The psychoactive plant cannabinoid, Δ9‐tetrahydrocannabinol, is antagonized by Δ8‐ and Δ9‐tetrahydrocannabivarin in mice in vivo

Pertwee, Roger G.; Thomas, Adèle; Stevenson, Lesley; Ross, Ruth A.; Varvel, Stephen A.; Lichtman, Aron H.; Martin, Billy R.; Razdan, Raj K.

doi:10.1038/sj.bjp.0707124

Cited by 90 publications

(94 citation statements)

References 25 publications

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“…D 9 -Tetrahydrocannabivarin (THCV) is a naturally occurring analog of THC, but with different pharmacological effects. It is has been reported to behave as both a CB 1 /CB 2 agonist and/or a CB 1 / CB 2 -neutral antagonist (20)(21)(22)(23)(24), probably dose-dependent, with agonism observed at high doses and antagonism at low doses (19). However, there is little evidence of CB 1 agonism in vivo compared with the observed in vivo effects of THC at similar doses.…”

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confidence: 51%

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study

et al. 2016

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OBJECTIVE Cannabidiol (CBD) and D9 -tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSIn this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDLcholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated. RESULTSCompared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = 21.2 mmol/L; P < 0.05) and improved pancreatic b-cell function (HOMA2 b-cell function [ETD = 244.51 points; P < 0.01]), adiponectin (ETD = 25.9 3 10 6 pg/mL; P < 0.01), and apolipoprotein A (ETD = 26.02 mmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (2898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated. CONCLUSIONSTHCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.

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confidence: 51%

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study

et al. 2016

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“…THC has been well characterized to exert its actions through activation of CB 1 (Devane et al, 1988;Matsuda et al, 1990;Pertwee, 1997) and CB 2 (Munro et al, 1993;Pertwee et al, 2007) receptors. The CB 1 receptor is responsible for the multitude of the behavioral actions of THC and is predominately expressed in presynaptic neurons (Huang et al, 2001;Szabo and Schlicker, 2005), especially GABAergic interneurons (Katona et al, 1999) in the brain, while the CB 2 receptor is highly expressed in immune cells (Galiègue et al, 1995;Pettit et al, 1996;Schatz et al, 1997;Carayon et al, 1998).…”

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confidence: 99%

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Wilkerson

Niphakis

Grim

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (D 9 -tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis (4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED 50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required m-opioid, CB 1 , and CB 2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

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“…presses the pharmacological profile of a neutral CB1 antagonist in vitro (673,681,855) as it antagonizes CB1 agonistinduced […”

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confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

366

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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The psychoactive plant cannabinoid, Δ⁹‐tetrahydrocannabinol, is antagonized by Δ⁸‐ and Δ⁹‐tetrahydrocannabivarin in mice in vivo

Abstract: Background and purpose: To follow up in vitro evidence that D 9 -tetrahydrocannabivarin extracted from cannabis (eD 9 -THCV) is a CB 1 receptor antagonist by establishing whether synthetic D

Cited by 90 publications

References 25 publications

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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