Opioid-enhancing antinociceptive effects of delta-9-tetrahydrocannabinol and amitriptyline in rhesus macaques.

Cover image for Experimental and Clinical Psychopharmacology“Cannabinoids can enhance the antinociceptive effects of opioids in a synergistic manner, potentially reducing the analgesic dosage of opioids and improving pain therapy. This strategy has also been used as a rationale to combine certain antidepressants and opioids.

In this experiment, opioid-induced thermal antinociception was assessed in rhesus macaques using a warm-water tail-withdrawal procedure with 3 water temperatures (40, 50, and 55 °C). In general, the acute antinociceptive effects of intramuscular (i.m.) cumulative doses of heroin were studied alone or in combination with i.m. (-)-trans-delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), or the tricyclic antidepressant amitriptyline.

A nonantinociceptive dose of THC (1 mg/kg) shifted the ED50 for the heroin dose-effect curve 3.6-fold leftward at 50 °C and 1.9-fold leftward at 55 °C compared with heroin alone. When the cannabinoid type-1 receptor (CB1R) antagonist, rimonabant, was administered prior to the most effective THC-heroin combination, rimonabant blocked the THC enhancement of heroin antinociception. When CBN (1-3.2 mg/kg) was administered prior to heroin, or 1 mg/kg of CBN was administered prior to a combination of 0.32 mg/kg of THC and heroin, no shifts were evident in the heroin dose-effect curves at either temperature.

However, similar to THC, amitriptyline (0.32-1 mg/kg) administered prior to heroin significantly shifted the heroin dose-effect curve leftward. Heroin produced both dose- and temperature-dependent thermal antinociception in nonhuman primates and THC produced opioid-enhancing effects in a CB1R-dependent manner. These effects of THC were not shared by cannabinol, but were quantitatively similar to that of amitriptyline.”

https://www.ncbi.nlm.nih.gov/pubmed/31464475

https://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000313

Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications.

European Journal of Pharmacology“The biological effects of endocannabinoid system are mediated by two types of receptors, cannabinoid 1 (CB1) and cannabinoid 2 receptor (CB2). They play a pivotal role in the management of pain, inflammation, cancer, obesity and diabetes mellitus.

CB2 receptor activity downregulation is hallmark of inflammation and oxidative stress. Strong evidence display the relation between activation of CB2 receptors with decrease in the pro-inflammatory cytokines and pro-apoptotic factors. Numerous in vitro and in vivo studies have been validated to confirm the role of CB2 receptor in the management of obesity, hyperlipidemia and diabetes mellitus by regulating glucose and lipid metabolism.

Activation of CB2 receptor has led to reduction of inflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6), Nuclear factor kappa beta (NF-κβ) and also amelioration of reactive oxygen species and reactive nitrogen species playing role in apoptosis. Many studies confirmed the role of CB2 receptors in the insulin secretion via facilitating calcium entry into the pancreatic β-cells. CB2 receptors also displayed improvement in the neuronal and renal functions by decreasing the oxidative stress and downregulating inflammatory cascade.

The present review addresses, potential role of CB2 receptor activation in management of diabetes and its complications. It also includes the role of CB2 receptors as an anti-oxidant, anti-apoptotic and anti-inflammatory for the treatment of DM and its complications. Also, an informative summary of CB2 receptor agonist drugs is provided with their potential role in the reduction of glucose levels, increment in the insulin levels, decrease in the hyperglycaemic oxidative stress and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31461639

https://www.sciencedirect.com/science/article/pii/S0014299919305801?via%3Dihub

Myrcene and terpene regulation of TRPV1.

Publication Cover“Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization.

Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1.

These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.”

https://www.ncbi.nlm.nih.gov/pubmed/31446830

https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1654347

The effectiveness of self-directed medical cannabis treatment for pain

Complementary Therapies in Medicine“The prior medical literature offers little guidance as to how pain relief and side effect manifestation may vary across commonly used and commercially available cannabis product types. We used the largest dataset in the United States of real-time responses to and side effect reporting from patient-directed cannabis consumption sessions for the treatment of pain under naturalistic conditions in order to identify how cannabis affects momentary pain intensity levels and which product characteristics are the best predictors of therapeutic pain relief.

Between 06/06/2016 and 10/24/2018, 2987 people used the ReleafApp to record 20,513 cannabis administration measuring cannabis’ effects on momentary pain intensity levels across five pain categories: musculoskeletal, gastrointestinal, nerve, headache-related, or non-specified pain. The average pain reduction was –3.10 points on a 0–10 visual analogue scale (SD = 2.16, d = 1.55, p < .001).

Whole Cannabis flower was associated with greater pain relief than were other types of products, and higher tetrahydrocannabinol (THC) levels were the strongest predictors of analgesia and side effects prevalence across the five pain categories. In contrast, cannabidiol (CBD) levels generally were not associated with pain relief except for a negative association between CBD and relief from gastrointestinal and non-specified pain.

These findings suggest benefits from patient-directed, cannabis therapy as a mid-level analgesic treatment; however, effectiveness and side effect manifestation vary with the characteristics of the product used.

The results suggest that Cannabis flower with moderate to high levels of tetrahydrocannabinol is an effective mid-level analgesic.”

https://www.ncbi.nlm.nih.gov/pubmed/31519268

https://www.sciencedirect.com/science/article/abs/pii/S0965229919308040

“UNM study confirms cannabis flower is an effective mid-level analgesic medication for pain treatment. Cannabis likely has numerous constituents that possess analgesic properties beyond THC, including terpenes and flavonoids, which likely act synergistically for people that use whole dried cannabis flower, Cannabis offers the average patient an effective alternative to using opioids for general use in the treatment of pain with very minimal negative side effects for most people.”  https://news.unm.edu/news/unm-study-confirms-cannabis-flower-is-an-effective-mid-level-analgesic-medication-for-pain-treatment

Opportunities for cannabis in supportive care in cancer.

 Related image“Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain.

However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments.

Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer.

There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms.

Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild.

Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31413731

https://journals.sagepub.com/doi/10.1177/1758835919866362

Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug.

Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol.  Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system.

Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss.

THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals).

Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits.

The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.

Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance.

Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth.

Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.

Further explorations are required to exploit cannabinoids for an effective cancer management.”

http://www.cancerjournal.net/preprintarticle.asp?id=263538

“Could Cannabis Kill Cancer Cells? A New Study Looks Promising”  https://www.portlandmercury.com/blogtown/2019/08/15/26977361/could-cannabis-kill-cancer-cells-a-new-study-looks-promising

“Study Reviews How Marijuana Compounds Inhibit Tumor Growth And Kill Cancer Cells” https://www.marijuanamoment.net/study-reviews-how-marijuana-compounds-inhibit-tumor-growth-and-kill-cancer-cells/

Is Cannabis of Potential Value as a Therapeutic for Inflammatory Bowel Disease?

“Cannabis is commonly used by patients with inflammatory bowel disease (IBD) to ameliorate their symptoms.

Patients claim that cannabis reduces pain, increases appetite, and reduces the need for other medications.

In conclusion, considering the mechanism of action of phytocannabinoids and the accumulating evidence of their anti-inflammatory effects in experimental and in vitro studies, it is reasonable to assume that cannabis can be of benefit in the treatment of IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31388856

https://link.springer.com/article/10.1007%2Fs10620-019-05763-8

Cannabis Use Motivations among Adults Prescribed Opioids for Pain versus Opioid Addiction.

Pain Management Nursing“Cannabis has been linked to reduced opioid use, although reasons for cannabis use among adults prescribed opioids are unclear.

The purpose of this study was to determine whether motivations for cannabis use differ between adults prescribed opioids for persistent pain versus those receiving opioids as medication-assisted treatment for opioid use disorder.

RESULTS:

More than half the sample (n = 122) reported current, daily cannabis use and 63% reported pain as a motivation for use. Adults with persistent pain were more likely to be older, female, and have higher levels of education (p < .05). Adults with opioid use disorder were more likely to report “enhancement” (p < .01) and relief of drug withdrawal symptoms (p < .001) as motivations for cannabis use. The most common reasons for cannabis use in both populations were social and recreational use and pain relief.

CONCLUSIONS:

Both studied populations have unmet health needs motivating them to use cannabis and commonly use cannabis for pain. Persistent pain participants were less likely to use cannabis for euphoric effects or withdrawal purposes. Nurses should assess for cannabis use, provide education on known risks and benefits, and offer options for holistic symptom management.”

https://www.ncbi.nlm.nih.gov/pubmed/31375419

https://www.painmanagementnursing.org/article/S1524-9042(19)30096-7/fulltext

Olivia Newton John says medicinal cannabis is key to her cancer recovery

“Olivia Newton-John says medicinal marijuana is a key part of her treatment for stage four cancer. In an exclusive interview with 60 Minutes reporter Liz Hayes, Newton-John says that not only has cannabis assisted with her pain management, sleep and anxiety – but it’s having affects on her physical health too. “I’m incredibly pro cannabis,” she told Liz Hayes. “If I don’t take the cannabis, I can feel the pain so I know it’s working.”

 “Newton-John is maintaining her health with a combination of conventional and alternative medicines and remedies. But her husband of ten years, John Easterling, says he’s confident medicinal cannabis is contributing significantly to maintaining her health.
Easterling, who spent years cultivating herbs from the Amazon, has long held a strong belief in the medicinal power of plants. In a greenhouse at the Santa Barbara ranch the couple share in California, he grows various strains of cannabis that he uses to help treat his wife. “Cannabis can be used for so many things,” he told Hayes. “I don’t use the word cure…. but I’m confident. We had MRIs showing a lesser number of tumours, and the majority of the other ones are shrinking.”
 “Now a cannabis convert, Newton-John is joining the fight for medicinal cannabis to be legalised. She and Easterling want Australians to have greater access to the plant, like they do in their home state of California – where both medicinal and recreational cannabis is legal.  She’s also hoping to break down the stigma surrounding cannabis use.
“It’s not a drug, it’s a herb and a plant,” she told Hayes. “I think when people use the word drug, it’s a misconception as to what it is and it gets people thinking, ‘oh it’s just another drug’, but it’s not.” Doctors at the Olivia Newton-John Research Institute will conduct a clinical trial to determine the effectiveness of medicinal cannabis later this year.”
 
 “EXCLUSIVE: Olivia Newton-John and Chloe Lattanzi emotional interview | 60 Minutes Australia” https://www.youtube.com/watch?v=rJtPgpedcFo&feature=share

“Olivia Newton-John: ‘Medicinal cannabis enhanced my quality of life’.  For this special 60 Minutes report, Olivia Newton-John tells Liz Hayes that despite her latest diagnosis she was “getting strong again” and that her quality of life had been greatly enhanced by medicinal cannabis, grown for her by her husband John. Olivia and John are strong believers in the power of plants particularly cannabis. “I really believe the cannabis has made a huge difference,” says Olivia. “I’m confident,” John concurs. Olivia, John and Chloe are now cannabis converts, and now want medicinal cannabis legalised as an alternative treatment in Australia.” https://www.9news.com.au/national/olivia-newton-john-60-minutes-medical-cannabis-advocate-after-cancer-treatment-news/da315271-7387-47e0-a14e-c7fbb9a4b18b

“I have to credit again my wonderful husband because he gives me Cannabis oil that he makes for me, grows the plants here. We’re so lucky in California that we can grow our own, and so he’s made me these incredible tinctures that help with my pain and with sleep, and everything.” https://www.today.com/video/watch-olivia-newton-john-s-full-interview-with-natalie-morales-1455610947796

 Olivia Newton-John: “The choices of your treatment is a very personal thing. I can’t tell anyone else what they should do. I’d like to tell you all something that I did that people should know about. I’ve mixed traditional medicine and herbal medicine and homoeopathic medicine and a lot of mind-body spiritual focus. Staying positive and believing I can get well is really important. I’m very fortunate that I have a husband who’s a plant medicine man who helps me with herbs and medicinal cannabis, it’s been a huge part of my journey. I weaned myself off morphine with cannabis and I just want people to know that that is possible and it’s not going to kill you. If we can start teaching people that cannabis can help keep the pain away and not kill you, that’s an important message to get out there. I want to see an end to cancer in my lifetime. I’ve had three bouts with cancer. I am living with it well, and I think I’m going to see an end of it. And that’s my dream, that it will be gone.” https://www.image.ie/life/olivia-newton-john-shares-her-advice-for-women-with-cancer-154470
 “”I want to see an end to cancer in my lifetime. And if it could be through cannabis, or helping people with cannabis, the patients, particularly who are in pain, that’s my goal. I want everyone to have access to this amazing plant”” https://www.facebook.com/watch/?v=269501097009373
 ““I truly believe medicinal cannabis will play a huge part in defeating cancer.”“I absolutely believe all patients should have the right to try. It is a matter of common-sense and it is a compassionate thing to do for people,” she said,” https://starinvesting.com.au/medicinal-cannabis-to-play-huge-role-in-beating-cancer-olivia-newton-john/
Olivia Newton-John reveals she’s using marijuana grown by her husband to fight cancer – and says reports she was on death’s door hurt her deeply. Australian singing sensation Olivia Newton-John says she has been using marijuana grown by her husband to help her through her cancer battle. ‘I really believe the cannabis has made a huge difference,'”
“‘It Has Helped Incredibly’. It’s an amazing plant, a maligned plant, but it’s helping so many people.”” https://www.inquisitr.com/5330159/home-grown-cannabis-is-helping-olivia-newton-john-amid-cancer-battle-it-has-helped-incredibly/
“Olivia Newton-John says she uses cannabis to treat her stage 4 breast cancer… and her husband grows it at home” https://www.dailymail.co.uk/tvshowbiz/article-6782847/Olivia-Newton-John-uses-cannabis-treat-stage-4-breast-cancer.html
““I’m Living With Cancer and It’s Going Away!” Olivia Newton John Declares That Her Body is “Winning” Against Stage 4 Cancer” https://www.survivornet.com/articles/im-living-with-cancer-and-its-going-away-olivia-newton-john-declares-that-her-body-is-winning-against-stage-4-cancer/
“Mainstream media has reported that the cannabis tincture she takes helps with pain, but Amazon John Easterling eagerly expounds on its many healing properties, including the potential to cause cancer cell death. “Cannabis initiates a number of healing responses that can result in apoptosis, cancer cell death—while healing and strengthening the body,” he detailed. His focus is on the plant as chemovar, a more scientific approach to looking at the many compounds, via terpene and cannabinoid extraction from the whole plant to treat the cancer and the entire body, building the immune system so it can aid in fighting the disease.“ https://culturemagazine.com/olivia-newton-john-and-john-easterling/
“Medicinal cannabis is a big part of my recovery. I’m living proof that it works. It’s a healing herb.” https://www.facebook.com/watch/?v=1580591005362546

Cannabichromene is a cannabinoid CB2 receptor agonist.

British Journal of Pharmacology banner“Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 – tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.

KEY RESULTS:

CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.

CONCLUSIONS AND IMPLICATIONS:

CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31368508

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14815