Tag Archives: cannabinoid

Synergistic interactions of endogenous opioids and cannabinoid systems.

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 Brain Research

“Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Delta(9)-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia.

The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Delta(9)-THC versus AEA. Tolerance to Delta(9)-THC, but not AEA, involves a decrease in the release of dynorphin A.

Our preclinical studies indicate that Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940.

We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.”

https://www.ncbi.nlm.nih.gov/pubmed/10612710

https://www.sciencedirect.com/science/article/pii/S0006899399019083?via%3Dihub

Synergistic interactions between cannabinoid and opioid analgesics.

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Life Sciences

“Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects.

Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, enhances the potency of opioids such as morphine in animal models.

In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception.

A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.”

 https://www.ncbi.nlm.nih.gov/pubmed/14706563
https://www.sciencedirect.com/science/article/pii/S0024320503010129?via%3Dihub

Interaction of the cannabinoid and opioid systems in the modulation of nociception

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“Cannabinoids and opioids produce antinociceptive synergy.

Cannabinoids such as Δ-9-tetrahydrocannabinol (THC) release endogenous opioids and endocannabinoids such as anandamide (AEA) also alter endogenous opioid tone.

Opioids and cannabinoids bind distinct receptors that co-localize in areas of the brain involved with the processing of pain signals. Therefore, it is logical to look at interactions of these two systems in the modulation of both acute and chronic pain.

This review summarizes the data indicating that with cannabinoid/opioid therapy one may be able to produce long-term antinociceptive effects at doses devoid of substantial side effects, while preventing the neuronal biochemical changes that accompany tolerance.

The clinical utility of modulators of the endocannabinoid system as a potential mimic for THC-like drugs in analgesia and tolerance-sparing effects of opioids is a critical future direction also addressed in the review.”

https://www.tandfonline.com/doi/abs/10.1080/09540260902782794

Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with malignant diseases.

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“The aim of this review was to assess the efficacy of cannabis preparations for relieving pain in patients with malignant diseases, through a systematic review of randomized controlled trials (RCTs), which were predominantly double-blind trials that compared cannabis preparation to a placebo.

RESULTS:

Fifteen of the 18 trials demonstrated a significant analgesic effect of cannabinoids as compared to placebo. The most commonly reported adverse effects were generally well tolerated, mild to moderate. The main side effects were drowsiness, nausea, vomiting and dry mouth. There is evidence that cannabinoids are safe and modestly effective in neuropathic pain and also for relieving pain in patients with malignant diseases. The proportion of “responders” (patients who at the end of 2 weeks of treatment reported ≥30% reduction in pain intensity on a scale of 0-10, which is considered to be clinically important) was 43% in comparison with placebo (21%).

CONCLUSION:

The target dose for relieving pain in patients with malignant diseases is most likely about 10 actuations per day, which is about 27 mg tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD), and the highest approved recommended dose is 12 actuations per day (32 mg THC/30 mg CBD). Further large studies of cannabinoids in homogeneous populations are required.”

https://www.ncbi.nlm.nih.gov/pubmed/29719417

https://www.dovepress.com/pharmacotherapeutic-considerations-for-use-of-cannabinoids-to-relieve–peer-reviewed-article-JPR

Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal.

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“Cannabidiol (CBD), a non-intoxicating cannabinoid, may be a promising novel smoking cessation treatment due to its anxiolytic properties, minimal side-effects and research showing it may modify drug cue salience.

We used an experimental medicine approach with dependent cigarette smokers to investigate if (1) overnight nicotine abstinence, compared with satiety, will produce greater attentional bias (AB), higher pleasantness ratings of cigarette-related stimuli and increased craving and withdrawal; (2) CBD in comparison to placebo, would attenuate AB, pleasantness of cigarette-related stimuli, craving and withdrawal and not produce any side-effects.

FINDINGS:

When participants received placebo, tobacco abstinence increased AB (p=.001, d =.789) compared with satiety. However, CBD reversed this effect, such that automatic AB was directed away from cigarette cues (p=.007, d= .704) and no longer differed from satiety (p=.82). Compared with placebo, CBD also reduced explicit pleasantness of cigarette images (p=.011; d=.514). Craving (Bayes Factor: 7.07) and withdrawal (Bayes Factor: 6.48) were unaffected by CBD, but greater in abstinence compared with satiety. Systolic blood pressure decreased under CBD during abstinence.

CONCLUSIONS:

A single 800mg oral dose of cannabidiol (CBD) reduced the salience and pleasantness of cigarette cues, compared with placebo, after overnight cigarette abstinence in dependent smokers. CBD did not influence tobacco craving or withdrawal or any subjectively rated side-effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29714034

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14243

“Cannabidiol reduces attentional bias to cigarette cues in nicotine addicts, study finds” http://www.psypost.org/2018/06/cannabidiol-reduces-attentional-bias-cigarette-cues-nicotine-addicts-study-finds-51351

β-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity.

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Biomedicine & Pharmacotherapy

“Parkinson’s disease (PD) is one of the most common neurodegenerative diseases resulting from the continuous death of dopaminergic neurons in substantia nigra. MPP+ (1-methyl-4-phenylpyridinium) has been reported to be a major neurotoxin causing neurotoxic insults on dopaminergic neurons in humans.

β-Caryophyllene (BCP), an important cannabinoid derived from the essential oils of different species, has displayed pharmacological properties in different kinds of tissues and cells. However, neuroprotective effects of BCP in PD haven’t been reported before.

Our results indicate that treatment with MPP+ in SH-SY5Y cells led to a significant decrease in cell viability, which was restored by BCP. Additionally, BCP suppressed MPP+-induced release of lactic dehydrogenase (LDH) and the generation of reactive oxygen species (ROS). In contrast, BCP treatment restored the reduction in mitochondrial membrane potential (MMP) induced by MPP+. BCP treatment increased intracellular GSH and GPx activity.

Also, we found that the antioxidant effects of BCP against MPP+- induced neurotoxicity are dependent on cannabinoid receptor type 2 (CB2R). Moreover, our results indicated that BCP prevented MPP+-induced apoptosis of SH-SY5Y through inhibiting the up-regulation of cleaved Caspase-3, Bax, and restoring the expression of Bcl-2. Besides, BCP markedly suppressed HO-1 activation and c-Jun N-terminal Kinase (JNK) phosphorylation.

We conclude that BCP might act as a promising therapeutic agent against MPP+ toxicity in neuronal cells.”

https://www.ncbi.nlm.nih.gov/pubmed/29710667
https://www.sciencedirect.com/science/article/abs/pii/S0753332217370269
“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

The role of cannabinoid signaling in acute and chronic kidney diseases.

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 Image result for Kidney Int. “The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes.

Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease.

This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans.

In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people.

In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications.”

https://www.ncbi.nlm.nih.gov/pubmed/29706358

Cannabis, from Plant to Pill.

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British Journal of Clinical Pharmacology banner

“The therapeutic application of Cannabis is attracting substantial public and clinical interest. The Cannabis plant has been described as a veritable ‘treasure trove’, producing more than a hundred different cannabinoids, although the focus to date has been on the psychoactive molecule delta-9-tetraydrocannabinol (THC) and cannabidiol (CBD).

Other numerous secondary metabolites of Cannabis the terpenes, some of which share the common intermediary geranyl diphosphate (GPP) with the cannabinoids, are hypothesised to contribute synergistically to their therapeutic benefits, an attribute that has been described as the ‘entourage effect’.

The effective delivery of such a complex multicomponent pharmaceutical relies upon the stable genetic background and standardised growth of the plant material, particularly if the raw botanical product in the form of the dried pistillate inflorescence (flos) is the source.

Following supercritical CO2 extraction of the inflorescence (and possibly bracts), the secondary metabolites can be blended to provide a specific ratio of major cannabinoids (THC:CBD) or individual cannabinoids can be isolated, purified and supplied as the pharmaceutical. Intensive breeding strategies will provide novel cultivars of Cannabis possessing elevated levels of specific cannabinoids or other secondary metabolites.”

https://www.ncbi.nlm.nih.gov/pubmed/29701252

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.13618

The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.

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Drug and Alcohol Dependence Home

“There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis.

The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users.

CONCLUSIONS:

Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/29689485

https://www.drugandalcoholdependence.com/article/S0376-8716(18)30184-4/fulltext

Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.

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“Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Sailsbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies.

This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects.

RESULTS:

Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control.

CONCLUSION:

Patient comfort, satisfaction and treatment adherence may benefit from these interventions.”

https://www.ncbi.nlm.nih.gov/pubmed/29683408

https://www.futuremedicine.com/doi/10.2217/nmt-2017-0056