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Journal: Cannabis and cannabinoid research


Background: Benzodiazepines are a class of medication with sedative properties, commonly used for anxiety and other neurological conditions. These medications are associated with several well-known adverse effects. This observational study aims to investigate the reduction of benzodiazepine use in patients using prescribed medical cannabis. Methods: A retrospective analysis was performed on a cohort of 146 medical cannabis patients (average age 47 years, 61% female, 54% reporting prior use of cannabis) who reported benzodiazepine use at initiation of cannabis therapy. These data are a part of a database gathered by a medical cannabis clinic (Canabo Medical). Descriptive statistics were used to quantify associations of the proportion of benzodiazepine use with time on medical cannabis therapy. Results: After completing an average 2-month prescription course of medical cannabis, 30.1% of patients had discontinued benzodiazepines. At a follow-up after two prescriptions, 65 total patients (44.5%) had discontinued benzodiazepines. At the final follow-up period after three medical cannabis prescription courses, 66 total patients (45.2%) had discontinued benzodiazepine use, showing a stable cessation rate over an average of 6 months. Conclusion: Within a cohort of 146 patients initiated on medical cannabis therapy, 45.2% patients successfully discontinued their pre-existing benzodiazepine therapy. This observation merits further investigation into the risks and benefits of the therapeutic use of medical cannabis and its role relating to benzodiazepine use.


Cannabidiol (CBD) is 1 of > 100 cannabinoids found in Cannabis sativa L. (Cannabis spp. or Cannabis). Despite its complex and rapidly evolving regulatory status in the United States, projected retail sales of CBD products-hemp, Cannabis and pharmaceutical-are as high as $1.9 billion by 2020. CBD products can currently be purchased online, over the counter, and at Cannabis-specific dispensaries throughout most parts of the country, despite the fact that CBD is presently deemed a Schedule I controlled substance by the U.S. Drug Enforcement Administration and renounced as a dietary supplement ingredient by the U.S. Food and Drug Administration (FDA). These products are largely unregulated, and are being used predominantly to treat specific medical conditions. Recent FDA approval of Epidiolex (CBD) as a treatment for certain pediatric seizure disorders will prompt scheduling of CBD and likely alter FDA enforcement of the Federal Food, Drug, and Cosmetic Act (FD&C), which to date has mostly been in the form of warning letters. Persuasive legal arguments contend that CBD’s legal status is based on its source. According to these arguments, there are three legal sources. CBD-derived from: (1) parts of the Cannabis plant that do not meet the definition of cannabis in the Controlled Substances Act (CSA); (2) imported “non-psychoactive hemp”; and (3) “Industrial hemp” cultivated as part of a state pilot program per the 2014 Farm Act. Although CBD’s lawful status with respect to the CSA appears to be expanding, its future regulatory status with respect to the FD&C Act is difficult to predict.


Introduction: Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro. Materials and Methods: Potassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real time using FLIPR® membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 min. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels. Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%. Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.


Background: The emergence of a multidrug-resistant strain of Plasmodium falciparum (Pf Pailin) raises concern about malaria control strategies. Unfortunately, the role(s) of natural plants/remedies in curtailing malaria catastrophe remains uncertain. The claims of potential antimalarial activity of Cannabis sativa in vivo have not been well established nor the consequences defined. This study was, therefore, designed to evaluate the effects of whole cannabis consumption on malaria-infected host. Methods: Thirty mice were inoculated with dose of 1×107 chloroquine-resistant Plasmodium berghei ANKA-infected erythrocyte and divided into six treatment groups. Cannabis diet formulations were prepared based on weighted percentages of dried cannabis and standard mice diet and the study animals were fed ad libitum. Chemosuppression of parasitemia, survival rates, parasite clearance, and recrudescence time were evaluated. Histopathological studies were performed on the prefrontal cortex (PFC) and hippocampus of the animals after 14 days' consumption of cannabis diet formulation by naive mice. Results: There was a significant difference (p<0.05) in the day-4 chemosuppression of parasitemia between the animals that were fed C. sativa and chloroquine relative to the untreated controls. There was also a significant difference in the survival rate (p<0.05) of animals fed C. sativa diet (40%, 20%, 10%, and 1%) in contrast to control animals on standard mice diet. A parasite clearance time of 2.18±0.4 was recorded in the chloroquine treatment group, whereas recrudescence in chloroquine group occurred on day 7. There were slight histomorphological changes in the PFC and cell densities of the dentate gyrus of the hippocampus of animals that were fed C. sativa.Conclusions:C. sativa displayed mild antimalarial activity in vivo. There was evident reduction in symptomatic manifestation of malaria disease, though unrelated to levels of parasitemia. This disease tolerance status may be beneficial, but may also constitute a transmission burden through asymptomatic carriage of parasites by habitual cannabis users.


Introduction: Phytocannabinoids, characteristic compounds produced by medical cannabis, interact with cannabinoid (CB) receptors (CB1 and CB2) as well as other receptor systems to exhibit their corresponding pharmacological effects. In their natural form, CBs such as Δ9-tetrahydrocannabinolic acid and cannabidiolic acid are inactive at these receptors, while their decarboxylated forms (Δ9-tetrahydrocannabinol and cannabidiol, respectively) are potent ligands at CB receptors. Thus, extraction and processing of medical cannabis for active constituents are important. Purpose and Methods: Patients consuming medical cannabis often have limited alternative treatment options and in recent years, medical cannabis extracts have been popular as a substitute for dried cannabis plants, despite limited studies on these derivatives. We investigated three disparate cannabis cultivars and compared four chemical extraction methods head to head, viz. Soxhlet, ultrasound-assisted supercritical fluid, and microwave-assisted extractions, for their efficiency. We further characterized the chemical compositions of these extracts. Results: Microwave extraction consistently produced completely decarboxylated phytocannabinoid extracts. Factors such as temperature and exposure time play important roles in the decarboxylation of phytocannabinoids, thereby generating pharmacologically active CBs, and these conditions may differ for each cannabis cultivar. Conclusion: Chemical consistency and potency due to active compounds are in turn important in producing consistent and reliable medical cannabis extracts and their derivatives. These processes must be subject to higher levels of scientific rigor as the patient population around the world are seeking the help of such extracts for various clinical conditions, and as medical cannabis industry is receiving acceptance in various countries.


Introduction:Cannabis sativa has been used for centuries in treating pain. However, the analgesic role of many of its constituents including terpenes is unknown. This research examined the contributions of terpenes (volatile oil) and cannabinoids in cannabis-mediated analgesia in rats. Methods: Animals received intraperitoneal administration of either vehicle, 10.0 or 18.0 mg/kg morphine, or various doses of the extract without terpenes, isolated terpenes, Δ9-tetrahydrocannabinol (THC), or the full extract. Thirty minutes later animals were tested on hotplate and tail-flick tests of thermal nociception. One week later, rats received a second administration of test articles and were tested 30 min later in the abdominal writhing test of inflammatory nociception. Results: In the thermal assays, hotplate and tail-flick latencies for morphine-treated rats were dose dependent and significantly higher than vehicle-treated animals. All the cannabinoid compounds except for the isolated terpenes produced dose-dependent increases in hotplate and tail-flick latencies. In the inflammatory nociceptive assay, animals treated with vehicle and isolated terpenes demonstrated increased abdominal writhing, whereas all the cannabinoid compounds significantly decreased abdominal writhing responses. Conclusions: Overall, THC alone produced robust analgesia equivalent to the full cannabis extract, whereas terpenes alone did not produce analgesia. These data suggest the analgesic activity of cannabis is largely mediated by THC, whereas terpenes alone do not cause alterations in cannabis-mediated analgesia.


Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: # NCT01874886.


Introduction and Objective: Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB1). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure-activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules. To extend the SAR investigation of the indole-2-carboxamide class of CB1 allosteric modulators, azaindole (pyrrolopyridine) rings were used to replace the indole ring of Org27569 analogs to explore the potential of azaindole-2-carboxamides as CB1 allosteric modulators. Using 6- and 7-azaindole in lieu of the indole moiety within this class of CB1 allosteric modulators indeed improved the aqueous solubility. Materials and Methods: We synthesized 6- and 7-azaindole-2-carboxamides and their indole-2-carboxamide counterparts. The molecules were evaluated by [3H]CP55,940 binding and [35S]GTPγS binding assays for their allosteric modulation of the CB1 receptor. Results: The 7-azaindole-2-carboxamides lost the ability to bind to the CB1 receptor. The 6-azaindole-2-carboxamides (e.g., 3c and 3d) showed markedly reduced binding affinities to the CB1 receptor in comparison with their indole-2-carboxamide counterparts. However, they behaved similarly as indole-2-carboxamides in potentiating the orthosteric agonist binding and inhibiting the orthosteric agonist-induced G-protein coupling. The results indicated that some azaindole scaffolds (e.g., 6-azaindole) are worth further exploration, whereas the 7-azaindole ring is not a viable bioisostere of the indole ring in the Org27569 class of CB1 allosteric modulators.


Introduction: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are bioactive cannabinoids. We recently showed that acute THC administration drives region-dependent changes in the mouse brain lipidome. This study tested the hypothesis that cell lines representing cell types present in the central nervous system (CNS), neurons (N18 cells), astrocytes (C6 glioma cells), and microglia (BV2 cells) would respond differently to THC, CBD, or their combination. This experimental strategy also allowed us to test the hypothesis that THC and CBD are metabolized differently if presented in combination and to test the hypothesis that responses to CBD are not like the fatty acid amide hydrolase (FAAH) inhibitor URB597. Finally, we tested the hypothesis that CBD’s CNS effects would differ in the N-acyl phosphatidyl ethanolamine-specific phospholipase D (NAPE-PLD) knockout (KO) compared to wild-type (WT) mice. Methods: N18, C6, and BV2 cells were stimulated with 1 μM THC, 1 μM CBD, 1 μM THC:CBD, 1 μM URB597, or vehicle for 2 h and lipids extracted. Adult female WT and NAPE-PLD KO mice were injected with 3 mg/kg CBD or vehicle i.p., brains collected 2 h later, eight brain regions dissected, and lipids extracted. Extracted lipids were characterized and quantified using high-pressure liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS). Results: Lipid levels in each cell type were differentially affected by THC, CBD, or THC:CBD with a few exceptions. In all cell lines, THC increased levels of arachidonic acid and CBD increased levels of N-acyl ethanolamines (NAEs), including N-arachidonoyl ethanolamine. More THC remained when cells were coincubated with CBD; however, levels of THC metabolites were cell-type dependent. CBD and URB597 caused very different lipid profiles in the cell-based assays with the primary similarity being increases in NAEs. CBD increased levels of NAEs in the WT hippocampus, cerebellum, thalamus, cortex, midbrain, and brainstem; however, NAEs did not increase in any brain region after CBD in NAPE-PLD KO mice. Conclusions: CBD and THC differentially modify the lipidome of the brain and CNS-type cell lines. Increases in NAEs observed after CBD treatment had previously been attributed to FAAH inhibition; however, data here suggest the alternative hypothesis that CBD is activating NAPE-PLD to increase NAE levels.


Introduction: Long-term consequences of medicinal cannabis use in people with multiple sclerosis (PwMS) are unknown. This study investigated whether PwMS using cannabis had lower resting brain glucose uptake (GU) and worse clinical test results compared with nonusers. Methods: Sixteen PwMS, eight users, underwent clinical testing followed by [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography imaging. Results: Users had lower cognitive function test scores, but performed similarly on the other clinical evaluations. Accounting for disease duration, resting brain GU was similar between the groups. Conclusions: Lower cognitive function was not associated with resting brain GU. Cognitive dysfunction may be a contraindication or consequence of cannabis use in PwMS.