The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study.

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Image result for integrative cancer therapies“Cancer-related cachexia and anorexia syndrome (CACS) is a common phenomenon in cancer patients. Cannabis has been suggested to stimulate appetite but research on this issue has yielded mixed results. The current study aimed to evaluate the effect of dosage-controlled cannabis capsules on CACS in advanced cancer patients.

Methods: The cannabis capsules used in this study contained two fractions of oil-based compounds. The planned treatment was 2 × 10 mg per 24 hours for six months of tetrahydrocannabinol (THC) 9.5 mg and cannabidiol (CBD) 0.5 mg. If patients suffered from side effects, dosage was reduced to 5 mg × 2 per day (THC 4.75 mg, CBD 0.25 mg). Participants were weighed on every physician visit. The primary objective of the study was a weight gain of ≥10% from baseline.

Results: Of 24 patients who signed the consent form, 17 started the cannabis capsules treatment, but only 11 received the capsules for more than two weeks. Three of six patients who completed the study period met the primary end-point. The remaining three patients had stable weights. In quality of life quaternaries, patients reported less appetite loss after the cannabis treatment (p=0.05). Tumor necrosis factor-α (TNF-α) levels decreased after the cannabis treatment but without statistical significance. According to patients’ self-reports, improvement in appetite and mood as well as a reduction in pain and fatigue was demonstrated.

Conclusions: Despite various limitations, this preliminary study demonstrated a weight increase of ≥10% in 3/17 (17.6%) patients with doses of 5mgx1 or 5mgx2 capsules daily, without significant side effects. The results justify a larger study with dosage-controlled cannabis capsules in CACS.”

https://www.ncbi.nlm.nih.gov/pubmed/31595793

“The primary objective of the study was a weight gain of ≥10% from baseline. Despite various limitations, the current preliminary study demonstrated a weight increase of ≥10% in 3/17 (17.6%) of the patients with doses of 5 mg × 1 or 5 mg × 2 capsules daily, without significant side effects.”

https://journals.sagepub.com/doi/10.1177/1534735419881498

Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

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 Publication Cover“Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system.

Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic).

Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation.

One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia .

Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells.

The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release.

This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R’s role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception.

We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons.

This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.”

https://www.ncbi.nlm.nih.gov/pubmed/31596190

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1668100?journalCode=wjdd20

The effect of cannabis laws on opioid use.

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International Journal of Drug Policy“Many Americans rely on opioids at varying dosages to help ameliorate their suffering. However, empirical evidence is mounting that opioids are ineffective at controlling non-cancer related chronic pain, and many argue the strategies meant to relieve patient suffering are contributing to the growing opioid epidemic.

Concurrently, several states now allow the use of medical cannabis to treat a variety of medical conditions, including chronic pain. Needing more exploration is the impact of cannabis laws on general opioid reliance and whether chronic pain sufferers are opting to use cannabis medicinally instead of opioids.

METHODS:

This study investigates the effect of Medical Marijuana Laws (MML)s on opioid use and misuse controlling for a number of relevant factors using data from several years of the National Survey on Drug Use and Health and multivariate logistic regression and longitudinal analysis strategies.

RESULTS:

Results provide evidence that MMLs may be effective at reducing opioid reliance as survey respondents living in states with medical cannabis legislation are much less apt to report using opioid analgesics than people living in states without such laws, net other factors. Results further indicate that the presence of medicinal cannabis legislation appears to have no influence over opioid misuse.

CONCLUSION:

MMLs may ultimately serve to attenuate the consequences of opioid overreliance.”

https://www.ncbi.nlm.nih.gov/pubmed/31590091

https://www.sciencedirect.com/science/article/abs/pii/S0955395919302567?via%3Dihub

Δ9-Tetrahydrocannabinol Derivative-Loaded Nanoformulation Lowers Intraocular Pressure in Normotensive Rabbits.

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“Δ9-Tetrahydrocannabinol-valine-hemisuccinate, a hydrophilic prodrug of Δ9-tetrahydrocannabinol, synthesized with the aim of improving the ocular bioavailability of the parent molecule, was investigated in a lipid-based nanoparticle dosage form for ocular delivery.

RESULTS:

A peak intraocular pressure (IOP) drop of 30% from baseline was observed in rabbits treated with SLNs loaded with Δ9-tetrahydrocannabinol-valine-hemisuccinate at 90 minutes. Treated eyes of rabbits receiving Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs had significantly lower IOP than untreated eyes until 360 minutes, whereas the group receiving the emulsion formulation showed a drop in IOP until 90 minutes only. In comparison to marketed pilocarpine and timolol maleate ophthalmic solutions, Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs produced a greater effect on IOP in terms of both intensity and duration. In terms of tissue concentrations, significantly higher concentrations of Δ9-tetrahydrocannabinol-valine-hemisuccinate were observed in iris-ciliary bodies and retina-choroid with SLNs.

CONCLUSION:

Δ9-Tetrahydrocannabinol-valine-hemisuccinate formulated in a lipid-based nanoparticulate carrier shows promise in glaucoma pharmacotherapy.

TRANSLATIONAL RELEVANCE:

Glaucoma therapies usually focus on decreased aqueous humor production and increased outflow. However, such therapy is not curative, and there lies a need in preclinical research to focus efforts on agents that not only affect the aqueous humor dynamics but also provide neuroprotection. Historically, there have been bench-scale studies looking at retinal ganglion cell death post-axonal injury. However, for a smooth translation of this in vitro activity to the clinic, animal models examining IOP reduction, i.e., connecting the neuroprotective activity to a measurable outcome in glaucoma management (IOP), need to be investigated. This study investigated the IOP reduction efficacy of cannabinoids for glaucoma pharmacotherapy in a normotensive rabbit model, bringing forth a new class of agents with the potential of IOP reduction and improved permeation to the back of the eye, possibly providing neuroprotective benefits in glaucoma management.”

https://www.ncbi.nlm.nih.gov/pubmed/31588378

“THC has been demonstrated to be effective in glaucoma management, helping to lower IOP in human subjects after smoking marijuana; however, the molecule fails to manifest a similar effect when dosed topically. This research explores molecular bioengineering and formulation-based strategies to improve the ocular bioavailability of THC, facilitating the molecule to translate into a dosage form capable of demonstrating a desired IOP-lowering effect even on topical application. These studies suggest that formulation development efforts along with prodrug derivatization can effectively improve the overall ocular bioavailability of THC. Thus, THC-VHS represents a potential new therapy option for the treatment and management of glaucoma by virtue of its superiority in lowering IOP when compared to antiholinergic and beta blockers, as studied in this model.”
https://tvst.arvojournals.org/article.aspx?articleid=2751570

The evaluation of Cannabidiol’s effect on the immunotherapy of Burkitt lymphoma.

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Biochemical and Biophysical Research Communications

“AF1q has a precise oncogenic function.

The purpose of this study is to investigate whether CBD has an effect on the AF1q/ICAM-1 regulatory axis in Burkitt’s lymphoma (BL), and thus has potential to enhance immunotherapy and reduce side effects.

 

RESULTS:

AF1q increased oncogenic growth and colony formation, and induced resistance against cell-mediated cytotoxic chemotherapy through attenuation of ICAM-1 expression in BL. CBD was able to reverse the acquired resistance mediated by AF1q/ICAM-1 regulatory axis.

CONCLUSION:

CBD holds potential to enhance the efficacy of immunotherapy for BL with hyperactive AF1q/ICAM-1 regulatory axis, and warrants further study.”

https://www.ncbi.nlm.nih.gov/pubmed/31587870

“Non-psychoactive CBD could potentially enhance the efficacy of immunotherapy in cancer treatment, especially against aggressive B.”

https://www.sciencedirect.com/science/article/pii/S0006291X1931890X?via%3Dihub

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

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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.

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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.

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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.

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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.

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 “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