in drug-induced psychosis and other psychiatric problems such as depression, mania, and anxiety in protracted consumption [43,49]. ...
Article
Background Although cannabinoids consumption represents a current social and health problem, especially in a historical context characterized by an open orientation for recreational and therapeutic purposes, risks regarding neurotoxicity of such substances is a frequently overlooked issue. Objective The present systematic review aims to summarize the available evidence regarding the mechanism of cannabinoids-induced brain damage as a substrate of neurological, psychiatric, and behavioral effects. Another objective is to provide support for future investigations and for legislative choices. Methods The systematic literature search through PubMed and Scopus and a critical appraisal of the collected studies were conducted. Search terms were “(("Cannabinoids" OR "THC" OR "CBD") AND "Brain” AND ("Damage" OR "Toxicity"))” in title and abstracts. Studies examining toxic effects on the brain potentially induced by cannabinoids on human subjects were included. Results At the end of the literature selection process, 30 papers were considered for the present review. The consumption of cannabinoids is associated with the development of psychiatric, neurocognitive, neurological disorders and, in some cases of acute consumption, even death. In this sense, the greatest risks have been related to the consumption of high-potency synthetic cannabinoids, although the consumption of phytocannabinoids is not devoid of risks. Conclusion The research carried out has allowed to highlight some critical points to focus on, such as the need to reinforce the toxic-epidemiologic monitor of new substances market and the importance of information for both medical personnel and general population, with particular attention to the mostly involved age groups.
... A pooled analysis of three Moroccan case-control studies also found an elevated risk of lung cancer among cannabis smokers who smoked tobacco (Berthiller et al. 2008). Smoking cannabis resulted in malignant changes in the respiratory tract, oropharyngeal cancers, and myocardial infarction (Ashton 2001). Cannabis smoking increased the risk of nasopharyngeal carcinoma in North Africa (Feng et al. 2009). ...
Chapter
Ayurveda has delineated a unique classification entitled ‘Upavisha varga’ comprising of certain semi-poisonous medicinal plants. Bhanga (Cannabis) is one amongst them in this category depicting its narcotic nature from Sanskrit synonyms. Bhanga has been in use since the Vedic age under the controversial plant of Soma that had special importance due to its mystical effects on the brain. All the texts of Ayurveda have described Bhanga in detail of its pharmacological properties, indications, various dosage forms, doses, pharmacovigilance aspects, and its extensive use in Indian Alchemy. The following review throws light on the occurrence and usage of Bhanga in excerpts from classical texts of Ayurveda from a pharmacological and pharmaceutical point of view thus, providing a rationale for its safe medical usage.KeywordsAyurveda Bhanga CannabisClassicalEvidenceReviewUpavishaVijaya
... A pooled analysis of three Moroccan case-control studies also found an elevated risk of lung cancer among cannabis smokers who smoked tobacco (Berthiller et al. 2008). Smoking cannabis resulted in malignant changes in the respiratory tract, oropharyngeal cancers, and myocardial infarction (Ashton 2001). Cannabis smoking increased the risk of nasopharyngeal carcinoma in North Africa (Feng et al. 2009). ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... A pooled analysis of three Moroccan case-control studies also found an elevated risk of lung cancer among cannabis smokers who smoked tobacco (Berthiller et al. 2008). Smoking cannabis resulted in malignant changes in the respiratory tract, oropharyngeal cancers, and myocardial infarction (Ashton 2001). Cannabis smoking increased the risk of nasopharyngeal carcinoma in North Africa (Feng et al. 2009). ...
Chapter
Cannabis has been used for recreation and in traditional medicine in Africa for centuries since its introduction by Arab traders from India. Though Cannabis contains a variety of phytochemicals, its psychotropic activity is attributed mainly to the psychoactive compound Δ-9-tetrahydrocannabinol (Δ-9-THC). Additionally, cannabidiol (CBD) and cannabinol (CBN) are two main non-psychoactive cannabinoids present in cannabis/marijuana. Cannabis leaves are predominantly used in herbal preparations to manage both human and animal ailments in Africa and elsewhere. Among humans, cannabis leaves are used to treat over 20 ailments, mainly including asthma, measles, diabetes, dysentery, tuberculosis, cancer, cough, malaria, and also as an abortifacient. In animals, Cannabis is used to manage over 15 ailments, with the common ones being: East Cost fever, heartwater, pneumonia, dysentery, and trypanosomiasis. Pharmacological research has highlighted the benefit of Cannabis in managing chronic diseases like cancer, Alzheimer’s disease, multiple sclerosis, and diabetes mellitus. Despite its medicinal uses, prolonged use of unprescribed Cannabis in humans results in social, psychological, physiological, and medical risks. This calls for regulated use and further pharmacological studies to establish efficacious but safe dosages. This chapter focuses on traditional ethnomedicinal uses in humans, ethnoveterinary uses, medical marijuana, and risks associated with cannabis use in Africa.KeywordsMedical cannabis/marijuanaPsychoactiveCannabinoidsEthnomedicineAfrica
... Hemp is also used as a supplement in treating cancer or in counteracting the effects of chronic stress/trauma [22]. Its positive effect is attributed to the active substances from the group of cannabinoids (cannabidiol (CBD), cannabichromene, cannabigerol, ∆9-tetrahydrocannabinol (THC), and cannabinol) and the content of phytochemicals [21,23]. During in vitro studies with human cell lines, the aqueous cannabis extract showed a protective effect against the cytotoxicity and apoptosis of the tested fibroblasts and keratinocytes [24]. ...
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We examined the effect of hemp extract on the activity of the antioxidant system (catalase, peroxidase, glutathione, superoxide dismutase, and total antioxidant capacity) in the hemolymph of adult honey bees (Apis mellifera). The bees were divided into three groups: (1) an experimental group fed with pure sugar syrup with cotton strips soaked with hemp extract put inside the cage; (2) an experimental group fed with a mixture of sugar syrup with hemp extract; and (3) a control group fed with a mixture of sugar and a water–glycerine solution. Hemolymph samples were collected on the 1st day of this study and then every week, until all bees in the group died. The activities of all antioxidant enzymes were higher for the experimental groups, compared to those for the control group. The highest antioxidant activities were noted in the group supplemented with cannabis with the use of syringes. Supplementation with hemp also increased the lifespan of bees in this group compared to that of the bees consuming only sugar syrup (control: 35 days), with 49 and 52 days for groups of cannabis on strips and in syrup, respectively. Hemp extract, thanks to its antioxidant properties, increased the activities of key antioxidant enzymes that protect the bee’s organisms against free radicals and thus delay the aging processes.
... However, most of them had important limitations [82][83][84][85]. For example, there is no differentiation between testing for tetrahydrocannabinol (THC) and its core metabolite (THC-COOH) [84], a water-soluble substance easily excreted [86] and detectable in body fluids giving a positive test for cannabis use for several days (or even weeks in heavy users), in absence of active component [87,88], wrongly believing that the person is DUIC. Additionally, in the terminal elimination phase of the metabolite, a single subject may produce consecutive specimens that could be tested positive, negative, and again positive, making it very hard to differentiate a new episode of consumption from a previous cannabis exposure [89]. ...
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Driving under the influence of alcohol has been shown to increase the risk of involvement in road traffic collisions (RTCs) however, less is known about the effects of illicit drugs, and a clear correlation between drug concentrations and RTC risk is still debated. The goal of this narrative review is to assess the current literature regarding the most detected psychoactive drugs in RTC (ethanol, amphetamines, cannabis, opioids and cocaine), in relation to driving performance. Evidence on impaired driving due to psychoactive substances, forensic issues relating to the assessment of the impact of drugs, blood cut-off values proposed to date as well as scientific basis for proposed legislative limits are discussed. At present there is no unequivocal evidence demonstrating a clear dose/concentration dependent impairment in many substances. Per se and zero tolerance approaches seem to have negative effect on drugged driving fatalities. However, the weight of these approaches needs further investigation.
... Journal of Cannabis Research (2022) 4:12 ones (Grotenhermen 2003). THC is responsible for the psychoactive property of cannabis and causes euphoria, drowsiness, hallucinations, and temporal distortions (Ashton 2001). CBD, another significant cannabinoid, on the other hand is not psychoactive; however, it has neuroprotective, sedating, anti-inflammatory, and analgesic impacts (Chakravarti et al. 2014;Hill 2019;Klimuntowski et al. 2020;Mechoulam et al. 2007). ...
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Background Δ ⁹ -tetrahydrocannabinol (THC) is the main psychoactive component and one of the most important medicinal compounds in cannabis. Whether in human body fluids and breath or in laboratory and field samples, rapid and easy detection of THC is crucial. It provides insights into the impact of THC on human organism and its medicinal benefits, it guides the cannabis growers to determine different stages of the growth of the plant in the field, and eventually it helps scientists in the laboratory to assure the quality of the products and determine their potency or better understand the product development procedures. The significance of fast THC detection in forensic analysis also cannot be overlooked. Electrochemical sensor technologies are currently in the focus of attention for fast, easy, and low-cost detection of THC. Method In this work, we review the recent advances in sensor technologies developed for the purpose of fast and accurate THC detection. The research works performed mostly in the past decade and those detecting THC directly without any derivatization were the main target of this review. The scope of this narrative review was the reports on detecting THC in synthetic samples and plants as well as oral fluid. Results Electrochemical sensor technologies are sensitive enough and have the potential for fast, easy, and low-cost detection of THC for roadside testing, THC trending in growing cannabis plants, THC product development and formulation for medical purposes, etc., and they can provide an alternative for costly chromatography and mass spectrometry-based methods. Conclusion The main challenges facing these sensors, however, are nonspecific interaction and the interference of compounds and species from the matrix. Special requirement for storing sensors modified with antibodies or proteins is another challenge in this field. Preparing long-lasting and reusable sensors is a field worthy of attention.
... Due to the difference in chemical structure, THC and CBD are found to have different pharmacological effects. THC is considered the main psychotropic constituent of cannabis, acting as a partial agonist at cannabinoid type 1 (CB1) and type 1 (CB2) receptors of the endocannabinoid system [3]. CBD is non-psychotropic and interacts with many receptors and proteins other than the CB1 and CB2 receptors in the body [2]. ...
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Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.
... Es inadecuado para uso intravenoso ya que es relativamente insoluble en agua. (5) 1.2 Epidemiología del uso de cannabis a nivel mundial y nacional Globalmente, el conjunto de compuestos más ampliamente utilizados entre las drogas reguladas a nivel internacional es el cannabis. Se estima que el número de individuos que han consumido cannabis podría ser 10 veces mayor que el número de individuos que han consumido cocaína, opiáceos u otras drogas reguladas a nivel internacional. ...
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RESUMEN El cannabis es un grupo de sustancias químicas presentes en la planta Cannabis sativa, conocida común-mente como marihuana. El principal cannabinoide psicoactivo y el más estudiado es el tetrahidrocanna-binol (THC). Es la droga ilegal de mayor uso tanto a nivel nacional como mundial. Globalmente, se esti-ma que cerca de 180 millones de personas la usan, principalmente jóvenes, quienes representan la pobla-ción más vulnerable. Su popularidad se debe en parte a sus efectos depresores del sistema nervioso, entre los cuales se encuentran relajación, sensación de bienestar y alteraciones en la percepción además de los innumerables mitos acerca de sus aplicaciones terapéuticas, entre las cuales se encuentran alivio de dolo-res crónicos, mayor concentración, y, recientemente, se ha comentado sobre el efecto neuroprotector de algunos cannabinoides y su papel en el tratamiento de enfermedades neurodegenerativas, como la enfer-medad de Alzheimer, la Esclerosis Múltiple y la enfermedad de Parkinson, siendo esta circunstancia la razón que justifica la realización de una revisión bibliográfica acerca de los efectos verdaderamente bené-ficos y sustentados científicamente, así como de los efectos neurotóxicos que podrían presentarse a corto y largo plazo, de tal forma que ambos puedan contrastarse para llegar a una conclusión. Cannabis is a group of chemicals present in the Cannabis sativa plant, commonly known as marijuana. The main psychoactive cannabinoid and the most studied is tetrahydrocannabinol (THC). Nationally and globally, it is the most commonly used illegal drug. It is estimated that around 180 million people consume it, mainly young people, who represent the most vulnerable population.
... Considerable variability in terms of sensitivity to the acute effects of cannabis has been found, with cannabis users reporting a wide range of subjective acute effects that are both positive, such as relaxation, happiness and laughter, as well as Brain Sci. 2021, 11, 1240 2 of 18 negative such as anxiety, panic attacks, and, less commonly, paranoia and psychosis-like symptoms [5]. ...
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High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Additionally, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signalling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data were available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/ amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG11–12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/ hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.
Article
Background: The use of cannabis among older adults is increasing in the United States. While cannabis use has been suggested to help alleviate chronic symptoms experienced by older adults, its potential adverse effects may lead to unintended consequences, including increased acute healthcare utilization related to its use. The objective of this study was to examine trends in cannabis-related emergency department (ED) visits in California. Methods: Using data from the Department of Healthcare Access and Information, we conducted a trend analysis of cannabis-related ED visits from all acute care hospitals in California from 2005 to 2019. For each calendar year, we determined the cannabis-related ED visit rate per 100,000 ED visits for adults aged ≥65 utilizing primary or secondary diagnosis codes. We estimated the absolute and relative changes in overall cannabis-related visit rates during the study period and by subgroup, including age (65-74, 75-84, ≥85), race/ethnicity, sex, payer/insurance, Charlson comorbidity index score, and cannabis-related diagnosis code. Results: The cannabis-related ED visit rate increased significantly for adults aged ≥65 and all subgroups (p < 0.001). The overall rate increased from 20.7 per 100,000 visits in 2005 to 395.0 per 100,000 ED visits in 2019, a 1804% relative increase. By race/ethnicity, older Black adults had the highest ED visit rate in 2019 and the largest absolute increase while older males had a higher ED visit rate in 2019 and a greater absolute increase than older women. Older adults with a higher Charlson score had a higher ED visit rate in 2019 and a larger absolute increase during the study period. Conclusion: Cannabis-related ED visits are increasing among older adults in California and are an adverse effect of cannabis use. Asking about cannabis use and providing education about its use should be a part of routine medical care for older adults.
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This chapter reviews the neuroimaging features of the potential effects of cannabis.
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The clinical practice of anesthesia has undergone many advances in the past few years, making this the perfect time for a new state-of-the-art anesthesia textbook for practitioners and trainees. The goal of this book is to provide a modern, clinically focused textbook giving rapid access to comprehensive, succinct knowledge from experts in the field. All clinical topics of relevance to anesthesiology are organized into 29 sections consisting of more than 180 chapters. The print version contains 166 chapters that cover all of the essential clinical topics, while an additional 17 chapters on subjects of interest to the more advanced practitioner can be freely accessed at www.cambridge.org/vacanti. Newer techniques such as ultrasound nerve blocks, robotic surgery and transesophageal echocardiography are included, and numerous illustrations and tables assist the reader in rapidly assimilating key information. This authoritative text is edited by distinguished Harvard Medical School faculty, with contributors from many of the leading academic anesthesiology departments in the United States and an introduction from Dr S. R. Mallampati. This book is your essential companion when preparing for board review and recertification exams and in your daily clinical practice.
Article
Objectives The objective of this retrospective cohort study was to evaluate the associations among preoperative cannabis use, postoperative opioid use, and postoperative outcomes following elective anterior cervical decompression and fusion (ACDF). Methods Patients who underwent one- or two-level ACDF were characterized preoperatively as active cannabis users, former users, or nonusers. Patients were also classified based on history of preoperative opioid use as chronic users, acute users, or nonusers. Groups were compared based on outcomes including the rate of emergency department visits six months postoperatively, rate of readmissions one year postoperatively, rate of reoperation two years postoperatively, and daily postoperative opioid use measured in milligram morphine equivalents (MMEs) at 0-6 months and 6-12 months postoperatively. Results Of the 198 patients included in this study, 13 (6.6%) were active cannabis users, 11 (5.6%) were former users, and 174 (87.8%) were nonusers. The rate of reoperation within two years was 23.1% for active cannabis users, 0% for former users, and 4.0% for nonusers (p=0.0075). The average daily opioid use in MMEs 6-12 months postoperatively was 49.4 for active cannabis users, 4.1 for former users, and 13.3 for nonusers (p=0.0014). For chronic opioid users, acute users, and nonusers, the average daily opioid use in MMEs 6-12 months postoperatively was 39.9, 18.4, and 5.7, respectively (p<.0001). Conclusions History of cannabis use is associated with increased postoperative opioid use and increased rate of reoperation following elective ACDF.
Chapter
The clinical practice of anesthesia has undergone many advances in the past few years, making this the perfect time for a new state-of-the-art anesthesia textbook for practitioners and trainees. The goal of this book is to provide a modern, clinically focused textbook giving rapid access to comprehensive, succinct knowledge from experts in the field. All clinical topics of relevance to anesthesiology are organized into 29 sections consisting of more than 180 chapters. The print version contains 166 chapters that cover all of the essential clinical topics, while an additional 17 chapters on subjects of interest to the more advanced practitioner can be freely accessed at www.cambridge.org/vacanti. Newer techniques such as ultrasound nerve blocks, robotic surgery and transesophageal echocardiography are included, and numerous illustrations and tables assist the reader in rapidly assimilating key information. This authoritative text is edited by distinguished Harvard Medical School faculty, with contributors from many of the leading academic anesthesiology departments in the United States and an introduction from Dr S. R. Mallampati. This book is your essential companion when preparing for board review and recertification exams and in your daily clinical practice.
Chapter
The clinical practice of anesthesia has undergone many advances in the past few years, making this the perfect time for a new state-of-the-art anesthesia textbook for practitioners and trainees. The goal of this book is to provide a modern, clinically focused textbook giving rapid access to comprehensive, succinct knowledge from experts in the field. All clinical topics of relevance to anesthesiology are organized into 29 sections consisting of more than 180 chapters. The print version contains 166 chapters that cover all of the essential clinical topics, while an additional 17 chapters on subjects of interest to the more advanced practitioner can be freely accessed at www.cambridge.org/vacanti. Newer techniques such as ultrasound nerve blocks, robotic surgery and transesophageal echocardiography are included, and numerous illustrations and tables assist the reader in rapidly assimilating key information. This authoritative text is edited by distinguished Harvard Medical School faculty, with contributors from many of the leading academic anesthesiology departments in the United States and an introduction from Dr S. R. Mallampati. This book is your essential companion when preparing for board review and recertification exams and in your daily clinical practice.
Article
Background Preclinical and clinical studies suggest a promising potential of cannabidiol (CBD) for the treatment of substance use disorders (SUD). We therefore aimed to assess the prevalence, patterns, and self-perceived benefits of non-prescription CBD use among SUD patients. Methods A sample of 469 SUD patients treated as inpatients was included to this study. Information on CBD use was assessed by a standardized questionnaire. The sociodemographic and clinical data were extracted from the electronic medical database. Results About one-third of the SUD patients reported that they had used CBD at least once, but only about 9% of them were using CBD on a regular basis for more than a year. More than 40% of those patients using CBD for more than a year reported that CBD helped them to relax and to sleep better, and more than 30% of them reported that it helped them to reduce pain and to feel less anxious. Conclusions Regular use of CBD does not seem to be a common phenomenon among SUD patients, presumably due to its lack of psychotropic effects. However, the results provide a weak indication of self-perceived beneficial effects of long-term CBD use regarding agitation, sleep disorders, anxiety, and pain.
Article
Objective The aim of this study was to determine the association of prenatal marijuana exposure with and without tobacco smoke exposure and small for gestational age (SGA) at birth. Methods We conducted a secondary analysis of the prospective Lifestyle and Early Achievement in Families (LEAF) cohort enrolled from 2010 to 2015. We included singleton nonanomalous liveborn pregnancies. We assessed marijuana use inclusive of any pregnancy urine specimen with a Δ9-THC-COOH concentration of more than 15 ng/mL by mass spectrometry, self-report on questionnaire, and/or electronic health record; and self-reported maternal tobacco use. Because of the high co-frequency of marijuana with tobacco exposure in pregnancy and the known association between tobacco and fetal growth restriction, we modeled the exposure as: both marijuana and tobacco (hereafter “co-use”), only marijuana, only tobacco, and neither (reference). Incidence of SGA in each group was compared with the neither group. The primary outcome was SGA less than 10th percentile, and secondarily less than 5th percentile, using parity-specific definitions per 2017 US natality reference data. Results Among 325 assessed mothers, 46% had neither exposure, 11% had only prenatal marijuana exposure, 20% only tobacco exposure, and 23% co-use exposure. A third (33%) of infants were SGA less than 10th percentile and 20% SGA less than 5th percentile. Marijuana exposure only was associated with an increased risk of SGA less than 10th percentile (43 vs. 26%; adjusted relative risk [aRR]: 1.66; 95% confidence interval [CI]: 1.02–2.69), and SGA less than5th percentile (30 vs. 13%; aRR: 2.26; 95% CI: 1.15–4.47). Tobacco was not associated with SGA less than 10th percentile, but was with SGA less than 5th percentile (26 vs. 13%; aRR: 2.01; 95% CI: 1.13, 3.56). Co-use was not associated with increased SGA risk in multivariate analysis, but was in sensitivity analysis when tobacco use was defined using a cotinine assay rather than self-report (SGA <10th percentile, aRR: 1.97; 95% CI: 1.24–3.15) and (SGA <5th percentile, aRR: 2.03; 95% CI: 1.09–3.78). Conclusion Prenatal marijuana exposure in addition to tobacco may increase the risk of SGA. Given the rising prevalence of marijuana use in pregnancy, further research is warranted to understand how in utero marijuana exposure may impact fetal growth and birthweight with and without tobacco exposure. Key Points
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Background The purpose of this study was to examine the influence of preoperative marijuana use on postoperative opioid use during the first three postoperative days (POD 1–3) after surgery, and on expectations of pain control, resiliency, and quality-of-life scores.Methods All patients presenting to a single institution undergoing elective hand or upper extremity outpatient surgery were asked to complete pre- and postoperative questionnaires. Preoperative questionnaires collected information on demographics, marijuana use, tobacco use, procedure type, self-assessed health, pain control expectations, and EuroQol-5D (EQ-5D) scores. At the first postoperative visit, patients self-reported opioid consumption from POD 1–3. Multivariate linear regression analysis was used to determine which patient characteristics were predictive of greater postoperative opioid consumption during POD 1–3.ResultsSelf-reported marijuana users were younger, less healthy, and more likely to use tobacco compared to non-users. Marijuana users and non-users were comparable in their use of pain medication (including non-opioids), rates of chronic pain diagnoses, and self-reported pain tolerance. EQ-5D scores were lower in marijuana users than non-users (0.64 vs. 0.72). Marijuana users and non-users were prescribed comparable quantities of opioids during the first 14 days after surgery (176 ± 148 vs 115 ± 87). Multiple linear regression analysis revealed that lower preoperative EQ-5D scores, rather than marijuana use, were associated with increased opioid consumption during POD 1–3.Conclusions Preoperative marijuana use was not independently associated with increased opioid use during POD 1–3 after elective hand and upper extremity surgery; instead, an association with lower preoperative EQ-5D scores was identified.Level of EvidenceII, prospective cohort study.
Article
Antiepileptic drugs have been successfully treating epilepsy and providing individuals sustained seizure freedom. However, about 30% of the patients with epilepsy present drug resistance, which means they are not responsive to the pharmacological treatment. Considering this, it becomes extremely relevant to pursue alternative therapeutic approaches, in order to provide appropriate treatment for those patients and also improve their quality of life. In the light of that, this review aims to discuss some innovative options for the treatment of epilepsy, which are currently under investigation, addressing strategies that go from therapeutic compounds to clinical procedures. For instance, peptides derived from animal venoms, such as wasps, spiders, and scorpions, demonstrate to be promising antiepileptic molecules, acting on a variety of targets. Other options are cannabinoids and compounds that modulate the endocannabinoid system, since it is now known that this network is involved in the pathophysiology of epilepsy. Furthermore, neurostimulation is another strategy, being an alternative clinical procedure for drug‐resistant patients who are not eligible for palliative surgeries. This article reviews the most innovative treatments for epilepsy, given the great percentage of drug resistant patients. The topics addressed include neuromodulation, peptides derived from animal venoms, cannabinoids and nanoparticles.
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Background The hypothesis that marijuana availability reduces opioid mortality merits more complete testing, especially in a country with the world's highest opioid death rate and 2nd highest cannabis-use-disorder prevalence. Methods The United States opioid mortality rate was compared in states and District of Columbia that had implemented marijuana legalization with states that had not, by applying joinpoint methodology to Centers for Disease Control and Prevention data. Variables included race/ethnicity and fentanyl-type opioids (fentanyls). Results After the same rates during 2010–2012, the opioid mortality rate increased more rapidly in marijuana-legalizing than non-legalizing jurisdictions (2010–2020 annual pairwise comparison p = 0.003 for all opioids and p = 0.0004 for fentanyls). During the past decade, all four major race/ethnicities in the U.S. had evidence for a statistically-significant greater increase in opioid mortality rates in legalizing than non-legalizing jurisdictions. Among legalizing jurisdictions, the greatest mortality rate increase for all opioids was in non-Hispanic blacks (27%/year, p = 0.0001) and for fentanyls in Hispanics (45%/year, p = 0.0000008). The greatest annual opioid mortality increase occurred in 2020, the first year of the COVID-19 pandemic, with non-Hispanic blacks having the greatest increase in legalizing vs. non-legalizing opioid-death-rate difference, from 32% higher in legalizing jurisdictions in 2019 to more than double in 2020. Conclusions Instead of supporting the marijuana protection hypothesis, ecologic associations at the national level suggest that marijuana legalization has contributed to the U.S.’s opioid epidemic in all major races/ethnicities, and especially in blacks. If so, the increased use of marijuana during the 2020–2022 pandemic may thereby worsen the country's opioid crisis.
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Background Illicit drug use (IDU) is often encountered in patients undergoing elective ambulatory surgical procedures such as endoscopy. Given the variety of systemic effects of these drugs, sedation and anesthetics are believed to increase the risk of cardiopulmonary complications during procedures. Procedural cancelations are common, regardless of the drug type, recency of use, and total dosage consumed. There is a lack of institutional and society recommendations regarding the optimal approach to performing outpatient endoscopy on patients with IDU. Aim To review the literature for current recommendations regarding the optimal management of outpatient elective endoscopic procedures in patients with IDU. Secondary aim is to provide guidance for clinicians who encounter IDU in endoscopic practice. Methods Systematic review of PubMed, CINAHL, Embase, and Google Scholar for articles presenting data on outcomes of elective procedures in patients using illicit drugs. Results There are no clinically relevant differences in periprocedural complications or mortality in cannabis users compared to non-users. Endoscopy in patients with remote cocaine use was also found to have similar outcomes to recent use. Conclusions Canceling endoscopic procedures in patients with recent IDU without consideration of the type of drug, dosage, and chronicity may lead to unnecessary delays in care and increased patient morbidity. Healthcare systems would benefit from additional guidelines for evaluating the patient with recent illicit drug use for acute intoxication and consider proceeding with procedures in the non-toxic population.
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The efficacy of chemotherapy depends on the tumor microenvironment. This microenvironment consists of a complex cellular network that can exert both stimulatory and inhibitory effects on tumor genesis. Given the increasing interest in the effectiveness of cannabis, cannabinoids have gained much attention as a potential chemotherapy drug. Cannabinoids are a group of marker compounds found in Cannabis sativa L., more commonly known as marijuana, a psychoactive drug used since ancient times for pain management. Although the anticancer potential of C. sativa, has been recognized previously, increased attention was generated after discovering the endocannabinoid system and the successful production of cannabinoid receptors. In vitro and in vivo studies on various tumor models have shown therapeutic efficiency by modifying the tumor microenvironment. However, despite extensive attention regarding potential therapeutic implications of cannabinoids, considerable clinical and preclinical analysis is needed to adequately define the physiological, pharmacological, and medicinal aspects of this range of compounds in various disorders covered in this review. This review summarizes the key literature surrounding the role of cannabinoids in the tumor microenvironment and their future promise in cancer treatment.
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Numerous agents with anxiolytic or stimulant effects have the potential to be overused, and their misuse is associated with serious side effects. In Saudi Arabia, the estimated percentage of Saudis who abuse drugs is around 7–8% and the age range is 12–22 years. Methamphetamine, captagon, tramadol, heroin, and cannabis/cannabinoids have been proven to be the most commonly abused drugs in Saudi Arabia, with methamphetamine being at the top of the list. The present study focuses on the chromatographic analytical methods used for the analysis of methamphetamine in combination with commonly abused drugs, aiming to point out the greenest among them. These mixtures have been chosen as they are analyzed periodically and frequently in criminal evidence and forensic medicine. Therefore, the chances of hazards for analysts and the environment are high if the mixtures are not handled appropriately. This study aims to compare 23 chromatographic methods used for the analysis of methamphetamine mixtures in four major combinations, and to assess their greenness by using three greenness assessment tools, namely, NEMI, ESA and AGREE, to recommend the greenest analytical method. The NEMI results were proven to have low discriminating abilities and, accordingly, the comparisons are based on ESA and AGREE scores. The analysis results show that the safest methods with the most eco-friendly results (based on ESA and AGREE) are the GC-MS method proposed by Mohammed et al. to analyze methamphetamine and captagon mixtures (ESA = 79 and AGREE = 0.57), the UHPLC–MS-MS method proposed by Busardò et al. to analyze methamphetamine and cannabis/cannabinoid mixtures (ESA = 78 and AGREE = 0.57), the LC-MS method proposed by Herrin et al. to analyze methamphetamine and tramadol mixtures (ESA = 81 and AGREE = 0.56), and the LC-MS method proposed by Postigo-et al to analyze methamphetamine and heroin mixtures (ESA = 76 and AGREE = 0.58).
Article
Objectives Canada legalized recreational cannabis in October 2018. Cannabis is increasingly available in numerous forms—especially edibles—that make children vulnerable to unintentional intoxication. We sought to: determine the frequency of visits due to cannabis intoxication pre- and post-legalization; characterize the clinical features and circumstances of cannabis intoxication in the paediatric population; and create greater awareness among healthcare providers about this issue. Methods We performed a retrospective chart review of Emergency Department visits at the Children’s Hospital of Eastern Ontario (Ottawa, ON) between March 2013 and September 2020. Inclusion criteria were: age <18 years; unintentional cannabis ingestion, identified by ICD-10 codes T40.7 and X42. We assessed basic demographics, clinical signs and symptoms, exposure details, investigations, and patient disposition. Results A total of 37 patients (22 male) met inclusion criteria, mean age 5.9±3.8 years. Most visits (32; 86%) occurred in the 2-year period after legalization. Altered levels of consciousness, lethargy/somnolence, tachycardia, and vomiting were the most common presenting signs and symptoms. The majority of exposures were to edibles (28; 76%) in the home setting (30; 81%). Poison control and child protective services were involved in 19 (51%) and 22 (59%) of cases, respectively. Twelve patients (32%) required admission to the hospital, the majority of whom stayed <24 h. Conclusions Our data confirm increased paediatric hospital visits related to unintentional cannabis exposures post-legalization. Consideration of this clinical presentation is critical for acute care providers. Advocacy for safe storage strategies and appropriate enforcement of marketing/packaging legislation are imperative for public health policymakers.
Article
Background: This study examined effects of oral delta-9-tetrahydrocannabinol (THC) in women at two phases of the menstrual cycle differing in circulating levels of estrogen (E). Pre-clinical findings indicate that E increases sensitivity to THC and other cannabinoids, raising the possibility that higher E may be a risk factor for adverse responses to THC in women. Methods: We examined subjective and behavioral responses to THC (7.5 and 15 mg oral) and placebo in women during the early follicular (EF) phase when E levels are low and the late follicular (LF) phase when E levels are higher. Outcome measures included self-report ratings of drug effects, cardiovascular measures, and biochemical verification of ovarian hormone levels. We hypothesized that women would exhibit greater responses to THC during the LF phase compared to the EF phase. Results: On most measures, responses to THC were similar during the two phases. However, on two self-report measures, "Wanting More" drug and anxiety, the effects occurred slightly earlier after drug administration in women who were tested during the EF phase. Conclusions: We conclude that the differences in levels of E occurring during the early and LF phase of the menstrual cycle do not strongly influence responses to THC. It remains to be determined whether responses are similarly stable across other cycle phases, or in women receiving exogenous hormone treatments.
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Background and aims: Cannabis and alcohol are frequently detected in fatal and injury motor vehicle crashes. While epidemiological meta-analyses of cannabis and alcohol have found associations with an increase in crash risk, convergent evidence from driving performance measures is insufficiently quantitatively characterized. Our objectives were to quantify the magnitude of the effect of cannabis and alcohol-alone and in combination-on driving performance and behaviour. Methods: Systematic review and meta-analysis. We systematically searched Academic Search Complete, CINAHL, Embase, Scopus, Google Scholar, MEDLINE, PsycINFO, SPORTDiscus and TRID. Of the 616 studies that underwent full-text review, this meta-analysis represents 57 studies and 1725 participants. We extracted data for hazard response time, lateral position variability, lane deviations or excursions, time out of lane, driving speed, driving speed variability, speed violations, time speeding, headway, headway variability and crashes from experimental driving studies (i.e. driving simulator, closed-course, on-road) involving cannabis and/or alcohol administration. We reported meta-analyses of effect sizes using Hedges' g and r. Results: Cannabis alone was associated with impaired lateral control [e.g. g = 0.331, 95% confidence interval (CI) = 0.212-0.451 for lateral position variability; g = 0.198, 95% CI = 0.001-0.395 for lane excursions) and decreased driving speed (g = -0.176, 95% CI = -0.298 to -0.053]. The combination of cannabis and alcohol was associated with greater driving performance decrements than either drug in isolation [e.g. g = 0.480, 95% CI = 0.096-0.865 for lateral position variability (combination versus alcohol); g = 0.525, 95% CI = 0.049-1.002 for time out of lane (versus alcohol); g = 0.336, 95% CI = 0.036-0.636 for lateral position variability (combination versus cannabis; g = 0.475, 95% CI = 0.002-0.949 for time out of lane (combination versus cannabis)]. Subgroup analyses indicated that the effects of cannabis on driving performance measures were similar to low blood alcohol concentrations. A scarcity of data and study heterogeneity limited the interpretation of some measures. Conclusions: This meta-analysis indicates that cannabis, like alcohol, impairs driving, and the combination of the two drugs is more detrimental to driving performance than either in isolation.
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Marijuana toxicosis is typically seen by companion animal veterinarians. However, with increased marijuana availability, there is a greater potential for toxicosis in other species. Herein we describe a case of suspected marijuana toxicosis in a female and a male American Mammoth donkey, aged 8 y and 20 y, respectively, fed cannabis buds. Both cases were presented because of depression and lethargy. However, the jenny had ataxia, mild colic, tachycardia, tachypnea, and decreased tongue tone. Plasma samples from the jenny on presentation and 3 d following hospitalization were submitted to the Kansas State Veterinary Diagnostic Laboratory to be screened for cannabinoids using high-pressure liquid chromatography coupled with tandem mass spectroscopy (HPLC-MS/MS). A single serum sample from the jack was taken on presentation and submitted to the Animal Health Diagnostic Center at Cornell University for Δ ⁹ -tetrahydrocannabinol (THC) and cannabidiol analysis using HPLC-MS/MS. THC was detected in all samples. Clinical signs were noted 24–36 h after ingestion, which included mild-to-moderate neurologic deficits, mild colic, tachycardia, tachypnea, and decreased tongue tone. Both donkeys recovered uneventfully within 24 h of peak effects. Utilizing a cannabinoid screening assay in collaboration with a veterinary diagnostic laboratory may be useful when an equine practitioner suspects marijuana toxicosis in a patient.
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Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.
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Objective To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products. Case Summary A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day pilot protocol. The participant attended two 7-hour in-lab days where he received 10 blood draws each day and completed self-administered pain and anxiety surveys. For both days, the participant took his prescribed dose of hydrocodone/acetaminophen (1/2 tablet of 7.5 mg/325 mg combination product) with the addition of 1 smoked pre-rolled marijuana cigarette (labeled as 0.5 g; 22.17% Δ9-tetrahydrocannabinol; 0.12% cannabidiol) on Day 2. Blood specimens were analyzed using mass spectrometry to quantify the difference of plasma hydrocodone levels between Day 1 and Day 2. Results Compared to Day 1, lower levels of pain and anxiety were reported during Day 2 with the addition of cannabis to oral hydrocodone/acetaminophen. Day 2 pharmacokinetic analysis also revealed more rapid absorption and overall lower levels of hydrocodone in plasma. Discussion Lower hydrocodone plasma levels in Day 2 may indicate cannabis’s effect on metabolism and reduce the risk of opioid toxicity. The quicker absorption rate of hydrocodone could explain lower pain and anxiety scores reported on the second day. Conclusion and Relevance A 2-day protocol was able to capture differences across time in pharmacokinetic and pharmacodynamic measurements. Larger studies can be designed to better characterize the potential drug-drug interaction of cannabis and opioids.
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The feeding value and impact of hemp stubble in the diet of ruminants is unknown. Fifteen Merino castrated male sheep were maintained in individual pens and fed one of three pelletised experimental inclusion diets, as a 0% (Control), 28% (Hemp 1), and 56% (Hemp 2) pellet that delivered a diet meeting the nutrient requirements of the animals. Inclusion of hemp stubble had no effect (P > 0.05) on either DM intake, live weight gain or the feed to gain ratio but positively impacted (P < 0.05) on nutrient digestibility. Hemp stubble inclusion increased the concentration (but not molar proportions) of acetic and butyric acids and increased both the concentrations and molar proportions of iso-butyric, iso-valeric, hexanoic and heptanoic acids, possibly due to increased protein digestibility and/or changes in the composition of rumen cellulolytic bacteria. Tetrahydrocannabinolic acid (THCA) was the only cannabinoid found in plasma in the sheep fed the hemp-containing diets, and this was found at very low concentrations (< 16 μg/L). The psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ 9-THC) was not detected in any plasma samples. THCA was detected in the liver of two sheep fed the Hemp 1 pellets and two sheep fed the Hemp 2 pellets. Cannabidiol (CBD) was detected in the liver of one sheep fed the Hemp 2 pellets (but no liver THCA was detected in this sheep). Δ 9-THC was detected in both the kidney fat and subcutaneous fat of all sheep fed hemp stubble, with the concentrations being higher (P < 0.05) in the sheep fed the Hemp 1 pellets. THCA was also detected in the subcutaneous fat of one of the sheep fed the Hemp 1 pellets. Four of the five sheep fed the Hemp 1 pellet and one of the five sheep fed Hemp 2 pellet had detectable levels of Δ 9-THC in the meat (loin). No other cannabinoids were detected in the meat. Current food standards regulations in Australia prohibit presence of any cannabinoid residues in commercial meat products; thus, determination of a withholding period is required to enable the safe feeding of hemp-stubble to sheep. Further research is also required to gain a greater understanding of the rumen metabolism of cannabinoids.
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The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer’s, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.
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Cannabis is the most commonly used psychotropic drug in the United States, after alcohol. Despite its apparent sedative and calming effects, cannabis and its main psychoactive constituent, ∆⁹-tetrahydrocannabinol (THC) can produce serious adverse effects including tachycardia and anxiety. These effects can be especially pronounced in women, who remain underrepresented in clinical cannabinoid research. The present study is one of the first to characterize the effects of single doses of oral THC on autonomic nervous system function in healthy adult women. Occasional female cannabis users participated in three laboratory sessions in which they received oral THC (7.5 and 15 mg) and placebo. Autonomic measures included heart rate (HR), blood pressure (BP), pre-ejection period (PEP) a measure of cardiac sympathetic functioning, and high frequency heart rate variability (HF-HRV) a measure of parasympathetic cardiac control. Autonomic responses were examined in relation to subjective drug effects. THC dose-dependently increased HR, decreased HF-HRV, and increased ratings of feeling a drug effect, cannabis-like intoxication, and anxiety. Although the drug did not significantly affect BP or PEP, HR was negatively related to both PEP and HF-HRV. HF-HRV, the measure of parasympathetic activity, was significantly negatively related to subjective measures of cannabis intoxication (but not anxiety) at the 15 mg dose only. PEP was not significantly related to any subjective measure. These results extend our knowledge of the autonomic effects of THC in relation to subjective drug experience. This and future studies will help us to understand risk factors related to cannabis use.
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As more states in the U.S legalize recreational and medicinal cannabis, rates of driving under the influence of this drug are increasing significantly. Aspects of this emerging public health issue potentially pit science against public policy. The authors believe that the legal cart is currently significantly ahead of the scientific horse. Issues such as detection procedures for cannabis-impaired drivers, and use of blood THC levels to gauge impairment, should rely heavily on current scientific knowledge. However, there are many, often unacknowledged research gaps in these and related areas, that need to be addressed in order provide a more coherent basis for public policies. This review focuses especially on those areas. In this article we review in a focused manner, current information linking cannabis to motor vehicle accidents and examine patterns of cannabis-impairment of driving related behaviors, their time courses, relationship to cannabis dose and THC blood levels, and compare cannabis and alcohol-impaired driving patterns directly. This review also delves into questions of alcohol-cannabis combinations and addresses the basis for of per-se limits in cannabis driving convictions. Finally, we distinguish between areas where research has provided clear answers to the above questions, areas that remain unclear, and make recommendations to fill gaps in current knowledge.
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Interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) have been characterized in mice as a distinct subset of effector cells, but their identity and properties in humans remain elusive. We report here that expression of CCR6 and CCR4 together identified human memory CD4+ T cells selectively producing IL-17 and expressing mRNA encoding the human ortholog of mouse RORgammat, a transcription factor, whereas CCR6 and CXCR3 identified T(H)1 cells producing interferon-gamma and T helper cells producing both interferon-gamma and IL-17. Memory T cells specific for Candida albicans were present mainly in the CCR6+CCR4+ T(H)-17 subset, whereas memory T cells specific for Mycobacterium tuberculosis were present in CCR6+CXCR3+ T helper type 1 subset. The elicitation of IL-17 responses correlated with the capacity of C. albicans hyphae to stimulate antigen-presenting cells for the priming of T(H)-17 responses in vitro and for the production of IL-23 but not IL-12. Our results demonstrate that human T(H)-17 cells have distinct migratory capacity and antigenic specificities and establish a link between microbial products, T helper cell differentiation and homing in response to fungal antigens.
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In humans, interleukin-1beta (IL-1beta) has been suggested as an essential cytokine for developing IL-17- or IL-17A-producing CD4(+) T helper 17 (Th17) cells. However, little is known about the relationship of IL-1 receptor expression and Th17 cell differentiation. We report here the presence of 2 distinct CD4(+) T-cell populations with and without expression of IL-1RI that correlates with the capacity to produce IL-17 in naive and memory CD4(+) T cells of human peripheral blood. IL-1RI(+) memory CD4(+) T cells had increased gene expression of IL17, RORC, and IRF4 even before T-cell receptor triggering, indicating that the effect of IL-1beta is programmed in these cells via IL-1RI. Although CD4(+) T cells from umbilical cord blood did not express IL-1RI, the cytokines IL-7, IL-15, and transforming growth factor-beta (TGF-beta) up-regulated IL-1RI expression on naive CD4(+) T cells, suggesting that IL-1RI(+) naive CD4(+) T cells develop in periphery. Furthermore, IL-17 production from the cytokine-treated naive CD4(+) T cells was induced by IL-1beta and this induction was blocked by IL-1R antagonist. These results indicate that human Th17 cell differentiation is regulated via differential expression of IL-1RI, which is controlled by IL-7 and IL-15.
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T-helper type 17 cells (TH17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. TH17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)- in retinal cells, suggesting a mechanism by which TH17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN- and inhibited proliferation of TH17. These findings suggest that TH1 cells may mitigate uveitis by antagonizing the TH17 phenotype through the IFN-–mediated induction of IL-27 in target tissue. The finding that IL-2 promotes TH17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of TH17 by IFN- and/or IL-27 could be used for the treatment of chronic inflammation.
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Foxp3(+)CD4(+) regulatory T (Treg) cells inhibit immune responses and temper inflammation. IL-17(+)CD4(+) T (Th17) cells mediate inflammation of autoimmune diseases. A small population of IL-17(+)Foxp3(+)CD4(+) T cells has been observed in peripheral blood in healthy human beings. However, the biology of IL-17(+)Foxp3(+)CD4(+) T cells remains poorly understood in humans. We investigated their phenotype, cytokine profile, generation, and pathological relevance in patients with ulcerative colitis. We observed that high levels of IL-17(+)Foxp3(+)CD4(+) T cells were selectively accumulated in the colitic microenvironment and associated colon carcinoma. The phenotype and cytokine profile of IL-17(+)Foxp3(+)CD4(+) T cells was overlapping with Th17 and Treg cells. Myeloid APCs, IL-2, and TGF-β are essential for their induction from memory CCR6(+) T cells or Treg cells. IL-17(+)Foxp3(+)CD4(+) T cells functionally suppressed T cell activation and stimulated inflammatory cytokine production in the colitic tissues. Our data indicate that IL-17(+)Foxp3(+) cells may be "inflammatory" Treg cells in the pathological microenvironments. These cells may contribute to the pathogenesis of ulcerative colitis through inducing inflammatory cytokines and inhibiting local T cell immunity, and in turn may mechanistically link human chronic inflammation to tumor development. Our data therefore challenge commonly held beliefs of the anti-inflammatory role of Treg cells and suggest a more complex Treg cell biology, at least in the context of human chronic inflammation and associated carcinoma.
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RORγt(+) T(H)17 cells are a proinflammatory CD4(+) T-cell population associated with autoimmune tissue injury. In mice, priming of T(H)17 requires TGF-β, which alone directs the priming of FOXP3(+) regulatory T cells (Treg), in association with inflammatory cytokines. Priming of human T(H)17 cells from conventional naive CD4(+) T cells under similar conditions, however, has proved difficult to achieve. Here, we report that differentiation of human T(H)17 cells preferentially occurs from FOXP3(+) naive Treg (NTreg) in the presence of IL-2 and IL-1β and is increased by IL-23 and TGF-β. IL-1β-mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of RORγt along with down-regulation of FOXP3. IL-17-secreting cells in NTreg cultures cosecreted TNF-α and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-γ and other T(H)17-associated cytokines. Polarized NTreg contained significant subpopulations of CCR6-expressing cells that were highly enriched in IL-17-secreting cells. Finally, analysis of CCR6 expression with respect to that of IL-1RI identified distinct IL-17-secreting subpopulations that had maintained or lost their suppressive functions. Together our results support the concept that priming of human T(H)17 from naive CD4(+) T cells preferentially takes place from FOXP3(+) Treg precursors in the presence of lineage-specific polarizing factors.
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Regulatory T cells (Tregs) suppress immune activation and are critical in preventing autoimmune diseases. While the ability of Tregs to inhibit proliferation of other T cells is well established, it is not yet clear whether Tregs also modulate inflammatory cytokines during an immune response. Here, we show that the expression of inflammatory cytokine receptors IL-1R1 and TNFR2 were higher on resting mature Tregs compared to naïve or memory T cells. While upon activation through the T cell receptor (TCR), expression of IL-1R1 and TNFR2 were upregulated on all T cell subsets, IL-1R1 maintained significantly higher expression on activated Tregs as compared to other T cell subsets. The decoy receptor for IL-1 (IL-1R2) was not expressed by any of the resting T cells but was rapidly upregulated and preferentially expressed upon TCR-stimulation on Tregs. In addition, we found that Tregs also expressed high levels of mRNA for IL-1 antagonist, IL-1RA. TCR-stimulation of naïve T cells in the presence of TGFbeta, which induces FOXP3 expression, however did not result in upregulation of IL-1R1 or IL-1R2. In addition, ectopic expression of FOXP3 in non-Tregs, while causing significant upregulation of IL-1R1 and IL-1R2, did not achieve the levels seen in bona fide Tregs. We also determined that resting human Tregs expressing IL-1R1 did not have higher suppressive capacity compared to IL-1R1- Tregs, suggesting that IL-1R1 does not discriminate suppressive resting Tregs in healthy individuals. Functionally, activated human Tregs displayed a capacity to neutralize IL-1beta, which suggests a physiological significance for the expression of IL-1 decoy receptor on Tregs. In conclusion, our findings that human Tregs preferentially express receptors for TNF and IL-1 suggest a potential function in sensing and dampening local inflammation.
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Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
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Recent studies have suggested a close relationship between CD4(+)FOXP3(+) regulatory T cells (Tregs) and proinflammatory IL-17-producing T helper cells (T(H)17) expressing the lineage-specific transcription factor RORgamma t. We report here the unexpected finding that human memory Tregs secrete IL-17 ex vivo and constitutively express RORgamma t. IL-17-secreting Tregs share some phenotypic and functional features with conventional T(H)17 cells, expressing high levels of CCR4 and CCR6 and low levels of CXCR3. However, unlike conventional T(H)17 cells, they express low levels of CD161 and mostly fail to cosecrete IL-22 and TNF-alpha ex vivo. Ex vivo secretion of IL-17 and constitutive expression of RORgamma t by human memory Tregs suggest that, in addition to their well-known suppressive functions, these cells likely play additional, as yet undescribed, proinflammatory functions.
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CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-beta plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORgammat, and RORalpha) involved in the development of Th17 cells have just been identified. The participation of TGF-beta in the differentiation of Th17 cells places the Th17 lineage in close relationship with CD4+CD25+Foxp3+ regulatory T cells (Tregs), as TGF-beta also induces differentiation of naive T cells into Foxp3+ Tregs in the peripheral immune compartment. The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation. Furthermore, we now appreciate the importance of Th17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
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The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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To examine patterns of self reported drinking, smoking, and illicit drug use among a representative United Kingdom sample of people born in 1979. Cross sectional, single phase survey based on a stratified cluster sample of 70 United Kingdom secondary schools during March and April 1995. Pupils completed a 406 item standardised questionnaire under examination conditions. United Kingdom state and private secondary schools. 7722 pupils aged 15 and 16. Reported use of alcohol, tobacco, and illicit drugs. Almost all the pupils had drunk alcohol, 36% (2772/7689) had smoked cigarettes in the past 30 days, and 42.3% (3264/7722) had at some time used illicit drugs, mainly cannabis. 43% (1546/3546) of boys and 38% (1529/4009) of girls had tried cannabis. Higher levels of smoking were associated with poorer school performance (20.4% (783/3840) with average performance v 44.1% (214/486) with below average performance, F = 79.06, P < 0.01). Levels of drug use in 15 and 16 year olds in 1995 were higher in Scotland than in England, Wales, or Northern Ireland. Drug experimentation was high among 15 and 16 year olds, and use of cannabis was particularly high among smokers. Cigarette smoking was more common among girls than boys.
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The effects of the active ingredient of Cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. Δ9-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Δ9-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of μ1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, Δ9-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common μ1 opioid receptor mechanism located in the ventral mesencephalic tegmentum.
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We previously reported that central-memory T cells (T(CM) cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector-memory T cells (T(EM) cells) (i.e., CCR7(-) T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4(+) T(CM) cell pool. T(CM) cells expressing CXCR3 secreted low amounts of interferon gamma, whereas CCR4(+) T(CM) cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3(+) T(CM) and CCR4(+) T(CM) cells invariably generated fully differentiated CCR7(-) Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5(+) T(CM) cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3(+) T(CM) and T(EM) cells. We conclude that antigen-specific memory T cells are distributed between T(EM) cells and different subsets of T(CM) cells. Our results also explain how the quality of primary T cell responses could be maintained by T(CM) cells in the absence of antigen.
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CD4CD25 Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4CD25 Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4CD25 Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25 T cells. Here we show that analysis of CD25 expression in human circulating CD4 T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25CCR7CD62LCTLA-4FOXP3 cells contained in the CD45RA/RO naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4 population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact-mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.
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T helper (T(H)) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered T(H)17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that T(H)17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (T(reg)) cells, which prevent tissue inflammation and mediate self-tolerance.
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The effector T-cell lineage shows great plasticity. Th17 cells are acknowledged to be instrumental in the response against microbial infection, but are also associated with autoimmune inflammatory processes. Here, we report that human regulatory T cells (CD4(pos)CD25(high)Foxp3(pos)CD127(neg)CD27(pos)) can differentiate into IL-17-producing cells, when stimulated by allogeneic antigen-presenting cells, especially monocytes, in the presence of rhIL-2/rhIL-15. These regulatory T cell (Treg)-derived IL-17-producing cells showed high expression of the Th17-related transcription factor RORgammat and were positively identified by CCR6 expression. This differentiation process was enhanced by exogenous IL-1beta, IL-23, and IL-21, whereas IL-6 or TGFbeta did not affect the emergence of IL-17-producing cells. The addition of IL-1 receptor antagonist (IL-1Ra), but not anti-IL-23 antibody, reduced IL-17-producing cell numbers. When an histone deacetylase (HDAC) inhibitor trichostatin A (TSA) was evaluated, we found a profound negative effect on the emergence of IL-17-producing cells from Tregs, implying that Treg differentiation into IL-17-producing cells depends on histone/protein deacetylase activity. Thus, the data suggest that epigenetic modification underlies the phenomenon of Treg plasticity here described.
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1. Chemical content, assay procedures, and pharmacokinetics of cannabis sativa are discussed briefly.2. Cannabinoid cellular effects relating to chromosomes and immunity including cellular metabolism and allergic reactions are presented.3. Gross and microscopic brain pathology due to cannabis use is reviewed involving EEG alterations, psychopathology including aggressive behaviour as well as properties of psychomotor impairment, tolerance and dependence.4. Cardiopulmonary effects of marihuana are recorded under pulmonary pharmacological effects including the macrophage defense system and effects of smoke constituents; under cardiovascular effects cardiac toxicity and possible mechanism of action are discussed.5. Alterations of reproductive hormonal production and maturation of reproductive cells by marihuana in males and females with attendant impairment of reproductive function or fertility including reproductive outcome are reported.6. Field studies with healthy chronic cannabis users in Jamaica, Greece and Costa Rica are related as to observed medical alterations.7. Potential clinical effects are summarized in point form.
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In response to public service announcements directed at adult chronic marijuana users who were concerned about their smoking, 225 individuals were interviewed anonymously by telephone. This study was conducted to determine if a population of chronic dysfunctional marijuana users existed who were both interested in being treated and not concurrently abusing alcohol and/or other psychoactive drugs. Most of the callers (73.8%) were experiencing adverse consequences associated only with marijuana use rather than in combination with other substances. Most (92%) expressed interest in being treated, while very few (18%) had ever been seen in a drug or alcohol treatment program.
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The identification and characterisation of regulatory T cells (Tregs) has recently opened up exciting opportunities for Treg cell therapy in transplantation. In this review, we outline the basic biology of Tregs and discuss recent advances and challenges for the identification, isolation and expansion of these cells for cell therapy. Tregs of thymic origin have been shown to be key regulators of immune responses in mice and humans, preventing autoimmunity, graft-versus-host disease and organ graft rejection in the transplantation setting. To date, a variety of different methods to isolate and expand Tregs ex vivo have been advocated. Although promising, relatively few clinical trials of human Treg cell infusion have been initiated. Many key questions about Treg cell therapy still remain and here we provide an in-depth analysis and highlight the challenges and opportunities for immune intervention with Treg-based therapeutics in clinical transplantation.
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T helper (Th) 17 cells have been recently discovered in both mouse and human. Here we show that interleukin-1 (IL-1) signaling on T cells is critically required for the early programming of Th17 cell lineage and Th17 cell-mediated autoimmunity. IL-1 receptor1 expression in T cells, which was induced by IL-6, was necessary for the induction of experimental autoimmune encephalomyelitis and for early Th17 cell differentiation in vivo. Moreover, IL-1 signaling in T cells was required in dendritic cell-mediated Th17 cell differentiation from naive or regulatory precursors and IL-1 synergized with IL-6 and IL-23 to regulate Th17 cell differentiation and maintain cytokine expression in effector Th17 cells. Importantly, IL-1 regulated the expression of the transcription factors IRF4 and RORgammat during Th17 cell differentiation; overexpression of these two factors resulted in IL-1-independent Th17 cell polarization. Our data thus indicate a critical role of IL-1 in Th17 cell differentiation and this pathway may serve as a unique target for Th17 cell-mediated immunopathology.
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Although adoptive transfer of regulatory T cells (Foxp3(+) Tregs) has proven to be efficacious in the prevention and treatment of autoimmune diseases and graft-versus-host disease in rodents, a major obstacle for the use of Treg immunotherapy in humans is the difficulty of obtaining a highly purified preparation after ex vivo expansion. We have identified latency-associated peptide (LAP) and IL-1 receptor type I and II (CD121a/CD121b) as unique cell-surface markers that distinguish activated Tregs from activated FOXP3(-) and FOXP3(+) non-Tregs. We show that it is feasible to sort expanded FOXP3(+) Tregs from non-Tregs with the use of techniques for magnetic bead cell separation based on expression of these 3 markers. After separation, the final product contains greater than 90% fully functional FOXP3(+) Tregs. This novel protocol should facilitate the purification of Tregs for both cell-based therapies as well as detailed studies of human Treg function in health and disease.
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Natural CD4(+)CD25(+) regulatory T cells (Treg) and interleukin 17 (IL-17)-producing T helper cells (T(H)17) carry out opposite functions, the former maintaining self-tolerance and the latter being involved in inflammation and autoimmunity. We report here that stimulation of human Natural Treg under T(H)17 polarizing conditions in the presence of IL-2 converts them into T(H)17 cells. Conversion of Tregs into T(H)17 cells occurs both from natural naïve Tregs (NnTregs) and, to a higher extent, from memory Tregs (MTregs). Among antigen presenting cells, fresh monocytes activated by microbial stimuli were the most efficient inducers of T(H)17 cells from Tregs. Conversion of Treg into T(H)17 cells was induced by IL-1beta and involved down-regulation of the Treg lineage transcription factor FOXP3 and suppressive functions. Our results indicate that, under inflammatory conditions, in the presence of IL-2, Treg can be converted into pro-inflammatory T(H)17 cells and establish a functional link between inflammation and autoimmunity.
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Blood samples from 425 suspected drugged drivers who were clinically impaired and negative for alcohol were analysed. Fifty-six percent of the samples were positive for tetrahydrocannabinol (THC). Tetrahydrocannabinol-positive blood samples were analysed for amphetamines, barbiturates, benzodiazepines, cocaine metabolites and opiates. Eighty-two percent of the samples were found to be positive for one or more drugs in addition to THC, and the concentrations of these drugs were often high. Thus, THC in combination with other drugs seems to be a much more frequent reason for impairment than THC alone among Norwegian drugged drivers.
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This study finds evidence for 24-h carry-over effects of a moderate social dose of marijuana on a piloting task. In separate sessions, nine currently active pilots smoked one cigarette containing 20 mg of delta 9 THC and one Placebo cigarette. Using an aircraft simulator, pilots flew just before smoking, and 0.25, 4, 8, 24, and 48 h after smoking. Marijuana impaired performance at 0.25, 4, 8, and 24 h after smoking. While seven of the nine pilots showed some degree of impairment at 24 h after smoking, only one reported any awareness of the drug's effects. The results support our preliminary study and suggest that very complex human/machine performance can be impaired as long as 24 h after smoking a moderate social dose of marijuana, and that the user may be unaware of the drug's influence.
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The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
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This review will summarize the pharmacokinetic properties of Δ1-tetrahydrocannabinol mainly in man, since only limited information is available in experimental animals. We will also review the metabolites of Δ1-THC, with particular emphasis on those metabolites which have either psychotomimetic properties similar to Δ1-THC or which are eliminated in man. Metabolic tranformations have mainly been elucidated in various in vitro systems and in experimental animals. Only recently, more extensive information on the metabolism of Δ1-THC in man has become available. The pharmacokinetics of the isomer of Δ1-THC, viz. Δ6-THC, will be dealt with very briefly, because it only represents a minute constituent of marihuana. Two other major cannabinoids, cannabinol (CBN) and cannabidiol (CBD), will also only be briefly reviewed, because available data for these compounds is somewhat limited. We will review only more significant and recent results, since an extensive survey of all published material in the area would be too voluminous. Thus, much of the early literature not directly related to pharmacokinetics and metabolisms is referred to in review articles and in proceedings of symposia. Unfortunately, two almost equally popular numbering systems are in use today. The biogenetically based monoterpene system (Δ1-THC) is used in this survey since it is applicable to both Δ1-THC, CBD, and CBN. The dibenzopyran (Δ9-THC) system which is also shown cannot be used for CBD but has lately been adopted by Chemical Abstracts. The use of these two systems has caused even more confusion when dealing with the metabolites. The chemistry of cannabinoids has been reviewed recently by Mechoulam and Harvey. Of more than 60 cannabinoids - the term cannabinoid is used for the typical C21-compounds and their transformation products - only Δ1-THC has profound psychoactive properties. CBN i.v. shows about 1/10 the potency of Δ1-THC in man, whereas CBD is devoid of psychotomimetic properties. Δ6-THC is about equipotent with Δ1-THC itself but is usually present in very small amounts compared to Δ1-THC, CBD, and CBN. The latter three compounds occur in marihuana-type cannabis preparations in concentrations usually around 1 to 2%.
Article
To compare the pulmonary hazards of smoking marijuana and tobacco, we quantified the relative burden to the lung of insoluble particulates (tar) and carbon monoxide from the smoke of similar quantities of marijuana and tobacco. The 15 subjects, all men, had smoked both marijuana and tobacco habitually for at least five years. We measured each subject's blood carboxyhemoglobin level before and after smoking and the amount of tar inhaled and deposited in the respiratory tract from the smoke of single filter-tipped tobacco cigarettes (900 to 1200 mg) and marijuana cigarettes (741 to 985 mg) containing 0.004 percent or 1.24 percent delta 9-tetrahydrocanabinol. As compared with smoking tobacco, smoking marijuana was associated with a nearly fivefold greater increment in the blood carboxyhemoglobin level, an approximately threefold increase in the amount of tar inhaled, and retention in the respiratory tract of one third more inhaled tar (P less than 0.001). Significant differences were also noted in the dynamics of smoking marijuana and tobacco, among them an approximately two-thirds larger puff volume, a one-third greater depth of inhalation, and a fourfold longer breath-holding time with marijuana than with tobacco (P less than 0.01). Smoking dynamics and the delivery of tar during marijuana smoking were only slightly influenced by the percentage of tetrahydrocanabinol. We conclude that smoking marijuana, regardless of tetrahydrocannabinol content, results in a substantially greater respiratory burden of carbon monoxide and tar than smoking a similar quantity of tobacco.
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In an effort to study the efficacy of attracting and intervening with adult marijuana users, 290 men and 92 women were screened for participation in a treatment-outcome study focused on marijuana cessation. The well-educated, self-referred sample reported using marijuana on 79 of the past 90 days before testing. Indices of the severity of marijuana abuse and general psychopathology were in the clinical range for a majority of Ss. Ss who did not report evidence of alcohol or other drug abuse (n = 144) reported less severe consequences of marijuana use and experienced less general psychological distress than Ss who also reported lifetime (n = 165) or current abuse (n = 73) of other substances in addition to marijuana. The findings indicate the need for clinical research targeting adults who are dependent on marijuana.
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Alcohol and illicit drug use are increasing among school children and young adults in the UK. Such increases have also been noted among university students and there is a need for a large survey across different universities and faculties. We report such a survey. Information about drinking, use of cannabis and other illicit drugs, other lifestyle variables, and subjective ratings of anxiety and depression was obtained by questionnaire in a cross-faculty sample of 3075 second-year university students (1610 men, 1447 women, 18 sex not stated) from ten UK universities. The questionnaire was personally administered during scheduled lecture hours and almost all the students participated. The sample reflected the interfaculty and sex distribution and the proportion of non-white students at UK universities. 11% of the students were non-drinkers. Among drinkers, 61% of the men and 48% of the women exceeded "sensible" limits of 14 units per week for women and 21 for men. Hazardous drinking (> or = 36 units per week for women, > or = 51 for men) was reported by 15% of the drinkers. Binge drinking was declared by 28% of drinkers. 60% of the men and 55% of the women reported having used cannabis once or twice and 20% of the sample reported regular cannabis use (weekly or more often). Experience with other illicit drugs was reported by 33% of the sample, most commonly LSD (lysergic acid diethylamide), amphetamines, Ecstasy (methylenedioxymethamphetamine), and amyl/butyl nitrate which had each been used by 13-18% of students. 34% of these had used several drugs. Drug use had started at school in 46% of the sample; 13% began after entering university. The overwhelming reason given for taking alcohol or drugs was pleasure. Subjective ratings of anxiety on the hospital anxiety depression scale were high, and sleep difficulties were common, but neither related to alcohol or drug use. There is a need for better education about alcohol, drugs, and general health in universities. Such education should include all faculties. It remains unclear whether university students' lifestyles are carried over into later life.
Article
Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. For many decades, the mechanism of action of cannabinoids, compounds which are structurally similar to delta 9-THC, was unknown. Tremendous progress has been made recently in characterizing cannabinoid receptors both centrally and peripherally and in studying the role of second messenger systems at the cellular level. Furthermore, an endogenous ligand, anandamide, for the cannabinoid receptor has been identified. Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC. The production of complex behavioral events by cannabinoids is probably mediated by specific cannabinoid receptors and interactions with other neurochemical systems. Cannabis also has great therapeutic potential and has been used for centuries for medicinal purposes. However, cannabinoid-derived drugs on the market today lack specificity and produce many unpleasant side effects, thus limiting therapeutic usefulness. The advent of highly potent analogs and a specific antagonist may make possible the development of compounds that lack undesirable side effects. The advancements in the field of cannabinoid pharmacology should facilitate our understanding of the physiological role of endogenous cannabinoids.
Article
The illegal use of cannabis has been increasing in many Western countries for the past two decades. Recently, some interest has been shown in modifying legislation and control. The need for general practitioners to be aware of the short- and long-term consequences of cannabis use is increasing, and more information is required about its effects on behaviour, psychological states and the respiratory and cardiovascular systems. The use of general practice populations to study the prevalence of cannabis use and its damaging effects is less represented in the literature than it should be, considering the extent of cannabis consumption. A study was carried out in 1995 to determine the prevalence of cannabis use in a general practice population and any associated health problems. As a pilot study, samples of cannabis were obtained for forensic analysis. Two questionnaires were used. One very short enquiry about the use, if any, of the drug, and a longer one about the effects of its use. Data concerning medical effects were included from patients' case notes. Samples of cannabis were obtained for forensic examination. A very high proportion (61%) of patients surveyed indicated some cannabis use (past or present). Thirty-seven per cent had used it in the previous 12 months. Users could be broadly divided into transitory experimenters, regular users and heavy users. Medical problems included those attributed to associated tobacco smoking, other illegal drug use and psychological problems. Benefits perceived by patients recording use were many. Polydrug use and legislation issues were difficult to separate from the effects of cannabis itself. Chest infections, anxiety and depression, and drug dependence were common diagnoses, and 13 of the 32 females in the study group had evidence of cervical smear abnormalities. Few serious damaging effects from cannabis use itself were identified, although chest infections and anxiety problems were common. Tobacco damage, associated drug use and criminal or legal issues dominated and obscured the important perceived benefits and the scientific understanding of the effects and side effects of the drug. More research into several identified areas is required.