Cannabinoid Therapies Research Articles

Opioids and Cannabinoids in Neurology Practice.

Opioid and cannabinoid therapies for chronic pain conditions including neuropathic pain are controversial. Understanding patient and prescribing factors contributing to risks and implementing risk mitigation strategies optimizes outcomes. The ongoing transformation from a biomedical model of pain care toward a biopsychosocial model has been accompanied by a shift away from opioid therapy for pain, in particular for chronic pain. Opioid overdose deaths and opioid use disorder have greatly increased in the last several decades, initially because of increases in opioid prescribing and more recently associated with illicit drug use, in particular fentanyl derivatives. Opioid risk mitigation strategies may reduce risks related to opioid prescribing and tapering or discontinuation. Opioid therapy guidelines from the Centers for Disease Control and Prevention have become the consensus best practice for opioid therapy. Regulatory agencies and licensing medical boards have implemented restrictions and other mandates regarding opioid therapy. Meanwhile, interest in and use of cannabinoids for chronic pain has grown in the United States. Opioid therapy is generally not recommended for the chronic treatment of neuropathic pain conditions. Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions (such as postherpetic neuralgia), and only as part of a multimodal treatment regimen. Opioid risk mitigation strategies include careful patient selection and evaluation, patient education and informed consent, querying the state prescription drug monitoring programs, urine drug testing, and issuance of naloxone as potential rescue medication. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. There is evidence for the efficacy of cannabinoids for neuropathic pain, with meaningful response rates in select patient populations.

Patients' perspectives on prescription cannabinoid therapies: a cross-sectional, exploratory, anonymous, one-time web-based survey among German patients.

Since cannabinoids were partially legalized as prescription medicines in Germany in 2017, they are mostly used when conventional therapies do not suffice. Ambiguities remain regarding use, benefits and risks. This web-based survey explored the perspectives of patients whose experiences are not well enough known to date. In an anonymous, exploratory, cross-sectional, one-time web-based observational study, participants receiving cannabinoid therapy on prescription documented aspects of their medical history, diagnoses, attitudes toward cannabinoids, physical symptoms, and emotional states. Participants completed the questionnaires twice here: first regarding the time of the survey and then, retrospectively, for the time before their cannabinoid therapy. Participants were recruited in a stratified manner in three German federal states. N = 216 participants (48.1% female, aged 51.8 ± 14.0) completed the survey, most of which (72%, n = 155) reported pain as their main reason for cannabinoid therapy. When comparing the current state with the retrospectively assessed state, participants reported greater satisfaction with their overall medical therapy (TSQM II: +47.9 ± 36.5, p < 0.001); improved well-being (WHO-5: +7.8 ± 5.9, p < 0.001) and fewer problems in PROMIS subscales (all p < 0.001). Patients suffering primarily from pain (72%, n = 155) reported a reduction of daily pain (NRS: -3.2 ± 2.0, p < 0.001), while participants suffering mainly from spasticity (8%, n = 17) stated decreased muscle spasticity (MSSS: -1.5 ± 0.6, p < 0.001) and better physical mobility (-0.8 ± 0.8, p < 0.001). Data suggests clinically relevant effects for most scores. Participants' attitudes toward cannabinoids (on a 5-point scale) improved (+1.1 ± 1.1, p < 0.001). Most patients (n = 146, 69%) did not report major difficulties with the cannabinoid prescription process, while (n = 27; 19%) had their cannabinoid therapy changed due to side effects. Most participants experienced their therapy with cannabinoids as more effective than their previous therapy. There are extensive limitations to this cross-sectional study: the originally intended representativeness of the dataset was not reached, partly due to the SARS-CoV-2 pandemic; the sample has a larger proportion of privately insured and self-paying patients. Results does not suggest that cannabinoid patients belong to a particular clientele. Effect sizes observed for pain reduction, quality of life, social participation, and other outcomes suggest a therapeutic potential, particularly in the treatment of chronic pain.

The Exploration of Cannabis and Cannabinoid Therapies for Migraine.

There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use. Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.

An analysis of cannabinoid hyperemesis syndrome Reddit posts and themes

Introduction Reddit hosts a large active community of members dedicated to the discussion of cannabinoid hyperemesis syndrome. We sought to describe common themes discussed and the most frequently mentioned triggers and therapies for cannabinoid hyperemesis syndrome exacerbations in the Reddit online community. Methods Data collected from six subreddits were filtered using natural language processing to curate posts referencing cannabinoid hyperemesis syndrome. Based on a manual review of posts, common themes were identified. A machine learning model was trained using the manually categorized data to automatically classify the themes for the rest of the posts so that their distributions could be quantified. Results From August 2018 to November 2022, 2683 unique posts were collected. Thematic analysis resulted in five overall themes: cannabinoid hyperemesis syndrome-related science; symptom timing; cannabinoid hyperemesis syndrome treatment and prevention; cannabinoid hyperemesis syndrome diagnosis and education; and health impacts. Additionally, 447 trigger and 664 therapy-related posts were identified. The most commonly mentioned triggers for cannabinoid hyperemesis syndrome episodes included: food and drink (n = 62), cannabinoids (n = 45), mental health (e.g., stress, anxiety) (n = 27), and alcohol (n = 22). Most commonly mentioned cannabinoid hyperemesis syndrome therapies included: hot water/bathing (n = 62), hydration (n = 60), antiemetics (n = 42), food and drink (n = 38), gastrointestinal medications (n = 38), behavioral therapies (e.g., meditation, yoga) (n = 35), and capsaicin (n = 29). Discussion Reddit posts for cannabinoid hyperemesis syndrome provide a valuable source of community discussion and individual reports of people experiencing cannabinoid hyperemesis syndrome. Mental health and alcohol were frequently reported triggers within the posts but are not often identified in the literature. While many of the therapies mentioned are well documented, behavioral responses such as meditation and yoga have not been explored by the scientific literature. Conclusions Knowledge shared via online social media platforms contains detailed information on self-reported cannabinoid hyperemesis syndrome disease and management experiences, which could serve as valuable data for the development of treatment strategies. Further longitudinal studies in patients with cannabinoid hyperemesis syndrome are needed to corroborate these findings.

Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain.

Since the discovery of α-synuclein as the major component in Lewy bodies, research into this protein in the context of Parkinson’s disease pathology has been exponential. Cannabinoids are being investigated as potential therapies for Parkinson’s disease from numerous aspects, but still little is known about the links between the cannabinoid system and the pathogenic α-synuclein protein; understanding these links will be necessary if cannabinoid therapies are to reach the clinic in the future. Therefore, the aim of this study was to investigate the time-course of alterations in components of the endocannabinoid system after viral-mediated α-synuclein overexpression in the rat brain. Rats were given unilateral intranigral injections of AAV-GFP or AAV-α-synuclein and sacrificed 4, 8 and 12 weeks later for qRT-PCR and liquid chromatography–mass spectrometry analyses of the endocannabinoid system, in addition to histological visualization of α-synuclein expression along the nigrostriatal pathway. As anticipated, intranigral delivery of AAV-α-synuclein induced widespread overexpression of human α-synuclein in the nigrostriatal pathway, both at the mRNA level and the protein level. However, despite this profound α-synuclein overexpression, we detected no differences in CB1 or CB2 receptor expression in the nigrostriatal pathway; however, interestingly, there was a reduction in the expression of neuroinflammatory markers. Furthermore, there was a reduction in the levels of the endocannabinoid 2-AG and the related lipid immune mediator OEA at week 12 post-surgery, indicating that α-synuclein overexpression triggers dysregulation of the endocannabinoid system. Although this research does show that the endocannabinoid system is impacted by α-synuclein, further research is necessary to more comprehensively understand the link between the cannabinoid system and the α-synuclein aspect of Parkinson’s disease pathology in order for cannabinoid-based therapies to be feasible for the treatment of this disease in the coming years.

The use of cannabinoid and non-cannabinoid supplementary therapies in patients undergoing treatment for Glioblastoma reveals an urgent need for guidance

Abstract Aims Glioblastoma (GBM) is currently an incurable malignancy with a very poor prognosis for the majority of patients. Many patients undergo debulking surgery, radiotherapy and chemotherapy however therapeutic options are limited, and this can lead to patients sourcing their own treatments. There is some evidence that cannabinoids have the effect of inhibiting GBM tumour growth through a variety of pathways, some of which include CB2 cannabinoid receptor pathway activation. We undertook a patient questionnaire to understand what alternative therapies patients are accessing and why, with a focus on cannabinoid use. Method We undertook a prospective observational questionnaire based qualitative study of 50 … consecutive patients undergoing treatment for glioblastoma at our centre. Results 43 patients responded to our questionnaire. 33% of patients were taking some kind of supplementary therapy with 25% taking cannabis derivatives, mainly CBD oil. There were no clear discriminators amongst our cohort including age or sex when considering the likelihood of taking cannabis derivatives. 6 out of 11 (55%) patients taking cannabis derivatives reported some positive effects with improved sleep and general wellbeing being most commonly reported. Patients reported spending between £10-£300 per month with an average of £42 per month. Cannabis products were obtained via the internet or from friends. Conclusion This small cohort of patients indicates that a significant proportion of glioblastoma patients investigate and use alternative therapies, in particular cannabis oil. NICE guidance for clinicians simply notes there is insufficient evidence to support the use of cannabis oil in the treatment of this disease. Given the publicity and interest in the utility of cannabis oil to treat cancers this leaves patients to research the use of these agents without access to robust clinical data to guide their use or indeed to conclude they are not beneficial. The accessing of these compounds, potentially by a sizeable number of patients, leaves them vulnerable to unregulated perhaps unscrupulous drug sources. This small study has further highlighted the unmet need for information and guidance on supplementary treatments for glioma patients and this poses a challenge to all those treating this group of patients to answer a question our patients are clearly wanting answered.

A survey of Wisconsin pharmacists about cannabinoid products: Are we ready to recommend?

BackgroundIn today’s culture, cannabis and its cannabinoids are used for both recreational and medicinal purposes. Patients are able to obtain medical and commercial cannabis products. Pharmacists should feel comfortable counseling their patients, given the increased interest, access, and use of these products. ObjectivesThe objective of this survey was to assess the familiarity, attitudes, and knowledge of Wisconsin pharmacists regarding products containing cannabinoids. MethodsAn anonymous, Web-based survey was administered to 511 Wisconsin pharmacists using the Pharmacy Practice Enhancement and Action Research Link. The survey was adapted from a nationally developed survey with established validity evidence. Survey items evaluated pharmacists’ knowledge of the legality and the pharmacokinetic and pharmacodynamic properties of cannabis. The survey included knowledge (22 items), familiarity (14 items), and attitude (8 items) scales as well as pharmacist demographics and workplace type. Descriptive statistics, Fisher exact test, and Cronbach's alpha were calculated. ResultsThe survey had a response rate of 19.3%. Nearly 75% of respondents were unfamiliar with the testing practices and pesticide regulations on cannabis production. Pharmacists were also unfamiliar with doses related to commercially available cannabinoid products. A quarter reported that they counsel at least monthly on cannabinoid therapies, but results showed that the majority are uncomfortable with the pharmacology and pharmacotherapy of these compounds. Over two-thirds reported that they need further education on cannabinoids and ranked continuing pharmacy education credits and webinars as their preferred method of learning. Over two-thirds at least somewhat agreed that they would feel comfortable recommending a Food and Drug Administration (FDA)-approved treatment, but a similar proportion reported that they would not recommend non-FDA approved cannabinoid treatments. ConclusionWisconsin pharmacists require more education to fill knowledge gaps regarding the therapeutic uses of cannabinoid products.

The endocannabinoid system as a therapeutic target for schizophrenia: Failures and potentials

Owing to its psychotropic effects, Cannabis has been stigmatized by its recreational use leading to a dramatic decline in the experimentations about its medical use in the twentieth century. The medical properties of the plant – known since ancient times – have received increased attention over recent years; yet, the research on its potential application in the field of psychiatry is still nascent. In this connection, the non-psychotropic cannabidiol (CBD) has emerged as a phytocannabinoid compound with promising antipsychotic effects. In addition, advances in our understanding of the endocannabinoid system, along with accumulating evidence implicating this system in the pathophysiology of schizophrenia, have stimulated research by the pharmaceutical industry to explore whether alteration of this system can be of medical benefit. This review examines the current state of evidence regarding the clinical potential of cannabinoid-based drugs as a treatment for schizophrenia, while discussing various limitations with the therapeutic approaches considered so far. In the second part, the author highlights the most promising strategies, as well as the most interesting directions one could follow, in the emerging field of cannabinoid therapies for schizophrenia.

Cannabinoid Administration Does Not Affect Mean Arterial Pressure or Glomerular Filtration Rate in DOCA‐Salt Hypertensive Rats

Hypertension remains the leading cause of cardiovascular disease – the leading cause of morbidity and mortality worldwide, and effective pharmacological options remain limited. Recent studies have shown HTN may result from increased renal inflammation and elevated renal sensory nerve activity, particularly in the deoxycorticosterone acetate (DOCA)-salt rat model of salt-sensitive hypertension. Cannabinoid administration is demonstrated to mitigate peripheral inflammation as well as sensory nerve activation in models of rheumatoid arthritis and cancer-related pain through cannabinoid receptor type 2 (CB2). Therefore, we hypothesized CB2 activation through either endogenous cannabinoid accumulation with a fatty acid amide hydrolase inhibitor (URB-597) or selective CB2 agonist (JWH-015) would attenuate DOCA-salt HTN and improve renal function and inflammation. To test this hypothesis, uninephrectomized male Sprague Dawley rats (300-400 g) received DOCA (100 mg, SC), 0.9% NaCl drinking water, and one of the following drug treatments administered by osmotic mini-pump for 21 days: JWH-015 (JWH; 1mg/kg/day; n=5), URB-597 (URB; 1mg/kg/day; n=5), or vehicle (VEH; 10% DMSO, 10% Tween 80, 80% PBS; n=10). 24-hour mean arterial pressure (MAP) was measured by implanted telemeters. Final glomerular filtration rate (GFR) and renal inflammation were assessed by transcutaneous FITC-sinistrin clearance and histological analysis, respectively. Data presented as mean ±SEM. Following the 21-day DOCA-salt treatment, MAP increased in VEH animals (∆62.6 ± 4.2 mmHg), and no differences in URB (∆74.4 ± 7.5 mmHg) or JWH (∆51.1 ± 6.0 mmHg) were detected vs. VEH. Regarding renal function, no improvements in GFR were detected in URB (0.81 ± 0.09 mL/min/100mg bodyweight) nor JWH (0.78 ± 0.06 mL/min/100mg bodyweight) treatments vs. VEH (0.73 ± 0.07 mL/min/100 mg bodyweight). Finally, no differences in bodyweight, kidney, or heart weights were detected between any treatment groups. Renal inflammation analysis and final serum cannabinoid concentration measurements are currently underway. Collectively, these data did not support our initial hypothesis, as no mitigating effects of either URB or JWH on MAP or renal function were detected in this model of hypertension. Though similar doses reportedly mitigate inflammation and pain in other preclinical models disease including rheumatoid arthritis and cancer-related pain, we conclude peripheral CB2 activation through exogenous or endogenous cannabinoid therapies (JWH-015 and URB-597) do not prevent the renal or cardiovascular pathophysiology in this preclinical model of salt-sensitive hypertension. Future dose-response studies are required to evaluate any potential effect beneficial effect of cannabinoid treatment in this model.

Sleep Neurology's Toolkit at the Crossroads: Challenges and Opportunities in Neurotherapeutics Lost and Found in Translation.

We find ourselves at our present crossroads with a well-traveled toolkit, perhaps too well worn but with aspirational hopes and dreams for the field of sleep neurotherapeutics. This volume is organized thematically into six topical domains that parallel the major subspecialty areas of contemporary clinical sleep neurology practice, as well as novel directions and opportunities. The issue begins with an overview of the central disorders of hypersomnolence, including narcolepsy, idiopathic hypersomnia and other hypersomnia disorders, and the related use of the entire broad range of stimulant and wake-promoting pharmacotherapies. Next, the range of behavioral therapies, application of light and light restriction and melatonin therapies, and hypnotic pharmacotherapies useful in insomnia and circadian sleep–wake rhythm disorders are reviewed, followed by an overview of treatment options for sleep-related breathing disorders including positive airway pressure and the novel approach of hypoglossal neurostimulation for obstructive sleep apnea. The parasomnias and sleep-related movement disorders, including NREM disorders of arousal, REM parasomnias (nightmares and isolated sleep paralysis and idiopathic/isolated REM sleep behavior disorder, and restless legs syndrome are then discussed, and the applications of sleep neurotherapeutics in sleep and neurological disease are reviewed, including neurodevelopmental, epileptic, autoimmune encephalopathies, and neurodegenerative diseases. Last, the novel directions and opportunities in sleep neurology offered by cannabinoid therapies and machine learning/artificial intelligence methodology conclude this comprehensive survey of contemporary sleep neurology. We hope that you find this volume to be a useful and inspirational support tool for the work that matters most, your care of all our sleep neurology patients in the clinics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01032-7.

Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties

BackgroundCannabis has been documented for use in alleviating anxiety. However, certain research has also shown that it can produce feelings of anxiety, panic, paranoia and psychosis. In humans, Δ9-tetrahydrocannabinol (THC) has been associated with an anxiogenic response, while anxiolytic activity has been attributed mainly to cannabidiol (CBD). In animal studies, the effects of THC are highly dose-dependent, and biphasic effects of cannabinoids on anxiety-related responses have been extensively documented. A more precise assessment is required of both the anxiolytic and anxiogenic potentials of phytocannabinoids, with an aim towards the development of the ‘holy grail’ in cannabis research, a medicinally-active formulation which may assist in the treatment of anxiety or mood disorders without eliciting any anxiogenic effects.ObjectivesTo systematically review studies assessing cannabinoid interventions (e.g. THC or CBD or whole cannabis interventions) both in animals and humans, as well as recent epidemiological studies reporting on anxiolytic or anxiogenic effects from cannabis consumption.MethodThe articles selected for this review were identified up to January 2020 through searches in the electronic databases OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO.ResultsAcute doses of CBD were found to reduce anxiety both in animals and humans, without having an anxiogenic effect at higher doses. Epidemiological studies tend to support an anxiolytic effect from the consumption of either CBD or THC, as well as whole plant cannabis. Conversely, the available human clinical studies demonstrate a common anxiogenic response to THC (especially at higher doses).ConclusionBased on current data, cannabinoid therapies (containing primarily CBD) may provide a more suitable treatment for people with pre-existing anxiety or as a potential adjunctive role in managing anxiety or stress-related disorders. However, further research is needed to explore other cannabinoids and phytochemical constituents present in cannabis (e.g. terpenes) as anxiolytic interventions. Future clinical trials involving patients with anxiety disorders are warranted due to the small number of available human studies.

Attitudes and knowledge about cannabis and cannabis-based therapies among US neurologists, nurses, and pharmacists

Use of cannabinoid therapies is on the rise in the United States, but responses of healthcare professionals and their knowledge of these therapies have been mixed. More information is needed about factors associated with healthcare professionals' attitudes and knowledge about medical cannabis. We conducted an online survey of US-based neurologists, nurse practitioners (NPs)/nurses, and pharmacists in August–September of 2018 (n = 451). We constructed perceived knowledge and attitudes scales and a knowledge index from multiple items and assessed state cannabis laws, participant's sociodemographics, workplace type and policies, and patient population. We used ordinary least-squares regression to examine associations among study variables. Over 80% of participants supported use and legalization of medical cannabis, especially cannabidiol (CBD) for epilepsy and when prescribed by a medical provider, but 40–50% (depending on item) felt unfamiliar with cannabinoid pharmacology and clinical applications. A total of 43% favored legal recreational cannabis. Pharmacists scored higher on the knowledge test than neurologists and NPs/nurses, but NPs/nurses had more favorable attitudes than neurologists and higher perceived knowledge than pharmacists. Both knowledge indicators predicted attitudes. State cannabis access and favorable workplace policies were associated with higher knowledge and more favorable attitudes. Healthcare professionals see potential in cannabis therapies but report significant knowledge gaps. Professional cannabinoid education is needed to address growing patient and provider demand for knowledge about cannabinoid therapies.

Pharmacists and the future of cannabis medicine

ObjectivesTo summarize the history and evolution of cannabis use and policies and to review current therapeutic uses, safety, and the central role pharmacists can play. SummaryCannabis regulation and use have evolved over the centuries and are becoming more widely accepted, with over two-thirds of states in the United States having an approved cannabis program. However, changing policy and a paucity of controlled clinical trials has led to questions on the safety and effectiveness of cannabinoid therapies. Although there are conditions for which cannabinoids may be helpful, potential contraindications, adverse effects, and drug-drug interactions should be taken into account. ConclusionPharmacists are in a unique position based on their accessibility, knowledge, and skills to guide product selection, dosing, and discuss drug interactions and adverse effects to educate patients on safe cannabis use, whether it be delta-9-tetrahydrocannabinol, cannabidiol, or a combination thereof. Pharmacists and pharmacy organizations, moreover, should advocate for an integral role in the medical cannabis movement to ensure patient safety and evaluate cannabinoid pharmacology, pharmacokinetics, drug-drug interactions, safety, and efficacy through rigorous investigations.

Medical cannabis for chronic pain: can it make a difference in pain management?

Globally, chronic pain is a major therapeutic challenge and affects more than 15% of the population. As patients with painful terminal diseases may face unbearable pain, there is a need for more potent analgesics. Although opioid-based therapeutic agents received attention to manage severe pain, their adverse drug effects and mortality rate associated with opioids overdose are the major concerns. Evidences from clinical trials showed therapeutic benefits of cannabis, especially delta-9-tetrahydrocannabinol and cannabinoids reduced neuropathic pain intensity in various conditions. Also, there are reports on using combination cannabinoid therapies for chronic pain management. The association of cannabis dependence and addiction has been discussed much and the reports mentioned that it can be comparatively lower than other substances such as nicotine and alcohol. More countries have decided to legalise the medicinal use of cannabis and marijuana. Healthcare professionals should keep themselves updated with the changing state of medical cannabis and its applications. The pharmacokinetics and safety of medical cannabis need to be studied by conducting clinical research. The complex and variable chemically active contents of herbal cannabis and methodological limitations in the administration of cannabis to study participants, make the clinical research difficult.

Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington's disease.

Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown. Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation. This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.

Urinary cannabinoid levels during nabiximols (Sativex®)-medicated inpatient cannabis withdrawal

Nabiximols (Sativex®) is a buccal spray containing both ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD). It has shown promise as an agonist substitution therapy for treating cannabis withdrawal and dependence. Monitoring urinary cannabinoid levels during treatment is important for determination of cannabinoid pharmacokinetics and for treatment adherence during clinical trials. Here, we use a recently described hydrolysis method to liberate urinary CBD from its glucuronide conjugate, and describe the trajectory of urinary CBD, THC, 11-nor-9-carboxy-THC (THC-COOH), and 11-hydroxy-THC (11-OH-THC) in patients receiving nabiximols treatment (or placebo) during cannabis withdrawal. Urine and plasma samples were taken before and during a 6-day inpatient treatment regime and during a 3-day drug-free washout. Urine was hydrolysed with red abalone β-glucuronidase, and CBD, THC, THC-COOH, and 11-OH-THC were quantified in daily urine using liquid chromatography-tandem mass spectrometry. Overall, urine and plasma cannabinoid levels followed similar trajectories and closely reflected the dosing schedule. During nabiximols treatment, CBD levels in urine and plasma rose markedly, while concentrations of THC and its metabolites remained at, or slightly above, pre-treatment levels. Following hydrolysis, urinary CBD was detected at levels 50 and 200 times as high as those in non-hydrolysed plasma and non-hydrolysed urine, respectively. THC, THC-COOH, and 11-OH-THC concentrations were also amplified by urinary hydrolysis. This method allows sensitive assessment of urinary CBD, and may prove useful in clinical studies involving nabiximols or other cannabinoid therapies.

Abstract B83: Cannabinoids as an adjuvant therapy for pancreatic cancer

Abstract In over 20 states, cancer patients have access to cannabinoids (aka medical marijuana) to treat symptoms of chemotherapy, such as nausea and lack of appetite. However, new evidence, both scientific and empirical, suggests that higher doses of cannabinoids may be an effective adjuvant alongside traditional chemotherapy agents, such as Gemcitibine. While daily dosages of 10 to 40mg are commonly used to control nausea, pancreatic cancer cells are known to over express the endo-cannabinoid receptor CB1 one hundred fold, requiring much higher dosages. Cannabinoids target different receptors than traditional chemotherapy agents with low combinatorial toxicity, and as such present a class of new treatments. In an n=1 study of a patient with stage IV pancreatic adeno-carcinoma, we augmented the standard Gemcitibine chemotherapy with balanced initial doses of 50mg THC and 50mg CBD that increased over a four week period to achieve a 12.5 mg/kg total cannabinoid dosage. Curiously, after ten days the patient stopped presenting signs of cannabinoid use, such as red eyes, slurred speech and clumsiness. However, the patient’s CA-19-9 marker increased from 8,800 ul/L at diagnosis to 25,500. Over the next four weeks, dosage of CBD was held constant and THC was increased to 1050mg daily for a combined dosage of 20mg/kg. At week 6, the CA-19-9 marker began decreasing and cannabinoid dosage was leveled off, although a higher dosage was planned for weeks 8-12. At week 15, CA-19-9 markers dropped to pre-diagnosis levels and a CAT scanned revealed shrinkage of the tumor. Rate of decrease in CA-19-9 exceeded previously published rates for patients with positive outcomes from Gemcitibine alone. Although many pancreatic cancer patients have access to cannabinoids, issues such as potency, purity and bio-availablity will impact future adjuvant cannabinoid therapies. We have addressed these issues with existing technology in the hopes of supporting large scale trials that will examine the efficacy of Gemcitibine + cannabinoid adjuvants in the treatment of pancreatic cancer. Citation Format: Andy D. Hospodor. Cannabinoids as an adjuvant therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B83.

Current Status and Future of Cannabis Research

Cannabis sativa has a long history of medicinal use and contains phytocannabinoids that demonstrate therapeutic activity in preclinical models of numerous disease states. Widespread clinical use of cannabis has preceded the evidence base. Randomized controlled trials are needed to understand the safety, efficacy, and optimal dosages of standardized cannabis preparations. In addition to regulatory and legal challenges,certain botanical and pharmacologic factors that complicate the collection and interpretation of clinical data on the efficacy of cannabinoid therapies are reviewed.

CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer's disease.

The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-) mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(+/+) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

Prospects for cannabinoid therapies in viral encephalitis

Cannabinoids are promising therapies to support neurogenesis and decelerate disease progression in neuroinflammatory and degenerative disorders. Whether neuroprotective effects of cannabinoids are sustainable during persistent viral infection of the CNS is not known. Using a rodent model of chronic viral encephalitis based on Borna Disease (BD) virus, in which 1 week treatment with the general cannabinoid WIN 55,212-2 has been shown to be neuroprotective (Solbrig et al., 2010), we examine longer term (2 week treatment) effects of a general (CB1 and CB2) cannabinoid receptor agonist WIN55,212-2 (1mg/kg ip twice per day) or a specific (CB2) cannabinoid receptor agonist HU-308 (5mg/kg ip once daily) on histopathology, measures of frontostriatal neurogenesis and gliogenesis, and viral load. We find that WIN and HU-308 differ in their ability to protect new BrdU+ cells. The selective CB2 agonist HU increases BrdU+ cells in prefrontal cortex (PFC), significantly increases BrdU+ cells in striatum, differentially regulates polydendrocytes vs. microglia/macrophages, and reduces immune activation at a time WIN-treated rats appear tolerant to the anti-inflammatory effect of their cannabinoid treatment. WIN and HU had little direct viral effect in PFC and striatum, yet reduced viral signal in hippocampus. Thus, HU-308 action on CB2 receptors, receptors known to be renewed during microglia proliferation and action, is a nontolerizing mechanism of controlling CNS inflammation during viral encephalitis by reducing microglia activation, as well as partially limiting viral infection, and uses a nonpsychotropic cannabinoid agonist.