The molecular mechanisms that underpin the biological benefit of full spectrum cannabis extract in the treatment of neuropathic pain and inflammation.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease“Cannabis has been shown to be beneficial in the treatment of pain and inflammatory diseases.

The biological effect of cannabis is mainly attributed to two major cannabinoids, tetrahydrocannabinol and cannabidiol. In the majority of studies to-date, a purified tetrahydrocannabinol and cannabidiol alone or in combination have been extensively examined in many studies for the treatment of numerous disorders including pain and inflammation. However, few studies have investigated the biological benefits of full-spectrum cannabis plant extract.

Given that cannabis is known to generate a large number of cannabinoids along with numerous other biologically relevant products including terpenes, studies involving purified tetrahydrocannabinol and/or cannabidiol may not precisely consider the potential biological benefits of the full-spectrum cannabis extracts. This may be especially true in the role of cannabis as a treatment of pain and inflammation. Herein, we review the pre-clinical physiological and molecular mechanisms in biological systems that are affected by cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/32201189

“Full-spectrum cannabis extract demonstrates several convincing beneficial anti-inflammatory and analgesic effects in preclinical studies. Full-spectrum cannabis extract may represent a promising therapeutic agent that seems to benefit a variety of conditions associated with pain and inflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S0925443920301162?via%3Dihub

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Analgesic Effects of Cannabinoids for Chronic Non-cancer Pain: a Systematic Review and Meta-Analysis with Meta-Regression.

SpringerLink “There is growing interest in using cannabinoids for chronic pain.

We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the analgesic efficacy and adverse effects of cannabinoids for chronic non-cancer pain.

PubMed, EMBASE, Web of Science, Cochrane CENTRAL and clinicaltrials.gov were searched up to December 2018. Information on the type, dosage, route of administration, pain conditions, pain scores, and adverse events were extracted for qualitative analysis. Meta-analysis of analgesic efficacy was performed. Meta-regression was performed to compare the analgesic efficacy for different pain conditions (neuropathic versus non-neuropathic pain). Risk of bias was assessed by The Cochrane Risk of Bias tool, and the strength of the evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Forty-three randomized controlled trials were included. Meta-analysis was performed for 33 studies that compared cannabinoids to placebo, and showed a mean pain score (scale 0-10) reduction of -0.70 (p < 0.001, random effect). Meta-regression showed that analgesic efficacy was similar for neuropathic and non-neuropathic pain (Difference = -0.14, p = 0.262).

Inhaled, oral, and oromucosal administration all provided statistically significant, but small reduction in mean pain score (-0.97, -0.85, -0.45, all p < 0.001). Incidence of serious adverse events was rare, and non-serious adverse events were usually mild to moderate. Heterogeneity was moderate.

The GRADE level of evidence was low to moderate. Pain intensity of chronic non-cancer patients was reduced by cannabinoids consumption, but effect sizes were small. Efficacy for neuropathic and non-neuropathic pain was similar.”

https://www.ncbi.nlm.nih.gov/pubmed/32172501

https://link.springer.com/article/10.1007%2Fs11481-020-09905-y

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The role of the cannabinoid system in opioid analgesia and tolerance.

“Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of mitogen-activated protein kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian target of rapamycin (mTOR).

One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest reduce the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception.

Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G protein coupled receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations, to post-receptor interactions through shared signal transduction pathways.

This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.”

https://www.ncbi.nlm.nih.gov/pubmed/32167427

http://www.eurekaselect.com/180186/article

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Antinociceptive and Immune Effects of Delta-9-tetrahydrocannabinol or Cannabidiol in Male Versus Female Rats with Persistent Inflammatory Pain.

Journal of Pharmacology and Experimental Therapeutics: 373 (1)

“Chronic pain is the most common reason reported for using medical cannabis.

The goal of this research was to determine if the two primary phytocannabinoids, THC and CBD, are effective treatments for persistent inflammatory pain.

These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain, in that THC maintains its efficacy with short-term treatment in both sexes, and does not induce immune activation.

SIGNIFICANCE STATEMENT: CBDs and THCs pain-relieving effects are examined in male and female rats with persistent inflammatory pain to determine if individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provided preliminary insight into immune-related effects of cannabinoid-based therapy for pain.”

https://www.ncbi.nlm.nih.gov/pubmed/32179573

http://jpet.aspetjournals.org/content/early/2020/03/16/jpet.119.263319

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A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain.

“The 20% prevalence of chronic pain in the general population is a major health concern given the often profound associated impairment of daily activities, employment status, and health-related quality of life in sufferers. Resource utilization associated with chronic pain represents an enormous burden for healthcare systems. Although analgesia based on the World Health Organization’s pain ladder continues to be the mainstay of chronic pain management, aside from chronic cancer pain or end-of-life care, prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain is rarely sustainable.

As the endocannabinoid system is known to control pain at peripheral, spinal, and supraspinal levels, interest in medical use of cannabis is growing.

A proprietary blend of cannabis plant extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal cannabinoids is formulated as an oromucosal spray (USAN name: nabiximols) and standardized to ensure quality, consistency and stability. This review examines evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain conditions.

Cumulative evidence from clinical trials and an exploratory analysis of the German Pain e-Registry suggests that add-on THC:CBD oromucosal spray (nabiximols) may have a role in managing chronic neuropathic pain, although further precise clinical trials are required to draw definitive conclusions.”

https://www.ncbi.nlm.nih.gov/pubmed/32104061

https://www.dovepress.com/a-review-of-scientific-evidence-for-thccbd-oromucosal-spray-nabiximols-peer-reviewed-article-JPR

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain.” https://www.sciencedaily.com/releases/2007/10/071024141745.htm

“Marijuana Relieves Chronic Pain, Research Shows” https://www.webmd.com/pain-management/news/20100830/marijuana-relieves-chronic-pain-research-show#1

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Cannabis and Pain Treatment-A Review of the Clinical Utility and a Practical Approach in Light of Uncertainty.

Logo of rmmj“Over the past decade the phenomenon of cannabis as a legitimate form of treatment for pain has overwhelmed the medical community, especially in the field of pain. From a status of a schedule 1 substance having no currently accepted medical use and being considered to have high potential for abuse, its use has mushroomed to over 50,000 legal medical users per year in Israel alone. There appear to be many reasons behind this phenomenon-medical, sociological, and economical. Thus, what is cannabis? An abusive substance or a medication? Should it be incorporated into current biomedical practice, and how should it be administered? Finally, what is the evidence for the beneficial and detrimental effects of cannabis? This article reviews and discusses the current literature regarding the beneficial and the detrimental effects of medical cannabis in the treatment of pain. We further discuss the problems and challenges facing the medical community in this domain and offer a practical approach to deal with these challenges.”

https://www.ncbi.nlm.nih.gov/pubmed/32017678

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Cannabinoids in the descending pain modulatory circuit: Role in inflammation.

Pharmacology & Therapeutics“The legalization of cannabis in some states has intensified interest in the potential for cannabis and its constituents to lead to novel therapeutics for pain.

Our understanding of the cellular mechanisms underlying cannabinoid actions in the brain have lagged behind opioids; however, the current opioid epidemic has also increased attention on the use of cannabinoids as alternatives to opioids for pain, especially chronic pain that requires long-term use.

Endogenous cannabinoids are lipid signaling molecules that have complex roles in modulating neuronal function throughout the brain.

In this review, we discuss cannabinoid functions in the descending pain modulatory pathway, a brain circuit that integrates cognitive and emotional processing of pain to modulate incoming sensory inputs. In addition, we highlight areas where further studies are necessary to understand cannabinoid regulation of descending pain modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/32004514

https://www.sciencedirect.com/science/article/abs/pii/S0163725820300231?via%3Dihub

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An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester (CBDA-ME) in a preclinical model of peripheral neuropathic pain.

Publication cover image“Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

KEY RESULTS:

In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

CONCLUSION AND IMPLICATIONS:

Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.”

https://www.ncbi.nlm.nih.gov/pubmed/31981216

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14997

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The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence.

 “Given the growing challenges in chronic pain management coupled with the ongoing consequences of the opioid epidemic, pain management practitioners are looking into more effective, innovative, and safer alternatives to treat pain.

Cannabis-based medicine had been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits.

While historically more attention has been paid to the psychoactive component of the cannabis plant Δ9-tetrahydrocannabinol (THC), there have been fewer scientific studies on the medical use of the cannabidiol (CBD) – a non-psychoactive component of the cannabis plant.

RECENT FINDINGS:

By examining recent literature, we investigated the use of CBD and its potential role in pain management. Since there are currently no approved pharmaceutical products that contain CBD alone for the management of pain, this review focused on nabiximols (which is a combined product of THC/CBD in a 1:1 ratio) as the only pharmaceutical product available that contains CBD and is being used for the management of pain.

It is difficult to definitely attribute the therapeutic properties to CBD alone since it is always administered with THC.

Based on the available literature, it is difficult to make a recommendation for the use of CBD in chronic pain management. It is also important to note that there are many CBD products currently available as supplements, but these products are non-pharmaceuticals and lack the appropriate clinical studies to support their efficacy claims.”

https://www.ncbi.nlm.nih.gov/pubmed/31980957 

https://link.springer.com/article/10.1007%2Fs11916-020-0835-4

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β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

molecules-logo “Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs.

Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence.

Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain.

BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31892132

https://www.mdpi.com/1420-3049/25/1/106

“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

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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