Tag Archives: Cannabinoids

Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans.

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“Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.

PURPOSE:

The objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms.

The non-selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity.

In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.”

https://www.ncbi.nlm.nih.gov/pubmed/29745439

https://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13370

Emerging Role of (Endo)Cannabinoids in Migraine.

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“In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain.

Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors.

We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura.

Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29740328

https://www.frontiersin.org/articles/10.3389/fphar.2018.00420/full

Marijuana Use Is Not Associated With Progression to Advanced Liver Fibrosis in HIV/Hepatitis C Virus-coinfected Women.

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“Marijuana (hereafter “tetrahydrocannabinol [THC]”) use has been associated with liver fibrosis progression in retrospective analyses of patients with chronic hepatitis C (HCV). We studied long-term effects of THC on fibrosis progression in women coinfected with human immunodeficiency virus (HIV)/HCV enrolled in the Women’s Interagency HIV Study (WIHS).

CONCLUSIONS:

In this large cohort of HIV/HCV-coinfected women, THC was not associated with progression to significant liver fibrosis. Alcohol use was independently associated with liver fibrosis, and may better predict fibrosis progression in HIV/HCV-coinfected women.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967608/

https://academic.oup.com/cid/article/63/4/512/2595097

Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling

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Cellular and Molecular Life Sciences

“Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease.

In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy.

Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis.”

https://link.springer.com/article/10.1007/s00018-018-2834-8

http://www.x-mol.com/paper/661834

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease.

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CNS Drugs

“Alzheimer’s disease is a multifactorial disorder for which there is no disease-modifying treatment yet.

CB2 receptors have emerged as a promising therapeutic target for Alzheimer’s disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

OBJECTIVE:

The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer’s disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer’s disease, contributing to the instigation of the disease.

METHODS:

Lymphoblastoid cell lines from patients with Alzheimer’s disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells.

RESULTS:

We report here that PGN33 normalized the increased proliferative activity of Alzheimer’s disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells.

CONCLUSION:

Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/29736745

https://link.springer.com/article/10.1007%2Fs40263-018-0515-7

LH-21, A Peripheral Cannabinoid Receptor 1 Antagonist, Exerts Favorable Metabolic Modulation Including Antihypertensive Effect in KKAy Mice by Regulating Inflammatory Cytokines and Adipokines on Adipose Tissue.

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“Patients with obesity are susceptible to hypertension and diabetes. Over-activation of cannabinoid receptor 1 (CB1R) in adipose tissue is proposed in the pathophysiology of metabolic disorders, which led to the metabolic dysfunction of adipose tissue and deregulated production and secretion of adipokines.

In the current study, we determined the impact of LH-21, a representative peripheral CB1R antagonist, on the obesity-accompanied hypertension and explored the modulatory action of LH-21 on the adipose tissue in genetically obese and diabetic KKAy mice.

3-week LH-21 treatment significantly decreased blood pressure with a concomitant reduction in body weight, white adipose tissue (WAT) mass, and a slight loss on food intake in KKAy mice. Meanwhile, glucose handling and dyslipidemia were also markedly ameliorated after treatment. Gene expression of pro-inflammatory cytokines in WAT and the aortae were both attenuated apparently by LH-21, as well the mRNA expression of adipokines (lipocalin-2, leptin) in WAT. Concomitant amelioration on the accumulation of lipocalin-2 was observed in both WAT and aortae. In corresponding with this, serum inflammatory related cytokines (tumor necrosis factor α, IL-6, and CXCL1), and lipocalin-2 and leptin were lowered notably.

Thus according to current results, it can be concluded that the peripheral CB1R antagonist LH-21 is effective in managing the obesity-accompanied hypertension in KKAy mice. These metabolic benefits are closely associated with the regulation on the production and secretion of inflammatory cytokines and adipokines in the WAT, particularly alleviated circulating lipocalin-2 and its accumulation in aortae.”

https://www.ncbi.nlm.nih.gov/pubmed/29731737

https://www.frontiersin.org/articles/10.3389/fendo.2018.00167/full

Enhanced endocannabinoid tone as a potential target of pharmacotherapy.

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“The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms.

Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids.

The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake.

To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound.

In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF2α-EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels.

Ultimately, further clinical and preclinical studies are warranted to develop medicines for enhancing endocannabinoid tone.”

https://www.ncbi.nlm.nih.gov/pubmed/29729263

https://www.sciencedirect.com/science/article/pii/S0024320518302352

Antinociceptive Synergy between 9 -Tetrahydrocannabinol and Opioids after Oral Administration

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“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia

The analgesic effects of opioids, such as morphine and codeine, in mice are enhanced by oral administration of the cannabinoid 9 -tetrahydrocannabinol (9 -THC).

These findings suggest that the use of a low-dose combination of analgesics is a valid and effective approach for the treatment of pain and necessitates further study.

In summary, we have observed that 9 -THC enhances the antinociceptive effects of morphine and codeine in a synergistic fashion. This is the first report of a true synergistic interaction between oral 9 -THC and morphine or codeine, since previous studies have only examined one-dose combinations.

Much more work needs to be done to elucidate the mechanisms by which cannabinoids and opioids interact to produce analgesia. However, the implication that a combination of drugs may be more effective than either drug alone, and at the same time possibly reduce the occurrence of side effects, should provoke further study on analgesic drug interactions.”

http://jpet.aspetjournals.org/content/jpet/304/3/1010.full.pdf

http://healthdocbox.com/Substance_Abuse/71109245-Antinociceptive-synergy-between-9-tetrahydrocannabinol-and-opioids-after-oral-administration.html

Molecular and cellular basis of cannabinoid and opioid interactions.

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 Pharmacology Biochemistry and Behavior

“Cannabinoids and opioids have been shown to possess several similar pharmacological effects, including analgesia and stimulation of brain circuitry that are believed to underlie drug addiction and reward. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs.

The present review addresses the recent advances in the study of biochemical and molecular mechanisms underlying opioid and cannabinoid interaction. Several hypothesis have been formulated to explain this cross-modulation including the release of opioid peptides by cannabinoids or endocannabinoids by opioids and interaction at the level of receptor and/or their signal transduction mechanisms.

Moreover it is important to consider that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception.

Further studies are needed since a better knowledge of the opioid-cannabinoid interaction may lead to exciting therapeutic possibilities.”

https://www.ncbi.nlm.nih.gov/pubmed/15927245

https://www.sciencedirect.com/science/article/pii/S0091305705001450?via%3Dihub

Opioids and cannabinoids interactions: involvement in pain management.

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“Among several pharmacological properties, analgesia is the most common feature shared by either opioid or cannabinoid systems.

Cannabinoids and opioids are distinct drug classes that have been historically used separately or in combination to treat different pain states.

Indeed, it is widely known that activation of either opioid or cannabinoid systems produce antinociceptive properties in different pain models.

Moreover, several biochemical, molecular and pharmacological studies support the existence of reciprocal interactions between both systems, suggesting a common underlying mechanism.

Further studies have demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception.

These interactions may lead to additive or even synergistic antinociceptive effects, emphasizing their clinical relevance in humans in order to enhance analgesic effects with lower doses and consequently fewer undesirable side effects.

Thus, the present review is focused on bidirectional interactions between opioids and cannabinoids and their potent repercussions on pain modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/20017728

http://www.eurekaselect.com/71318/article