Biosynthetic origins of unusual cannabimimetic phytocannabinoids in Cannabis sativa L: A review


“Plants of Cannabis sativa L. (Cannabaceae) produce an array of more than 160 isoprenylated resorcinyl polyketides, commonly referred to as phytocannabinoids. These compounds represent molecules of therapeutic importance due to their modulation of the human endocannabinoid system (ECS).

While understanding of the biosynthesis of the major phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has grown rapidly in recent years, the biosynthetic origin and genetic regulation of many potentially therapeutically relevant minor phytocannabinoids remains unknown, which limits the development of chemotypically elite varieties of C. sativa.

This review provides an up-to-date inventory of unusual phytocannabinoids which exhibit cannabimimetic-like activities and proposes putative metabolic origins. Metabolic branch points exploitable for combinatorial biosynthesis and engineering of phytocannabinoids with augmented therapeutic activities are also described, as is the role of phytocannabinoid remodelling to accelerate therapeutic portfolio expansion in C. sativa.”

Inhibitory Effects of Cannabinoids on Acetylcholinesterase and Butyrylcholinesterase Enzyme Activities

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Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two cholinergic enzymes catalyzing the reaction of cleaving acetylcholine into acetate and choline at the neuromuscular junction. Abnormal hyperactivity of AChE and BChE can lead to cholinergic deficiency, which is associated with several neurological disorders including cognitive decline and memory impairments.

Preclinical studies support that some cannabinoids including cannabidiol (CBD) and tetrahydrocannabinol (THC) may exert pharmacological effects on the cholinergic system, but it remains unclear whether cannabinoids can inhibit AChE and BChE activities.

Herein, we aimed to evaluate the inhibitory effects of a panel of cannabinoids including CBD, Δ8-THC, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabicitran (CBT), cannabidivarin (CBDV), cannabichromene (CBC), and cannabinol (CBN) on AChE and BChE activities.

Results: Cannabinoids including CBD, Δ8-THC, CBG, CBGA, CBT, CBDV, CBC, and CBN (at 200 µM) inhibited the activities of AChE and BChE by 70.8, 83.7, 92.9, 76.7, 66.0, 79.3, 13.7, and 30.5%, and by 86.8, 80.8, 93.2, 87.1, 77.0, 78.5, 27.9, and 22.0%, respectively. The inhibitory effects of these cannabinoids (with IC50 values ranging from 85.2 to >200 µM for AChE and 107.1 to >200 µM for BChE) were less potent as compared to the positive control galantamine (IC50 1.21 and 6.86 µM for AChE and BChE, respectively). In addition, CBD, as a representative cannabinoid, displayed a competitive type of inhibition on both AChE and BChE. Data from the molecular docking studies suggested that cannabinoids interacted with several amino acid residues on the enzyme proteins, which supported their overall inhibitory effects on AChE and BChE.

Conclusion: Cannabinoids showed moderate inhibitory effects on the activities of AChE and BChE enzymes, which may contribute to their modulatory effects on the cholinergic system. Further studies using cell-based and in vivo models are warranted to evaluate whether cannabinoids’ neuroprotective effects are associated with their anti-cholinesterase activities.”

“Previously published work from our group has shown that medicinal plants and their derived natural products show neuroprotective and anti-inflammatory properties.

Notably, cannabinoids from Cannabis sativa (C. sativa) have been increasingly evaluated in studies to treat chronic pain, inflammation, multiple sclerosis, post-traumatic stress disorder, and neurological diseases, specifically AD.

Furthermore, a study implicated that phytochemicals of C. sativa, including several cannabinoids, are inhibitors of AChE,

In summary, several cannabinoids exhibited moderate inhibitory effects against the activities of cholinesterases including AChE and BChE.”

“Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer’s Disease Therapy”

Cannabis decriminalization and racial disparity in arrests for cannabis possession

Social Science & Medicine

“Rationale: Minorities often bear the brunt of unequal enforcement of drug laws. In the U.S., Blacks have been disproportionately more likely to be arrested for cannabis possession than Whites despite a similar rate of cannabis use. Decriminalizing cannabis has been argued as a way to reduce racial disparity in cannabis possession arrests. To date, however, the empirical evidence to support this argument is almost non-existent.

Objectives: To examine whether cannabis decriminalization was associated with reduced racial disparity in arrests for cannabis possession between Blacks and Whites in the U.S.

Methods: Using FBI Uniform Crime Report data from 37 U.S. states, cannabis possession arrest rates were calculated separately for Blacks and Whites from 2000 to 2019. A difference-in-differences framework was used to estimate the association between cannabis decriminalization and racial disparity in cannabis possession arrest rates (Blacks/Whites ratio) among adults and youths.

Results: Cannabis possession arrest rates declined over 70% among adults and over 40% among youths after the implementation of cannabis decriminalization in 11 states. Among adults, decriminalization was associated with a roughly 17% decrease in racial disparity in arrest rates between Blacks and Whites. Among youths, arrest rates declined among both Blacks and Whites but there was no evidence for a change in racial disparity between Blacks and Whites following decriminalization.

Conclusions: Cannabis decriminalization was associated with substantially lower cannabis possession arrest rates among both adults and youths and among both Blacks and Whites. It reduced racial disparity between Blacks and Whites among adults but not youths. These findings suggested that cannabis decriminalization had its intended consequence of reducing arrests and may have potential to reduce racial disparity in arrests at least among adults.”

“Cannabis decriminalization decreased arrests in both adults and youths.•

Cannabis decriminalization decreased arrests in both Blacks and Whites.•

Cannabis decriminalization decreased racial disparity in arrests only in adults.”

“Cannabis Decriminalization Reduces The Racial Disparity, A New Study Suggests”

Medical cannabis and automobile accidents: Evidence from auto insurance

“While many states have legalized medical cannabis, many unintended consequences remain under-studied. We focus on one potential detriment-the effect of cannabis legalization on automobile safety. We examine this relationship through auto insurance premiums.

Employing a modern difference-in-differences framework and zip code-level premium data from 2014 to 2019, we find that premiums declined, on average, by $22 per year following medical cannabis legalization. The effect is more substantial in areas near a dispensary and in areas with a higher prevalence of drunk driving before legalization.

We estimate that existing legalization has reduced health expenditures related to auto accidents by almost $820 million per year with the potential for a further $350 million reduction if legalized nationally.”

Cannabis legalization and driving under the influence of cannabis in a national U.S. Sample

Preventive Medicine Reports

“The relationship between cannabis legalization and traffic safety remains unclear. Physiological measures of cannabis impairment remain imperfect. This analysis used self-report data to examine the relationship between cannabis legalization and driving under the influence of cannabis (DUIC). Using a cross-sectional national sample (2016-2017) of 1,249 past-30-day cannabis users, we regressed self-reported DUIC (driving within three hours of “getting high”) on cannabis legalization (recreational and medical (recreational), medical only (medical), or no legal cannabis), adjusting for demographics, days of use (past 30 days), days of use*legal status, calibration weights, and geographic clustering. The risk of DUIC in recreational (risk ratio [RR] = 0.41, 95% confidence interval (CI):0.23-0.72) and medical (RR = 0.39, 95% CI:0.20-0.79) states was lower than in states without legal cannabis, with one exception. Among frequent cannabis users (≥20 days per month), there was a significantly lower risk of DUIC for those living in recreational states (RR = 0.70, 95% CI: 0.49-0.99), but not for those living in medical states (RR = 0.87, 95% CI: 0.60-1.24), compared to users living in states without legal cannabis. The risk of self-reported DUIC was lower in recreational and medical cannabis states compared to states without legal cannabis. The only exception was for frequent users in medical states, for whom there was no difference in risk compared to frequent users living in states without legal cannabis.”

“Users in medical cannabis states were less likely to report driving high.•

Users in recreational states were less likely to report driving high.”

Anti-inflammatory effects of recreational marijuana in virally suppressed youth with HIV-1 are reversed by use of tobacco products in combination with marijuana

Retrovirology | Home page

“Background: Marijuana’s putative anti-inflammatory properties may benefit HIV-associated comorbidities. How recreational marijuana use affects gene expression in peripheral blood cells (PBC) among youth with HIV-1 (YWH) is unknown.

Approach: YWH with defined substance use (n = 54) receiving similar antiretroviral therapy (ART) were assigned to one of four analysis groups: YWH with detectable plasma HIV-1 (> 50 RNA copies/ml) who did not use substances (H+V+S-), and YWH with undetectable plasma HIV-1 who did not use substances (H+V-S-), or used marijuana alone (H+V-S+[M]), or marijuana in combination with tobacco (H+V-S+[M/T]). Non-substance using youth without HIV infection (H-S-, n = 25) provided a reference group. PBC mRNA was profiled by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Differentially expressed genes (DEG) within outcome groups were identified by Significance Analysis of Microarrays and used for Hierarchical Clustering, Principal Component Analysis, and Ingenuity Pathways Analysis.

Results: HIV-1 replication resulted in > 3000 DEG involving 27 perturbed pathways. Viral suppression reduced DEG to 313, normalized all 27 pathways, and down-regulated two additional pathways, while marijuana use among virally suppressed YWH resulted in 434 DEG and no perturbed pathways. Relative to H+V-S-, multiple DEG normalized in H+V-S+[M]. In contrast, H+V-S+[M/T] had 1140 DEG and 10 dysregulated pathways, including multiple proinflammatory genes and six pathways shared by H+V+S-.

Conclusions: YWH receiving ART display unique transcriptome bioprofiles based on viral replication and substance use. In the context of HIV suppression, marijuana use, alone or combined with tobacco, has opposing effects on inflammatory gene expression.”

“Cannabis is effective in the treatment of HIV-associated peripheral neuropathic pain, improves appetite, and enhances overall quality of life in people with HIV. There is emerging evidence that marijuana use attenuates pro-inflammatory pathways in HIV-infected adults, as well as in non-human primates infected with simian immunodeficiency virus.”

Effects of cannabidiol on simulated driving and cognitive performance: A dose-ranging randomised controlled trial

SAGE Journals

“Background: Cannabidiol (CBD), a major cannabinoid of Cannabis sativa, is widely consumed in prescription and non-prescription products. While CBD is generally considered ‘non-intoxicating’, its effects on safety-sensitive tasks are still under scrutiny.

Aim: We investigated the effects of CBD on driving performance.

Methods: Healthy adults (n = 17) completed four treatment sessions involving the oral administration of a placebo, or 15, 300 or 1500 mg CBD in a randomised, double-blind, crossover design. Simulated driving performance was assessed between ~45-75 and ~210-240 min post-treatment (Drives 1 and 2) using a two-part scenario with ‘standard’ and ‘car following’ (CF) components. The primary outcome was standard deviation of lateral position (SDLP), a well-established measure of vehicular control. Cognitive function, subjective experiences and plasma CBD concentrations were also measured. Non-inferiority analyses tested the hypothesis that CBD would not increase SDLP by more than a margin equivalent to a 0.05% blood alcohol concentration (Cohen’s dz = 0.50).

Results: Non-inferiority was established during the standard component of Drive 1 and CF component of Drive 2 on all CBD treatments and during the standard component of Drive 2 on the 15 and 1500 mg treatments (95% CIs < 0.5). The remaining comparisons to placebo were inconclusive (the 95% CIs included 0 and 0.50). No dose of CBD impaired cognition or induced feelings of intoxication (ps > 0.05). CBD was unexpectedly found to persist in plasma for prolonged periods of time (e.g. >4 weeks at 1500 mg).

Conclusion: Acute, oral CBD treatment does not appear to induce feelings of intoxication and is unlikely to impair cognitive function or driving performance.”

“The results of this study suggest that acute, oral CBD treatment at doses up to 1500 mg does not induce feelings of intoxication and is unlikely to impair cognitive function or driving performance.”

Exploration of Multiverse Activities of Endocannabinoids in Biological Systems


“Over the last 25 years, the human endocannabinoid system (ECS) has come into the limelight as an imperative neuro-modulatory system. It is mainly comprised of endogenous cannabinoid (endocannabinoid), cannabinoid receptors and the associated enzymes accountable for its synthesis and deterioration. The ECS plays a proven role in the management of several neurological, cardiovascular, immunological, and other relevant chronic conditions. Endocannabinoid or endogenous cannabinoid are endogenous lipid molecules which connect with cannabinoid receptors and impose a fashionable impact on the behavior and physiological processes of the individual. Arachidonoyl ethanolamide or Anandamide and 2-arachidonoyl glycerol or 2-AG were the endocannabinoid molecules that were first characterized and discovered. The presence of lipid membranes in the precursor molecules is the characteristic feature of endocannabinoids. The endocannabinoids are released upon rapid enzymatic reactions into the extracellular space via activation through G-protein coupled receptors, which is contradictory to other neurotransmitter that are synthesized beforehand, and stock up into the synaptic vesicles. The current review highlights the functioning, synthesis, and degradation of endocannabinoid, and explains its functioning in biological systems.”

Efficacy of cannabis and its constituents in disease management: Insights from clinical studies

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“There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers’ attention to discover the scientific evidence of cannabis’s beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents such as megestrol acetate in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. As high as 572 patients and as low as nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.”

Anti-inflammation and gingival wound healing activities of Cannabis sativa L. subsp. sativa (hemp) extract and cannabidiol: An in vitro study

Archives of Oral Biology

“Objective: To evaluate the anti-inflammatory and gingival wound healing activities of Cannabis sativa L. subsp. sativa (hemp) extract and cannabidiol (CBD).

Design: The cellular bioactivities of hemp extract and CBD were determined the inhibition of TNF-α and IL-1β in LPS-induced murine macrophage (RAW 264.7) cells by using ELISA while wound healing activity in human gingival fibroblast (HGF-1) cells was performed by a scratch test assay. The cytotoxicity was also concerned and evaluated by MTT assay.

Results: The hemp extract and CBD significantly decreased TNF-α release by up to 91.05 ± 2.91% and 50.78 ± 7.21% of LPS activity, respectively, in a dose-dependent manner, compared to 10 µg/mL hydrocortisone (61.67 ± 3.79%). The hemp extract and CBD also significantly decreased IL-1β release, also in dose-dependent response, up to 78.03 ± 3.34% and 85.87 ± 1.11% of LPS activity, respectively, compared to 5 µg/mL hydrocortisone (80.81 ± 3.55%). The mean percentage of closure of the wound area was 27.92 ± 1.21% when exposed to 5 µg/mL hemp extract and 33.49 ± 1.67% when exposed to 0.5 µg/mL CBD, compared to 24.34 ± 2.29% for non-treated control.

Conclusions: Our study demonstrates that both hemp extract and CBD can inhibit TNF-α and IL-1β production in LPS-induced RAW 264.7 cells and promote wound healing in HGF-1 cells. This is the first to show that short-term exposure to hemp extract and CBD promoted gingival fibroblast wound healing, demonstrating that hemp extract and CBD have potential benefits in the treatment of oral inflammation and ulcers.”