Role of Cannabinoids and Terpenes in Cannabis-Mediated Analgesia in Rats.

View details for Cannabis and Cannabinoid Research cover image

“Cannabis sativa has been used for centuries in treating pain. However, the analgesic role of many of its constituents including terpenes is unknown. This research examined the contributions of terpenes (volatile oil) and cannabinoids in cannabis-mediated analgesia in rats.

Methods: Animals received intraperitoneal administration of either vehicle, 10.0 or 18.0 mg/kg morphine, or various doses of the extract without terpenes, isolated terpenes, Δ9-tetrahydrocannabinol (THC), or the full extract. Thirty minutes later animals were tested on hotplate and tail-flick tests of thermal nociception. One week later, rats received a second administration of test articles and were tested 30 min later in the abdominal writhing test of inflammatory nociception.

Results: In the thermal assays, hotplate and tail-flick latencies for morphine-treated rats were dose dependent and significantly higher than vehicle-treated animals. All the cannabinoid compounds except for the isolated terpenes produced dose-dependent increases in hotplate and tail-flick latencies. In the inflammatory nociceptive assay, animals treated with vehicle and isolated terpenes demonstrated increased abdominal writhing, whereas all the cannabinoid compounds significantly decreased abdominal writhing responses.

Conclusions: Overall, THC alone produced robust analgesia equivalent to the full cannabis extract, whereas terpenes alone did not produce analgesia. These data suggest the analgesic activity of cannabis is largely mediated by THC, whereas terpenes alone do not cause alterations in cannabis-mediated analgesia.”

https://www.ncbi.nlm.nih.gov/pubmed/31579834

“The work herein demonstrates that cannabis extracts can not only produce robust analgesia without the terpene-containing volatile oils, but isolated THC appears to be all that is required to produce such effects.”

https://www.liebertpub.com/doi/10.1089/can.2018.0054

How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review.

Neuroscience & Biobehavioral Reviews“The recent liberalisation of cannabis regulation has increased public and scientific debate about its potential benefits and risks. A key focus has been the extent to which cannabidiol (CBD) might influence the acute effects of delta-9-tetrahydrocannabinol (THC), but this has never been reviewed systematically. In this systematic review of how CBD influences the acute effects of THC we identified 16 studies involving 466 participants. Ten studies were judged at low risk of bias. The findings were mixed, although CBD was found to reduce the effects of THC in several studies. Some studies found that CBD reduced intense experiences of anxiety or psychosis-like effects of THC and blunted some of the impairments on emotion and reward processing. However, CBD did not consistently influence the effects of THC across all studies and outcomes. There was considerable heterogeneity in dose, route of administration and THC:CBD ratio across studies and no clear dose-response profile emerged. Although findings were mixed, this review suggests that CBD may interact with some acute effects of THC.”

https://www.ncbi.nlm.nih.gov/pubmed/31580839

“CBD influenced the effects of THC in some but not all studies. Several studies found that CBD reduced the acute effects of THC. CBD may reduce intense experiences of anxiety or psychosis-like effects of THC. CBD may blunt effects of THC on emotion and reward processing. CBD did not alter subjective intoxication or psychomotor effects of THC. CBD may influence the benefits and harms of cannabis”

https://www.sciencedirect.com/science/article/pii/S0149763419305615?via%3Dihub

Beyond THC and Endocannabinoids.

Image result for AR Annual Reviews“Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed. ”

https://www.ncbi.nlm.nih.gov/pubmed/31580774

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-010818-021441

Cannabinoids, Pain, and Opioid Use Reduction: The Importance of Distilling and Disseminating Existing Data.

View details for Cannabis and Cannabinoid Research cover image“The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions.

There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic.

Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials.

In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients.

Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use.

The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31579833

https://www.liebertpub.com/doi/10.1089/can.2018.0052

Neuroprotective protein hydrolysates from hemp (Cannabis sativa L.) seeds.

 “Hemp (Cannabis sativa L.) seeds are well known for their potential use as a source of nutrients, fiber, and bioactive compounds.

A hemp protein isolate, prepared from defatted hemp flour, was hydrolyzed by alcalase and flavourzyme under specific conditions.

The resulting hydrolysates were evaluated for the selection of potentially bioactive hemp protein hydrolysates (HPHs) owing to their DPPH scavenging and ferric reducing antioxidant power activity. In vitro cell-free experiments led to the identification of two bioactive HPHs, HPH20A and HPH60A + 15AF, which were used at 50 and 100 μg mL-1 on BV-2 microglial cells in order to evaluate the anti-neuroinflammatory activities.

Our results showed that HPH20A and HPH60A + 15AF down-regulated TNF-α, IL-1β, and IL-6 mRNA transcriptional levels in LPS-stimulated BV-2 microglial cells. In addition, HPH20A and HPH60A + 15AF up-regulated the gene expression of anti-inflammatory cytokine IL-10.

This study suggests for the first time that HPHs may improve the neuroinflammatory and inflammatory states, supporting the nutraceutical value of hemp seeds.”

https://www.ncbi.nlm.nih.gov/pubmed/31576391

https://pubs.rsc.org/en/content/articlelanding/2019/FO/C9FO01904A#!divAbstract

Endogenous cannabinoid modulation of restraint stress-induced analgesia in thermal nociception.

Journal of Neurochemistry banner“It is thought that endogenous cannabinoids have a role in the analgesia induced by specific forms of stress.

We examined if the role of endogenous cannabinoids is also dependent upon the mode of nociception, and whether this could be altered by drugs which block their enzymatic degradation.

These findings indicate the role of endocannabinoids in stress-induced analgesia differs with the type of thermal pain behaviour. However, by inhibiting their breakdown, endocannabinoids can be recruited to substitute for endogenous opioid signalling when their activity is blocked, indicating a degree of redundancy between opioid and cannabinoid systems.

Together these data suggest targeting endocannabinoid breakdown could provide an alternative, or adjuvant to mainstream analgesics such as opioids.”

https://www.ncbi.nlm.nih.gov/pubmed/31571215

https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14884

Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2.

Image result for LI laboratory investigations journal“The endocannabinoid (EC) system has been implicated in the pathogenesis of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD).

With the current study we aimed to verify the modulatory effect of endocannabinoid receptor 1 (CB1)-signaling on perilipin 2 (PLIN2)-mediated lipophagy.

In conclusion, these results suggest that loss of CB1 signaling leads to reduced PLIN2 abundance, which triggers lipophagy. Our new findings about the association between CB1 signaling and PLIN2 may stimulate translational studies analyzing new diagnostic and therapeutic options for NAFLD.”

https://www.ncbi.nlm.nih.gov/pubmed/31570772

“In conclusion, we demonstrated that the CB1 receptor knockout in vivo and pharmacologic antagonization of CB1 in cell culture decreased PLIN2 expression, which might be an essential step in lipid breakdown. Thus, pharmacologic modulation of the CB1-PLIN2 axis might represent a novel therapeutic approach for the treatment of steatosis.”

https://www.nature.com/articles/s41374-019-0327-5

Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature.

“Grade IV glioblastoma multiforme is a deadly disease, with a median survival of around 14 to 16 months. Maximal resection followed by adjuvant radiochemotherapy has been the mainstay of treatment since many years, although survival is only extended by a few months. In recent years, an increasing number of data from in vitro and in vivo research with cannabinoids, particularly with the non-intoxicating cannabidiol (CBD), point to their potential role as tumour-inhibiting agents. Herein, a total of nine consecutive patients with brain tumours are described as case series; all patients received CBD in a daily dose of 400 mg concomitantly to the standard therapeutic procedure of maximal resection followed by radiochemotherapy. By the time of the submission of this article, all but one patient are still alive with a mean survival time of 22.3 months (range=7-47 months). This is longer than what would have been expected.”

https://www.ncbi.nlm.nih.gov/pubmed/31570484

http://ar.iiarjournals.org/content/39/10/5797

Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus Through Bi-Directional Control of ERK1-2 Phosphorylation

Journal of Neuroscience“Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using in-vivo electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and epsilon oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1-2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD co-administration reverses these changes by down-regulating pERK1-2 signaling, as pharmacological re-activation of pERK1-2 blocked the inhibitory properties of CBD. These results identify vHipp pERK1-2 signaling as a critical neural nexus point mediating THC-induced affective disturbances and suggest a potential mechanism by which CBD may counteract the psychotomimetic and psychotropic side-effects of THC.

SIGNIFICANCE STATEMENT

Strains of marijuana with high levels of delta-9-tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) have been shown to underlie neuropsychiatric risks associated with high potency cannabis use. However, the mechanisms by which CBD mitigates the side effects of THC have not been identified. We demonstrate that THC induces cognitive and affective abnormalities resembling neuropsychiatric symptoms directly in the hippocampus, while dysregulating dopamine activity states and amplifying oscillatory frequencies in the ventral tegmental area via modulation of the extracellular signal-regulated kinase (ERK) signaling pathway. In contrast, CBD co-administration blocked THC-induced ERK phosphorylation, and prevented THC-induced behavioural and neural abnormalities. These findings identify a novel molecular mechanism that may account for how CBD functionally mitigates the neuropsychiatric side-effects of THC.”

https://www.ncbi.nlm.nih.gov/pubmed/31570536

https://www.jneurosci.org/content/early/2019/09/27/JNEUROSCI.0708-19.2019

“Western University researchers show how CBD blocks side-effects of THC in cannabis. Research out of Western University is showing for the first time how cannabidiol (CBD) helps to lessen negative psychiatric side effects of tetrahydrocannabinol (THC) in cannabis.”  https://globalnews.ca/news/5970908/western-university-research-cbd-thc-cannabis/

“Cannabis study reveals how CBD offsets the psychiatric side-effects of THC”  https://neurosciencenews.com/cbd-thc-psychosis-15002/

Absence of Entourage: Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors.

 View details for Cannabis and Cannabinoid Research cover image“Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro.

Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%.

Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/31559333

https://www.liebertpub.com/doi/10.1089/can.2019.0016

“Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence.”  https://www.ncbi.nlm.nih.gov/pubmed/31438532