Cannabinoid Formulations Research Articles

Nabiximols (NBX) suppresses tremor in a rat Harmaline model of essential tremor

BackgroundEssential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9–12 Hz in rats, comparable to that of human ET (4–12 Hz). PurposeInterestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET. MethodWe tested the effects of acute (single dose) and subchronic (10 days) treatment of NBX (at 5.2, 10.4 and 20.8 mg kg−1 p.o.) administered prior to harmaline and acute NBX (20.8 mg kg−1) administered post-harmaline in male SD rats. Propranolol (20 mg kg−1 i.p.) was used as a positive control. Observed Scoring (OS) was carried out prior to placement in a tremor-monitoring apparatus for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP). ResultsAcute and subchronic NBX significantly attenuated harmaline-induced tremor at 10.4 and 20.8 mg kg−1, respectively, for each parameter (OS, TI, and MPP) when administered pre-harmaline as did propranolol (20 mg kg−1). NBX did not attenuate harmaline-induced tremor when administered post-harmaline. ConclusionsThese data suggest efficacy of acute and subchronic NBX to reduce tremors, based on OS, TI and MPP readouts if administered prior to harmaline. These data are the first to indicate the preclinical effects of an oral botanical cannabinoid formulation, NBX, in an animal model of ET.

Cannabinoids in Integumentary Wound Care: A Systematic Review of Emerging Preclinical and Clinical Evidence.

This systematic review critically evaluates preclinical and clinical data on the antibacterial and wound healing properties of cannabinoids in integument wounds. Comprehensive searches were conducted across multiple databases, including CINAHL, Cochrane library, Medline, Embase, PubMed, Web of Science, and LILACS, encompassing records up to May 22, 2024. Eighteen studies met the inclusion criteria. Eleven were animal studies, predominantly utilizing murine models (n = 10) and one equine model, involving 437 animals. The seven human studies ranged from case reports to randomized controlled trials, encompassing 92 participants aged six months to ninety years, with sample sizes varying from 1 to 69 patients. The studies examined the effects of various cannabinoid formulations, including combinations with other plant extracts, crude extracts, and purified and synthetic cannabis-based medications administered topically, intraperitoneally, orally, or sublingually. Four animal and three human studies reported complete wound closure. Hemp fruit oil extract, cannabidiol (CBD), and GP1a resulted in complete wound closure in twenty-three (range: 5-84) days with a healing rate of 66-86% within ten days in animal studies. One human study documented a wound healing rate of 3.3 cm2 over 30 days, while three studies on chronic, non-healing wounds reported an average healing time of 54 (21-150) days for 17 patients by oral oils with tetrahydrocannabinol (THC) and CBD and topical gels with THC, CBD, and terpenes. CBD and tetrahydrocannabidiol demonstrated significant potential in reducing bacterial loads in murine models. However, further high-quality research is imperative to fully elucidate the therapeutic potential of cannabinoids in the treatment of bacterial skin infections and wounds. Additionally, it is crucial to delineate the impact of medicinal cannabis on the various phases of wound healing. This study was registered in PROSPERO (CRD42021255413).

Cannabinoids for Inflammatory Bowel Disease: A Scoping Review.

Purpose: Inflammatory bowel disease (IBD) has two main variants, ulcerative colitis (UC) and Crohn's disease (CD), which are characterized by a cycle of remission and relapse. The aim of this scoping review is to understand the landscape of unprescribed and prescribed cannabis use among patients with IBD and investigate objective clinical benefits. Methodology: A literature search was performed across Medline, Embase via Ovid, Scopus, and Cochrane Library databases. We included 40 studies (14 abstracts/letters, 7 randomized controlled trials [RCTs], 6 cohort studies [2 case-matched], 10 cross-sectional surveys, and 3 meta-analyses) in the review. Results: Between 11% and 17.6% of surveyed patients used cannabis for symptom control with a lifetime prevalence of 39.8-78.2%. Patients reported reduced abdominal pain, emotional distress, stool frequency, and anorexia. There was a higher rate of depression, tobacco, and alcohol use among patients with IBD who used cannabis. Individual studies showed patients who were prescribed cannabis were more likely to have had surgery for IBD (14.5% vs. 4.7%, p = 0.0008), require future abdominal surgery (odds ratio = 5.03), report a lower quality of life (p = 0.0001), currently be on corticosteroids (18.1% vs. 10.4%, p = 0.04) and opioids (27.7% vs. 6.4%, p = 0.0001). RCTs of cannabinoids reported mild reductions in disease activity and variable endoscopic inflammation improvement. Conclusions: Patients who use cannabis for IBD are a cohort with refractory disease and lower quality of life who report improvements in symptom management. However, the ability to reduce underlying disease activity appears very modest. Further trials using refined cannabinoid formulations may define a use in IBD.

Cannabis Science and Therapeutics: An Overview for Clinicians.

Cannabis-based therapeutics have garnered increasing attention in recent years as patients seek alternative treatments for various medical conditions. This narrative review provides a comprehensive overview of the science behind the medical use of cannabis, focusing on the medical evidence for commonly treated conditions. In addition, the review addresses the practical considerations of using cannabis as a therapeutic agent, offering insights into dosing strategies, variations in cannabinoid formulation, and individual patient responses. Precautions, adverse consequences, and drug interactions are also discussed, with a focus on patient safety and the potential risks associated with cannabis use.

Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study.

Cannabidiol (CBD) is a non-psychoactive cannabinoid, and available evidence suggests potential efficacy in the treatment of many disorders. DehydraTECH™2.0 CBD is a patented capsule formulation that improves the bioabsorption of CBD. We sought to compare the effects of CBD and DehydraTECH™2.0 CBD based on polymorphisms in CYP P450 genes and investigate the effects of a single CBD dose on blood pressure. In a randomized and double-blinded order, 12 females and 12 males with reported hypertension were given either placebo capsules or DehydraTECH™2.0 CBD (300 mg of CBD, each). Blood pressure and heart rate were measured during 3 h, and blood and urine samples were collected. In the first 20 min following the dose, there was a greater reduction in diastolic blood pressure (p = 0.025) and mean arterial pressure MAP (p = 0.056) with DehydraTECH™2.0 CBD, which was probably due to its greater CBD bioavailability. In the CYP2C9*2*3 enzyme, subjects with the poor metabolizer (PM) phenotype had higher plasma CBD concentrations. Both CYP2C19*2 (p = 0.037) and CYP2C19*17 (p = 0.022) were negatively associated with urinary CBD levels (beta = -0.489 for CYP2C19*2 and beta = -0.494 for CYP2C19*17). Further research is required to establish the impact of CYP P450 enzymes and the identification of metabolizer phenotype for the optimization of CBD formulations.

The Safety and Comparative Effectiveness of Non-Psychoactive Cannabinoid Formulations for the Improvement of Sleep: A Double-Blinded, Randomized Controlled Trial

Background Clinical evidence on the use of cannabidiol (CBD) for sleep remains limited. Even fewer studies have tested the comparative effectiveness of cannabinoid formulations found within CBD products used for sleep or how they compare to other complementary therapies such as melatonin. Methods Participants (N = 1,793 adults experiencing symptoms of sleep disturbance) were randomly assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15 mg CBD or 5 mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed over a period of 5 weeks (baseline week and 4 weeks of product use) using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. A linear mixed-effects regression model was used to assess the differences in the change in sleep disturbance through time between each active product arm and CBD isolate. Results All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p < 0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15 mg CBD isolate and formulations containing 15 mg CBD and 15 mg cannabinol (CBN), alone or in combination with 5 mg cannabichromene (CBC). There were also no significant differences in effect between 15 mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15 mg CBD and 15 mg CBN. Conclusions Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.

Cannabis and Sleep: A Systematic Review of the Effects of Cannabinoids on Sleep Disorders

Introduction: Sleep disorders are a common problem in society in the modern world. Patients are increasingly seeking alternative treatments for insomnia in order to reduce the side effects of prescription drugs. A new trend is the use of cannabinoids contained in cannabis plants to treat sleep disorders, making patients looking for a solution to their problem more and more eager.Aim of the study: The purpose of this paper is to present contemporary knowledge of the therapeutic benefits of cannabis compounds in treating sleep disorders and improving sleep parameters. Materials and methods: The National Center for Biotechnology Information/PubMed and Google Scholar medical databases were comprehensively analyzed by entering the keywords: cannabis, sleep disorders, insomnia, cannabinoids, THC, CBD in their respective configurations. Analyzing the searched literature, data from 18 scientific articles from the last five years (2017-2022) were evaluated.Results: Cannabinoids may have benefits in sleep-related disorders. The literature does not agree on the effectiveness of their use in treating sleep disorders. The highly variable availability of cannabinoid formulations on the market makes it difficult to develop appropriate dosages for the treatment of insomnia.Conclusions: Research on cannabis and sleep is in its early stages and needs to be continued in order to improve knowledge. There is a need for further long-term studies that are rigorously controlled and use larger study groups.

A review of studies evaluating medical cannabis for the chronic pain management

Introduction: Medical cannabis for patients with chronic pain related to various conditions has been the focus of numerous investigations. Cannabis-based medicine has been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits. &#x0D; State of knowledge: As the results of studies assessing medical cannabis in pain alleviate seem promising, only weak recommendations are available. Important factors to consider in the development of guidelines include optimal doses, routes of administration and used types of cannabinoids. In discussed studies no serious adverse events were reported and treatment was well tolerated by participants.&#x0D; Conclusions: Evidence suggests that cannabis-based medicine can be safe and effective in pain relief. Further high-quality randomised clinical trial studies are needed. It is important to assess the safety profile of each individual cannabinoid formulation and define the population that can benefit from cannabis therapy for establishment of prospective recommendations and guidelines.

Pharmacists’ expertise wanted on cannabinoid drug–drug interactions

Pharmacists know patients are using cannabis or are taking cannabidiol (CBD) for things like insomnia and pain—use of these products is only growing as is the number of different cannabinoid formulations. But little is known about the unintended interactions between cannabinoids and medications.

613 Evaluation of Non-Euphoric Phytocannabinoid Elixir 14 (NEPE-14) Application in Deep Partial-Thickness Burn Wounds

IntroductionCombat-related burn wounds can be caused by exposure to a wide variety of agents including heat, electricity, radiation, chemicals, and friction. Early intervention can decrease injury severity by preventing excess inflammation and improve long term healing outcomes. In recent years, numerous studies have demonstrated that cannabinoids can trigger anti-inflammatory responses and promote wound closure. This study investigates whether a proprietary, non-euphoric, topical cannabinoid formulation (NEPE-14) facilitates burn wound healing when compared with Silverlon®, the military standard of care for burns incurred while in the field.MethodsForty-eight deep-partial thickness burns were created on the dorsum of four anesthetized swine (Sus scrofa domestica) using a thermocoupled burn device at 100°C. One hour following burn, biopsies from each site were collected and either NEPE-14, NEPE-14 Vehicle Control, Silverlon®, or dry gauze was placed on the wound. Wounds were assessed on post-burn days (PBD) 3, 7 and 14. Assessments consisted of digital photographs, Laser-Speckle imagery (blood perfusion), FLIR imagery, MolecuLight® imagery and biopsies for histology and immunohistochemistry.ResultsBy PBD 14, no significant differences in re-epithelialization or contraction were observed between any of the tested treatment groups. Silverlon® had the highest percent re-epithelialization with 42%, and the Vehicle control has the lowest percent re-epithelialization with 28 %. Both NEPE-14 and dry gauze performed intermediately with 29% and 34% re-epithelialization, respectively. On PBD 14, the wounds of the NEPE-14 treated wounds contracted 8%, the vehicle control 7%, Silverlon® treated wounds 10%, and gauze treated wounds showed 9% contraction compared with the original wound area. Blood perfusion at PBD 14 indicated that NEPE-14 treated wounds had the lowest amount of observed blood flow and the gauze treated wounds contained the highest amount of observed blood flow. However, no statistically significant differences were observed.ConclusionsNo statistically significant results were seen between treatment groups for contraction, re-epithelialization, or blood perfusion. Although not significant, blood perfusion results indicate that NEPE-14 treatment had the lowest amount of blood flow, which can be seen as an indicator of healthy underlying tissue and a wound re-epithelializing. At PBD 14, all treatment groups had slightly contracted after increasing in wound area on PBD 3 and 7, which is a pattern seen in similar burn injury studies. We are currently awaiting histological analysis to strengthen our re-epithelialization results and evaluate burn wound progression.

Cannabis with breast cancer treatment: propitious or pernicious?

The online version contains supplementary material available at 10.1007/s13205-021-03102-1.

Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain.

The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients’ quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.

The anti-inflammatory effects of cannabidiol and cannabigerol alone, and in combination

Introduction/background and purposeStudies with Cannabis Sativa plant extracts and endogenous agonists of cannabinoid receptors have demonstrated anti-inflammatory, bronchodilator, and antitussive properties in the airways of allergic and non-allergic animals. However, the potential therapeutic use of cannabis and cannabinoids for the treatment of respiratory diseases has not been widely investigated, in part because of local irritation of airways by needing to smoke the cannabis, poor bioavailability when administered orally due to the lipophilic nature of cannabinoids, and the psychoactive effects of Δ9-Tetrahydrocannabinol (Δ9-THC) found in cannabis. The primary purpose of this study was to investigate the anti-inflammatory effects of two of the non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG) alone and in combination, in a model of pulmonary inflammation induced by bacterial lipopolysaccharide (LPS). The second purpose was to explore the effects of two different cannabinoid formulations administered orally (PO) and intraperitoneally (IP). Medium-chain triglyceride (MCT) oil was used as the sole solvent for one formulation, whereas the second formulation consisted of a Cremophor® EL (polyoxyl 35 castor oil, CrEL)-based micellar solution. ResultsExposure of guinea pigs to LPS induced a 97 ± 7% and 98 ± 3% increase in neutrophils found in bronchoalveolar lavage fluid (BAL) at 4 h and 24 h, respectively. Administration of CBD and CBG formulated with MCT oil did not show any significant effects on the LPS-induced neutrophilia measured in the BAL fluid when compared with the vehicle-treated groups. Conversely, the administration of either cannabinoid formulated with CrEL induced a significant attenuation of the LPS induced recruitment of neutrophils into the lung following both intraperitoneal (IP) and oral (PO) administration routes, with a 55–65% and 50–55% decrease in neutrophil cell recruitment with the highest doses of CBD and CBG respectively. A combination of CBD and CBG (CBD:CBG = 1:1) formulated in CrEL and administered orally was also tested to determine possible interactions between the cannabinoids. However, a mixture of CBD and CBG did not show a significant change in LPS-induced neutrophilia. Surfactants, such as CrEL, improves the dissolution of lipophilic drugs in an aqueous medium by forming micelles and entrapping the drug molecules within them, consequently increasing the drug dissolution rate. Additionally, surfactants increase permeability and absorption by disrupting the structural organisation of the cellular lipid bilayer. ConclusionIn conclusion, this study has provided evidence that CBD and CBG formulated appropriately exhibit anti-inflammatory activity. Our observations suggest that these non-psychoactive cannabinoids may have beneficial effects in treating diseases characterised by airway inflammation.

Anti-inflammatory Effect of Cannabidiol and Palmitoylethanolamide Containing Topical Formulation on Skin in a 12- O -Tetradecanoylphorbol-13-Acetate-Induced Dermatitis Model in Mice.

Chronic inflammatory skin disorders, such as atopic dermatitis, have significant disease burden worldwide. Although efficacious, the adverse effect profile of topical corticosteroids limits long-term use. As an alternative, cannabinoids have been shown to have anti-inflammatory therapeutic effects. The aim of this study was to assess the effects of a topical cannabinoid product using dermatitis mouse model. Thirty-five mice were randomized into treatment groups. 12- O -tetradecanoylphorbol-13-acetate was used as an irritant on 1 ear with the contralateral ear serving as a control. Ear edema was calipered. The test product containing 0.9% cannabidiol and palmitoylethanolamide was compared with a potent topical corticosteroid. Treatment with topical cannabinoid formulation reduced ear edema by 51.27% at 24 hours' and 65.69% at 48 hours' postapplication. Alternatively, mometasone reduced ear edema by 89.82% at 24 hours and 98.25% at 48 hours. Natural reduction (control) in ear edema was 26.32% at 24 hours and 44.21% at 48 hours. Both test groups resulted in significantly decreased edema when compared with baseline ( P < 0.05), as well as compared with the negative control group ( P < 0.05). Significant reduction in ear edema, a marker for localized cutaneous inflammation, could be attributed to anti-inflammatory properties of cannabinoids. Although effects were less robust than topical corticosteroid use, cannabinoid formulations have therapeutic promise for dermatitis.

Psychiatric Disorders and Cannabinoid Receptors.

With the increasing global use of medical and adult recreational use of cannabis and cannabinoids, this chapter provides overview of evidence from animal and human studies on psychiatric disorders and cannabinoid receptors. We review and present evaluation of the relationship between changes in the ECS and psychiatric disorders. Evidence suggests the existence of a relationship between changes in components of the ECS, and some of the symptoms present in psychiatric disorders. Both CB1Rs and CB2Rs are components of the endocannabinoid system with different cellular and tissue localization patterns that are differentially expressed in the CNS and PNS and are emerging targets for the treatment of number psychiatric disorders. As cannabis preparations are widely used for recreation globally, it is predictable that cannabis use disorders (CUDs) will increase and there is currently no available treatment for CUDs. Although major advances have been reported from cannabinoid and ECS research, there are gaps in scientific knowledge on long-term consequences of cannabis use. Adolescent and cannabis use during pregnancy presents further challenges, and more research will uncover the signaling pathways that couple the gut microbiota with the host ECS. Development of cannabis and cannabinoid nanomedicine for nanotherapy will certainly overcome some of the shortcomings and challenges in medicinal and recreational use of cannabis and cannabinoids. Thus, nanotechnology will allow targeted delivery of cannabinoid formulations with the potential to elevate their use to scientifically validated nanotherapeutic applications as the field of cannabis nanoscience matures.

Effect of a Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) formulation on cell monolayer viability and mitochondria integrity: Significance of the drug carrier/delivery system

Background: The increasing availability and abuse of recreational and medical cannabis has been associated with patients presenting with cyclical nausea, vomiting, intestinal cramps, and other manifestations, referred to as cannabinoid hyperemesis syndrome. An exact etiologic mechanism, especially on the cellular level, remains unclear. Continual studies are needed to address the effect of cannabinoid activity specifically addressing that which occurs in the gastrointestinal tract. Methods: Cannabinoids in general, are immiscible in water-based cell culture media. Homogenization was performed to bring a THC/CBD formulation into a workable state for in vitro testing. The human colon adenocarcinoma (HT-29) epithelia cell line was used throughout this study. Mitochondrial cytotoxicity testing was performed using a fluorescein conjugated monoclonal antibody to the organelle’s outer membrane protein. Mitochondrial morphology was performed by transmission electron microscopy utilizing a commercially available cannabidiol product. Cell cultures, incubated with 50 to 125 µg/ml of a THC/CBD formulation for 72-h, were viewed daily for the appearance of a monolayer degeneration or a cytopathogenic effect. Results: Cell monolayers treated with non-homogenized THC/CBD in phosphate-buffered saline or utilizing DMSO as analyte diluents, proved unremarkable. However, homogenization of the cannabinoid formulation at > 50 µg/ml affected a loss of monolayer confluency and mitochondrial membrane surface protein. Treatment of monolayers with CBD affected a loss of mitochondrial morphology as observed by an absence of organelle cristae and matrix structure. Mitochondrial loss of surface protein integrity occurred prior to monolayer degeneration. Conclusion: A cytotoxic effect was realized in colon cell cultures following treatment with a cannabinoid liquid tincture formulation at concentrations > 50 µg/ml. The degenerative effect by the cannabinoid formulation was directed initially to a marked loss of mitochondrial morphology and loss of [organelle] surface integrity, followed by a monolayer degeneration. Critically, the immiscible THC/CBD analyte mandated a size distribution of lipid globules to single digit of smaller µM particulates. Globule reduction was achieved by high speed homogenization. Additional studies in the animal model are needed to further address our findings in the search for an etiology to cannabinoid hyperemesis syndrome.

An oro-buccal nanoparticle delivered cannabis medicine for pain management in cancer: A clinical trial in progress.

TPS12127 Background: Cannabinoid molecules derived from Cannabis sativa L. have been posited to ameliorate conditions, including pain, chemotherapy induced nausea and multiple sclerosis associated spasticity. The clinical use of cannabinoids refers to a wide variety of formulations and extracts that may contain different active ingredients and adulterants as well as inter batch variability. Novel matrix formulations (e.g., water-soluble nanoparticles) for cannabis delivery may add further efficacy and tolerability to standard routes of administration (e.g., oral / gastrointestinal, inhaled, sublingual). This is further emphasized by the dysbiotic effects on the intestinal microbiome reported for oral formulations of medicinal cannabis, and which resulted in reduced efficacy. Similar results have been reported for other psychotropic compounds, such as alcohol and nicotine. Therapeutic use of cannabinoid formulations may be mode of delivery dependent in order to achieve safe, tolerable and effective doses. Methods: A water soluble oro-buccal nanoparticle spray with a racemic 1:1 mixture of Delta9Tetrahydrocannabinol (D9THC) and Cannabidiol (CBD), which bypasses the gastrointestinal system and first pass metabolism by accessing the systemic circulation via the facial lymphatics system, was investigated in patients with advanced cancer and unrelieved pain in a single ascending dose and multiple ascending dose in a first-in-human study. Results: The THC / CBD combination delivered as a submicron particle demonstrated safety, tolerability and a pharmacokinetic profile suitable for maintenance analgesic therapy. Preliminary analysis found an overall (n = 25) improvement in pain scores, especially in the subgroup of patients with bone metastases (n = 8), who obtained a greater than 30% average reduction in pain severity. 1 Clinical trial information: ACTRN12617001480370 .

Evidence for the use of cannabinoids in Parkinson’s disease

Cannabis and synthetic cannabinoid formulations have now been legally approved in several countries for treatment of patients with Parkinson's disease (PD). Hence, PD patients consult physicians more frequently for prescription of cannabinoids to alleviate symptoms that might not respond well to dopaminergic treatment. Despite the increasing volume of research generated in the field of cannabinoids and their effect on Parkinson's disease, there is still paucity of sufficient clinical data about the efficacy and safety in PD patients. There is increasing understanding of the endocannabinoid system, and the distribution of cannabinoid receptors in basal ganglia structures might suggest potential benefit on parkinsonian symptoms. Concerning clinical research, only one of to date four conducted randomized placebo-controlled trials showed an effect on motor symptoms with alleviation of levodopa-induced dyskinesia. There are a growing number of uncontrolled trials and case reports that suggest beneficial effects of cannabinoids in PD patients. However, the variety of substances investigated, the varying routes of intake, differing doses and time courses make it difficult to compare data. We here provide an overview of the current literature in this field and discuss a pragmatic approach for the clinical use of cannabinoids in PD.

Complete biosynthesis of cannabinoids and their unnatural analogues in yeast.

Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia1. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications2. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments3. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids4, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway5. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid6, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases7,8. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency9. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems.

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta-analysis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS because of their anti-excitotoxicity, anti-oxidant and anti-inflammatory effects. Preclinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta-analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; nine studies using cannabinoid treatment in transgenic SOD1-G93A ALS-model mice and one study in TDP-43 transgenic mice. Eight of the nine studies that used SOD1-G93A mice expressed similarly high copy numbers of the transgene while one study used a low-copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta-analysis of the mean difference in survival time across the seven studies showed an increase in survival of 3.84days (95% CI: 0.35-7.32days; p=0.031) for cannabinoid treated compared to control SOD1-G93A mice. It was not possible to conduct meta-analyses for motor function decline or weight loss. However, eight of nine studies reported significant improvements in measures of motor function decline and one reported non-significant improvements. Weight loss was significantly attenuated in four of five studies reporting this measure while the other study reported a non-significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS. OPEN SCIENCE BADGES: This article has received a badge for *Preregistration* because the study was pre-registered at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=89274. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. ReadtheEditorialHighlightforthisarticleonpage168.