Tag Archives: phytocannabinoids

Cannabis constituent synergy in a mouse neuropathic pain model.

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“Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain however, this is hampered by their side-effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side-effects.

We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy and sedation. CBD produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side-effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared to that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared to that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side-effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated.

These findings demonstrate that CBD synergistically enhances the pain relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side-effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28885457
https://insights.ovid.com/crossref?an=00006396-900000000-99155

Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats.

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Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Methamphetamine (METH) is a widely abused and a severely addictive psychostimulant. Relapse is the main cause of concern when treating addiction. It could manifest after a long period of abstinence. Previous studies showed that there is a strong connection between sleep impairment and relapse.

Also, it has been reported that cannabidiol might be a potential treatment for drug craving and relapse. In this study, we used conditioned place preference (CPP) to investigate whether Cannabidiol (CBD), a phytocannabinoid, can prevent METH-induced reinstatement in Rapid Eye Movement Sleep Deprived (RSD) rats.

In conclusion, the administration of CBD 10μg/5μl effectively prevents METH-induced CPP, even in a condition of stress. CBD can be considered an agent that reduces the risk of the relapse; however, this requires more investigation.”

https://www.ncbi.nlm.nih.gov/pubmed/28870635

http://www.sciencedirect.com/science/article/pii/S027858461730218X?via%3Dihub

Clinical and Pre-Clinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol.

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“The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.”

https://www.ncbi.nlm.nih.gov/pubmed/28875990

https://www.nature.com/npp/journal/vaop/naam/abs/npp2017209a.html

Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults.

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“Introduction: Cannabidiol (CBD) is a nonpsychoactive constituent of whole plant cannabis that has been reported to reduce anxiety-like behaviors in both pre-clinical and human laboratory studies. Yet, no controlled clinical studies have demonstrated its ability to reduce negative mood or dampen responses to negative emotional stimuli in humans. The objective of this study was to investigate the effects of CBD on responses to negative emotional stimuli, as a model for its potential anxiety-reducing effects.

Discussion: CBD did not dampen responses to negative emotional stimuli and did not affect feelings of social rejection. The high dose of CBD (900 mg) marginally reduced attentional bias toward happy and sad facial expressions, and produced a slight increase in late-session heart rate. CBD did not produce detectable subjective effects or alterations in mood or anxiety.

Conclusion: These findings indicate that CBD has minimal behavioral and subjective effects in healthy volunteers, even when they are presented with emotional stimuli. Further research into the behavioral and neural mechanisms of CBD and other phytocannabinoids is needed to ascertain the clinical function of this drug.”

https://www.ncbi.nlm.nih.gov/pubmed/28861510

 http://online.liebertpub.com/doi/10.1089/can.2017.0014

Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.

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British Journal of Pharmacology

“Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ9 -tetrahydrocannabinol (Δ9 -THC) have been extensively investigated, the bioactivity of Δ9 -THCA is largely unknown, despite its occurrence in different Cannabis preparations. The aim of this study was to determine whether Δ9 -THCA modulates the PPARγ pathway and has neuroprotective activity.

The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9 -THCA on mitochondrial biogenesis and PGC-1α expression was investigated in N2a cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein, and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). In vivo neuroprotective activity of Δ9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NP).

KEY RESULTS:

Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9 -THCA increases mitochondrial mass in neuroblastoma N2a cells, and prevents cytotoxicity induced by serum deprivation in STHdhQ111/Q111cells and by mutHtt-q94 in N2a cells. Δ9 -THCA, through a PPARγ-dependent pathway, was neuroprotectant in mice intoxicated with 3-NP, improving motor deficits and preventing striatal degeneration. In addition, Δ9 -THCA attenuated microgliosis, astrogliosis and the upregulation of proinflammatory markers induced by 3-NP.

CONCLUSION AND IMPLICATIONS:

Δ9 -THCA shows potent neuroprotective activity, worth consideration for the treatment of Huntington´s Disease and possibly other neurodegenerative and neuroinflammatory diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28853159

http://onlinelibrary.wiley.com/doi/10.1111/bph.14019/abstract

Cannabinoids as Anticancer Drugs.

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Advances in Pharmacology

“The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.sciencedirect.com/science/article/pii/S105435891730039X?via%3Dihub

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

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Advances in Pharmacology

“The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam’s professed “pharmacological treasure trove.””

https://www.ncbi.nlm.nih.gov/pubmed/28826544

http://www.sciencedirect.com/science/article/pii/S1054358917300273?via%3Dihub

Cannabinoids and Pain: Sites and Mechanisms of Action.

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Advances in Pharmacology

“The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB1R agonists, CB2R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB1R/non-CB2R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28826543

http://www.sciencedirect.com/science/article/pii/S1054358917300443?via%3Dihub

The Role of Nuclear Hormone Receptors in Cannabinoid Function.

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Elsevier

“Since the early 2000s, evidence has been accumulating that most cannabinoid compounds interact with the nuclear hormone family peroxisome proliferator-activated receptors (PPARs). This can be through direct binding of these compounds to PPARs, metabolism of cannabinoid to other PPAR-activating chemicals, or indirect activation of PPAR through cell signaling pathways. Delivery of cannabinoids to the nucleus may be facilitated by fatty acid-binding proteins and carrier proteins. All PPAR isoforms appear to be activated by cannabinoids, but the majority of evidence is for PPARα and γ. To date, little is known about the potential interaction of cannabinoids with other nuclear hormones. At least some (but not all) of the well-known biological actions of cannabinoids including neuroprotection, antiinflammatory action, and analgesic effects are partly mediated by PPAR-activation, often in combination with activation of the more traditional target sites of action. This has been best investigated for the endocannabinoid-like compounds palmitoylethanolamide and oleoylethanolamine acting at PPARα, and for phytocannabinoids or their derivatives activation acting at PPARγ. However, there are still many aspects of cannabinoid activation of PPAR and the role it plays in the biological and therapeutic effects of cannabinoids that remain to be investigated.”

https://www.ncbi.nlm.nih.gov/pubmed/28826538

http://www.sciencedirect.com/science/article/pii/S1054358917300364?via%3Dihub

Neuroprotection by (endo)cannabinoids in glaucoma and retinal neurodegenerative diseases.

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“Emerging neuroprotective strategies are being explored to preserve the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision.

Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina.

eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain.

Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28738764

http://www.eurekaselect.com/154386/article