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Evidence for Clinical Justification

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Over the past few years, a number of Australians have expressed interest in the use of cannabis for medicinal purposes. There have only been a limited number of well-designed clinical studies on medicinal cannabis and so it is hard for some doctors to find quality evidence to support decisions to prescribe medicinal cannabis.

The Commonwealth Department of Health, in conjunction with state and territory governments, has helped coordinate the development new clinical guidance documents for prescribers of medicinal cannabis products for treating chemotherapy-induced nausea and vomiting, epilepsy, multiple sclerosis, chronic non-cancer pain and palliative care, as well as an overview document.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Medicinal cannabis products: Patient information

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis in Australia: Overview

Description

This guidance summarises the limited and disparate data available for medicinal cannabis use in specific treatment settings. It does not recommend use, nor does it intend to fill the gap in research that currently exists. The document’s primary purpose is to support informed decision making and help the patient partner with their doctor in the therapeutic process by providing explanation and advice on the use of medicinal cannabis.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis in Australia: Overview

Description

This document reflects the evidence supporting the use of medicinal cannabis in treating chronic pain and the recommendations of the Chronic Pain Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the ‘Guidance to the use of medicinal cannabis in Australia – Overview‘.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis in the treatment of multiple sclerosis in Australia

Description

This document reflects the evidence supporting the use of medicinal cannabis in treating symptoms of MS, including pain, spasticity, bladder spasm, ataxia and tremor, adverse events, quality of life and disability and the recommendations of the Multiple Sclerosis Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the ‘Guidance to the use of medicinal cannabis in Australia – Overview‘.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis in the treatment of palliative care patients in Australia

Description

This document reflects the evidence supporting the use of medicinal cannabis in palliative care patients and the recommendations of the Palliative Care Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the ‘Guidance to the use of medicinal cannabis in Australia – Overview‘.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis in the treatment of epilepsy in paediatric and young adult patients in Australia

Description

This document reflects the evidence supporting the use of medicinal cannabis in treating epilepsy in particular patient groups and the recommendations of the Epilepsy Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the ‘Guidance to the use of medicinal cannabis in Australia – Overview‘.

Resource Details

Authors: Therapeutics Goods Administration

PDF: Guidance for the use of medicinal cannabis for the prevention or management of nausea and vomiting in Australia

Description

This document reflects the evidence supporting the use of medicinal cannabis in nausea and vomiting and the recommendations of the Nausea and Vomiting Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the ‘Guidance to the use of medicinal cannabis in Australia – Overview‘.

Treatment Considerations, Dosing & Titration

Citation Details

Authors: Maccallum, Caroline A. & Russo Ethan B.

Citation: Maccallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 2018;49:12-19.

Doi: 10.1016/j.ejim.2018.01.004

Abstract

Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.

Citation Details

Authors: Barrett, Frederick S. Schlienz, Nicolas J. Lembeck, Natalie. Waqas, Muhammad. & Vandrey, Ryan.

Citation: Barrett, Frederick S, et al. “Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs. Cannabis and Cannabinoid Research. 2018;3(1):85–93.

Doi: 10.1089/can.2017.0052

Abstract

Introduction: Cannabis has been historically classified as a hallucinogen. However, subjective cannabis effects do not typically include hallucinogen-like effects. Empirical reports of hallucinogen-like effects produced by cannabis in controlled settings, particularly among healthy research volunteers, are rare and have mostly occurred after administration of purified Δ-9 tetrahydrocannabinol (THC) rather than whole plant cannabis.

Methods: The case of a healthy 30-year-old male who experienced auditory and visual hallucinations in a controlled laboratory study after inhaling vaporized cannabis that contained 25 mg THC (case dose) is presented. Ratings on the Hallucinogen Rating Scale (HRS) following the case dose are compared with HRS ratings obtained from the participant after other doses of cannabis and with archival HRS data from laboratory studies involving acute doses of cannabis, psilocybin, dextromethorphan (DXM), and salvinorin A.

Results: Scores on the Volition subscale of the HRS were greater for the case dose than for the maximum dose administered in any other comparison study. Scores on the Intensity and Perception subscales were greater for the case dose than for the maximum dose of cannabis, psilocybin, or salvinorin A. Scores on the Somaesthesia subscale were greater for the case dose than for the maximum dose of DXM, salvinorin A, or cannabis. Scores on the Affect and Cognition subscales for the case dose were significantly lower than for the maximum doses of psilocybin and DXM.

Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis.

Citation Details

Authors: Pol, Peggy. Liebregts, Nienke. Brunt, Tibor. Amsterdam, Jan. Graaf, Ron. Korf, Dirk J. Brink, Wim. & Laar, Margriet.

Citation: Pol, Peggy, et al. “Cross‐Sectional and Prospective Relation of Cannabis Potency, Dosing and Smoking Behaviour with Cannabis Dependence: an Ecological Study.” Addiction, vol. 109, no. 7, 2014, pp. 1101–1109.

Doi: 10.1111/add.12508

Abstract

Background and Aims

Increased delta‐9‐tetrahydrocannabinol (THC) concentrations in cannabis may lead to higher THC exposure, cannabis dependence and treatment need, but users may also adapt the actual intake of THC through reduced inhalation of THC containing smoke (titration). We investigated whether consumers of stronger cannabis use less cannabis per joint or inhale less smoke than those using less potent cannabis and whether these factors predict cannabis dependence severity.

Methods

Heavy cannabis users (n = 98) brought their own cannabis, rolled a joint and smoked it ad libitum in a naturalistic setting. We analysed the content of the joint, its association with smoking behaviour and the cross‐sectional and prospective (1.5‐year follow‐up) relations between smoking behaviour and cannabis dependence severity (total number of DSM‐IV dependence symptoms).

Results

THC concentration in cannabis (range 1.10–24.70%) was correlated positively with cannabis dose per joint (b = 0.008, P = 0.01), but the resulting THC concentration per joint (range 0.24–15.72%) was associated negatively with inhalation volume (b = −0.05, P = 0.03). Smoking behaviour measures (number of puffs, inhaled volume, reduction of puff volume and puff duration while smoking) predicted follow‐up dependence severity, independently of baseline dependence severity and monthly THC dose (number of joints × cannabis dose × cannabis THC concentration). Monthly THC dose only predicted follow‐up dependence severity when unadjusted for baseline severity.

Conclusions

Cannabis users titrate their delta‐9‐tetrahydrocannabinol intake by inhaling lower volumes of smoke when smoking strong joints, but this does not fully compensate for the higher cannabis doses per joint when using strong cannabis. Thus, users of more potent cannabis are generally exposed to more delta‐9‐tetrahydrocannabinol. Smoking behaviour appears to be a stronger predictor for cannabis dependence severity than monthly delta‐9‐tetrahydrocannabinol dose.

Citation Details

Authors: Schlienz, Nicolas J. Lee, Dustin C. Stitzer, Maxine L. & Vandrey, Ryan.

Citation: Schlienz, et al. “The Effect of High-Dose Dronabinol (Oral THC) Maintenance on Cannabis Self-Administration.” Drug and Alcohol Dependence, vol. 187, 2018, pp. 254–260.

Doi: https://doi.org/10.1016/j.drugalcdep.2018.02.022.

Abstract

Background

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.

Methods

Non-treatment seeking daily cannabis users (N = 13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180–240 mg/day; 60–80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions.

Results

Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions.

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.

Citation Details

Authors: Parnes, Jamie E. Bravo, Adrian J. Conner, Bradley T. & Pearson, Matthew R.

Citation: Parnes, Jamie E., et al. “A Burning Problem: Cannabis Lessons Learned from Colorado.” Addiction Research &Amp; Theory, vol. 26, no. 1, 2018, pp. 3–10.

Doi: https://doi.org/10.1080/16066359.2017.1315410.

Abstract

With recent increases in cannabis’ popularity, including being legalized in several states, new issues have emerged related to use. Increases in the number of users, new products, and home growing all present distinct concerns. In the present review, we explored various cannabis-related concerns (i.e. use, acquiring, growing, and public health/policy) that have arisen in Colorado in order to provide information on emerging issues and future directions to mitigate negative outcomes that could occur in states considering, or that already have implemented, a legalized cannabis market. Specific to Colorado, issues have arisen related to edibles, vaporizers/’e-cannabis’, concentrates, growing, quantifying use, intoxicated driving, and arrests. Understanding cannabis dosing (including dose-dependent effects and related consequences), standardizing quantities, evaluating the safety of new products, and developing harm reduction interventions are important next steps for informing public policy and promoting health and well-being. Overall, increasing our knowledge of emerging issues related to cannabis is key to promoting the benefits and combating the potential harms of cannabis, especially for states legalizing medical or recreational cannabis.

Citation Details

Authors: Lee, Dayong. Vandrey, Ryan. Milman, Garry. Bergamaschi, Mateus. Mendu, Damodara. Murray, Jeannie. Barnes, Allan & Huestis, Marilyn.

Citation: Lee, Dayong, et al. “Oral Fluid/Plasma Cannabinoid Ratios Following Controlled Oral THC and Smoked Cannabis Administration.” Analytical and Bioanalytical Chemistry, vol. 405, no. 23, 2013, pp. 7269–7279.

Doi: 10.1007/s00216-013-7159-8

Abstract

With recent increases in cannabis’ popularity, including being legalized in several states, new issues have emerged related to use. Increases in the number of users, new products, and home growing all present distinct concerns. In the present review, we explored various cannabis-related concerns (i.e. use, acquiring, growing, and public health/policy) that have arisen in Colorado in order to provide information on emerging issues and future directions to mitigate negative outcomes that could occur in states considering, or that already have implemented, a legalized cannabis market. Specific to Colorado, issues have arisen related to edibles, vaporizers/’e-cannabis’, concentrates, growing, quantifying use, intoxicated driving, and arrests. Understanding cannabis dosing (including dose-dependent effects and related consequences), standardizing quantities, evaluating the safety of new products, and developing harm reduction interventions are important next steps for informing public policy and promoting health and well-being. Overall, increasing our knowledge of emerging issues related to cannabis is key to promoting the benefits and combating the potential harms of cannabis, especially for states legalizing medical or recreational cannabis.

Citation Details

Authors: Dryburgh, Laura M. Bolan, Nanthi S. Grof, Christopher P L. Galettis, Peter. Schneider, Jennifer. Lucas, Catherine J. & Martin, Jennifer H

Citation: Dryburgh, Laura M, et al. “Cannabis Contaminants – Sources, Distribution, Human Toxicity and Pharmacologic Effects.” British Journal of Clinical Pharmacology, 2018, pp. British journal of clinical pharmacology, 28 June 2018.

Doi: 10.1111/bcp.13695

Abstract

There has been a resurgence in interest and use of the cannabis plant for medical purposes. However, an in‐depth understanding of plant contaminants and toxin effects on stability of plant compounds and human bioavailability is needed. This systematic review aims to assess current understanding of the contaminants of cannabis and their effect on human health, leading to the identification of knowledge gaps for future investigation. A systematic search of seven indexed biological and biomedical databases and the Cochrane library was undertaken from inception up to December 2017. A qualitative synthesis of filtered results was undertaken after independent assessment for eligibility by two reviewers. The common cannabis contaminants include microbes, heavy metals and pesticides. Their direct human toxicity is poorly quantified but include infection, carcinogenicity, reproductive and developmental impacts. Cannabis dosing formulations and administration routes affect the transformation and bioavailability of contaminants. There may be important pharmacokinetic interactions between the alkaloid active ingredients of cannabis (i.e. phytocannabinoids) and contaminants but these are not yet identified nor quantified. There is significant paucity in the literature describing the prevalence and human impact of cannabis contaminants. Advances in the availability of cannabis globally warrant further research in this area, particularly when being used for patients.

Citation Details

Authors: Toennes, Stefan. Schneider, Kirsten. Kauert, Gerold. Wunder, Cora. Moeller, Manfred. Theunissen, Eef. & Ramaekers, Johannes.

Citation: Toennes, Stefan, et al. “Influence of Ethanol on Cannabinoid Pharmacokinetic Parameters in Chronic Users.” Analytical and Bioanalytical Chemistry, vol. 400, no. 1, 2011, pp. 145–152.

Doi: 10.1007/s00216-010-4449-2

Abstract

Cannabis is not only the most widely used illicit drug worldwide but is also regularly consumed along with ethanol. In previous studies, it was assumed that cannabis users develop cross-tolerance to ethanol effects. The present study was designed to compare the effects of ethanol in comparison to and in combination with a cannabis joint and investigate changes in pharmacokinetics. In this study, 19 heavy cannabis users participated and received three alcohol dosing conditions that were calculated to achieve steady blood alcohol concentrations (BAC) of about 0, 0.5 and 0.7 g/l during a 5-h time window. Subjects smoked a Δ9-tetrahydrocannabinol (THC) cigarette (400 μg/kg) 3 h post-onset of alcohol dosing. Blood samples were taken between 0 and 4 h after smoking. During the first hour, samples were collected every 15 min and every 30 min thereafter. Mean steady-state BACs reached 0, 0.36 and 0.5 g/l. The apparent elimination half-life of THC was slightly prolonged (1.59 vs. 1.93 h, p < 0.05) and the concentration 1 h after smoking was slightly lower (24 vs. 17 ng/ml, p < 0.05) with the higher ethanol dose. The prolonged THC elimination might be explained by a small ethanol-mediated change in distribution to and from deep compartments. Concentrations and pharmacokinetics of 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCA) were not significantly influenced by ethanol. However, THCA concentrations appeared lower in both ethanol conditions, which might also be attributable to changes in distribution. Though not significant in the present study, this might be relevant in the interpretation of cannabinoid concentrations in blood.

Pallative Care

Citation Details

Authors:Gil Bar-Sela, Marina Vorobeichik, Saher Drawsheh, Anat Omer, Victoria Goldberg, and Ella Muller

Citation: Gil Bar-Sela, Marina Vorobeichik, Saher Drawsheh, Anat Omer, Victoria Goldberg, and Ella Muller, “The Medical Necessity for Medicinal Cannabis: Prospective, Observational Study Evaluating the Treatment in Cancer Patients on Supportive or Palliative Care,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 510392, 8 pages, 2013.

Doi: 10.1155/2013/510392

Background: Cancer patients using cannabis report better influence from the plant extract than from synthetic products. However, almost all the research conducted to date has been performed with synthetic products. We followed patients with a medicinal cannabis license to evaluate the advantages and side effects of using cannabis by cancer patients.

Methods: The study included two interviews based on questionnaires regarding symptoms and side effects, the first held on the day the license was issued and the second 6–8 weeks later. Cancer symptoms and cannabis side effects were documented on scales from 0 to 4 following the CTCAE. The distress thermometer was used also.

Results: Of the 211 patients who had a first interview, only 131 had the second interview, 25 of whom stopped treatment after less than a week. All cancer or anticancer treatment-related symptoms showed significant improvement (𝑃 < 0.001). No significant side effects except for memory lessening in patients with prolonged cannabis use (𝑃 =0.002) were noted.

Conclusion: The positive effects of cannabis on various cancer-related symptoms are tempered by reliance on self-reporting for many of the variables. Although studies with a control group are missing, the improvement in symptoms should push the use of cannabis in palliative treatment of oncology patients.

Citation Details

Authors: S.K. Aggarwal, MD PhD

Citation: Aggarwal SK. Use of cannabinoids in cancer care: palliative care. Current Oncology. 2016;23(Suppl 2):S33-S36.

Doi: 10.3747/co.23.2962

PMCID: PMC4791145

Abstract

Integrating Cannabinoid Integrative Medicine into oncologic palliative care promises to improve overall health-related quality of life, to provide further relief from distressing symptoms and spiritual suffering, and to bring hope to patients and families facing terminal illness.

Citation Details

Authors: Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R.

Citation: Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Pain Physician. Opioid complications and side effects. 2008 Mar;11(2 Suppl):S105-20. Review.

Doi: 10.3747/co.23.2962

Abstract

Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions.

Cancer

Citation Details

Authors: G. Velasco, PhD, C. Sánchez, PhD, and M. Guzmán, PhD

Citation: Velasco G, Sánchez C, Guzmán M. Anticancer mechanisms of cannabinoids. Current Oncology. 2016;23(Suppl 2):S23-S32.

PMCID: PMC4791144

Abstract

To summarize, cannabinoids induce tumour cell death and inhibit tumour angiogenesis and invasion in animal models of cancer, and there are indications that they act similarly in patients with glioblastoma. Given that cannabinoids show an acceptable safety profile, clinical trials testing them as single drugs or, ideally, in combination therapies in glioblastoma and other types of cancer are both warranted and urgently needed.

Citation Details

Authors: Saoirse Elizabeth O’Sullivan

Citation: O’Sullivan, S. E. An update on PPAR activation by cannabinoidsBritish Journal of Pharmacology. 2016;173: 1899–1910.

Doi: 10.1111/bph.13497

Conclusion: The aims of this review were to update the evidence that cannabinoids have “gone nuclear” and to establish whether activation by cannabinoids of the PPARs, a major class of nuclear hormone receptors, plays a role in their physiological effects (O’Sullivan, 2007; O’Sullivan, 2013). Although our knowledge in this area has significantly increased, there are still many cannabinoids whose activity at PPARs remains unknown. For example, there is little known about the effects of phytocannabinoids on PPARα and the potential role for PPARδ activation by cannabinoids. We do now know that many of the well‐recognized responses to cannabinoids such as neuroprotection and analgesia are at least partly mediated by the activation of PPARs, although this is better investigated for some cannabinoids, such as OEA and PEA, than others. Despite the fact that anandamide and 2‐AG bind to both PPARα and PPARγ, few studies have probed this as a mechanism of action for these endocannabinoids, possibly because much of the characterisation of these compounds was carried out before PPARs were proposed as additional targets of cannabinoids. Finally, there are also many PPAR‐independent effects of cannabinoids, and the many factors that could be influencing the interactions between cannabinoids and PPARs remain to be established.

Citation Details

Authors: Sadiye Amcaoglu Rieder, Ashok Chauhan, Ugra Singh, Mitzi Nagarkatti, and Prakash Nagarkatti.

Citation:Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology. 2010;215(8):598-605.

Doi: 10.1016/j.imbio.2009.04.001

PMCID: PMC3005548

Conclusion
Cannabinoids have been approved in some countries for the treatment of chemotherapy-induced nausea and vomiting, and clinical trials show cannabinoids’ effectiveness in pain inhibition and appetite stimulation (Guzman 2003; Tramer et al. 2001). Anti-inflammatory therapeutic potential of cannabinoids is also evident from the studies discussed in this review paper. At the optimal concentrations, cannabinoids do induce apoptosis in immune cells, alleviating inflammatory responses and protecting the host from acute and chronic inflammation. The cumulative effect of cannabinoids on all cell populations of the immune system can be beneficial, when there is a need for immune suppression. For example, in patients with autoimmune diseases such as multiple sclerosis, arthritis and lupus, or in those with septic shock, where the disease is caused by activated immune cells, targeting the immune cells via CB2 agonists may trigger apoptosis and act as anti-inflammatory therapy. CB2 select agonists are not psychoactive and because CB2 is expressed primarily in immune cells, use of CB2 agonists could provide a novel therapeutic modality against autoimmune and inflammatory diseases. Clearly, additional research is necessary to validate these studies in humans through clinical trials. However, in other instances, such as in patients with breast cancer in which cannabinoid receptors may not be expressed by the cancer cells, cannabinoids may worsen the disease, because the immune system is weakened, and the breast cancer cells are resistant to cannabinoid-induced apoptosis. Thus, it is critical to balance the immunsuppressive effects with the anticancer properties, which require careful dose–response studies on these clinical outcomes. Overall, there exists a biphasic role for cannabinoids, and it depends on three key factors: (1) the type of cannabinoid, (2) the dose of cannabinoid, and (3) the type of cell that the cannabinoid is acting on. The degree of cannabinoid receptor expression may play role in some cases; however, the receptor-independent mechanism of action is evident for cannabinoids in some cell populations. In addition to the use of exogenous cannabinoids, in vivo manipulation of endocannabinoids may also offer novel treatment opportunities against cancer and autoimmune diseases.

Citation Details

Authors: Bandana Chakravarti, Janani Ravi, and Ramesh K. Ganju

Citation: Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: Current status and future implicationsOncotarget 2014;5:5852–5872.

Doi: 10.18632/oncotarget.2233

Conclusion

Cannabinoids exert a direct anti-proliferative effect on tumors of different origin. They have been shown to be anti-migratory and anti-invasive and inhibit MMPs which in turn degrade the extra-cellular matrix (ECM), thus affecting metastasis of cancer to the distant organs. Also, cannabinoids modulate other major processes in our body like energy metabolism, inflammation, etc. These data are derived not only from cell culture systems but also from more complex and clinically relevant animal models. Before cannabinoids could be used in clinical trials, there is need to explore more knowledge on several issues such as anti-tumorigenic and anti-metastatic mechanisms as well as which type of cancer patient populations would be more responsive for cannabinoid based therapies. Data presented in this review suggest that cannabinoids derived from different sources regulate differently signaling pathways, modulate different tumor cell types and host physiological system. It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism. Furthermore, endocannabinoids- AEA and 2-AG are broken down into secondary metabolites like prostaglandin (PGE2) and epoxyeicosatetraenoic acid (EE) which enhance tumor growth and metastasis in diverse cancer types. Understanding the exact signaling by which cannabinoids function will eventually lead to targeted clinical approach. Also, the difference in cellular response to cannabinoids in different cancer types might be due to the effect of the tumor environment which involves inflammatory cells, fibroblasts, endothelial cells, macrophages, etc. Thus, there is a need for an integrative understanding of the role of cannabinoids with respect to the tumor and its microenvironment. The diversity of affecting multiple signaling pathways might pave way for developing cannabinoids that selectively obstruct a particular pathway, thus opening avenues for specific targeted treatments.

Moreover, cannabinoids are more specific to cancer cells than normal cells. The administration of single cannabinoids might produce limited relief compared to the administration of crude extract of plant containing multiple cannabinoids, terpenes and flavanoids. Thus, combination of cannabinoids with other chemotherapeutic drugs might provide a potent clinical outcome, reduce toxicity, increase specificity and overcome drug resistance complications. Additional findings in in vitro and in vivo models are needed to support studies at preclinical setting.

Citation Details

Authors: Daniel A. Ladin, Eman Soliman, LaToya Griffin and Rukiyah Van Dross

Citation:Ladin DA, SolimanE,Griffin Land Van Dross R. Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents. Front. Pharmacol. 2016. 7:361.

Doi: 10.3389/fphar.2016.00361

Conclusion

To gain an understanding regarding the translational and therapeutic potential of cannabinoids, this review focused on examining the overall efficacy of these molecules in animal and human studies. The majority of in vivo animal studies discussed here indicate that cannabinoids from plant, synthetic and endogenous origin are capable of effectively decreasing tumor growth and invasion (Table 1). Furthermore, clinical studies evaluating cannabinoid efficacy in human subjects are limited, yet these studies showed that cannabinoids may be safe and effective anti-neoplastics. Because large scale clinical trials are lacking, examining the activity of cannabinoids in clinically translatable animal models (such as PDX) should be the goal of future research as this approach may provide a more accurate assessment of the therapeutic potential of cannabinoids.

This review also sought to couple in vivo animal studies with in vitro experiments in order to examine proposed cannabinoid mechanisms of action and to identify specific cellular targets. The studies reviewed herein indicate that cannabinoids elicit activity through cannabinoid receptor dependent and independent pathways. Moreover, processes such as ceramide production, ER-stress, autophagy, angiogenesis and matrix remodeling also appear to regulate the anti-tumor activity of cannabinoids. Hence, these investigations shed light on the role of cannabinoids on tumor growth in vivo and may ultimately pave the way for the development of novel cannabinoid therapeutics for cancer treatment.

Citation Details

Authors: Jenny Flygare, Birgitta Sander

Citation:Flygare J, Sander B. The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol. 2008;18(3):176–189.

Doi: 10.1016/j.semcancer.2007.12.008

Abstract

Endogenous arachidonic acid metabolites with properties similar to compounds of Cannabis sativa Linnaeus, the so-called endocannabinoids, have effects on various types of cancer. Although endocannabinoids and synthetic cannabinoids may have pro-proliferative effects, predominantly inhibitory effects on tumor growth, angiogenesis, migration and metastasis have been described. Remarkably, these effects may be selective for the cancer cells, while normal cells and tissues are spared. Such apparent tumor cell selectivity makes the endocannabinoid system an attractive potential target for cancer therapy. In this review we discuss various means by which the endocannabinoid system may be targeted in cancer and the current knowledge considering the regulation of the endocannabinoid system in malignancy.

Citation Details

Authors: C Andradas, MM Caffarel, E Perez-Gomez, M Salazar, M Lorente, G Velasco, M Guzman and C Sanchez.

Citation:  C Andradas, MM Caffarel, E Perez-Gomez, M Salazar, M Lorente, G Velasco, M Guzman and C Sanchez. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene. 2011 Jan 13;30(2):245-52.

Doi: 10.1038/onc.2010.402

Abstract

GPR55 is an orphan G protein-coupled receptor that may be engaged by some lipid ligands such as lysophosphatidylinositol and cannabinoid-type compounds. Very little is known about its expression pattern and physio-pathological relevance, and its pharmacology and signaling are still rather controversial. Here we analyzed the expression and function of GPR55 in cancer cells. Our data show that GPR55 expression in human tumors from different origins correlates with their aggressiveness. Moreover, GPR55 promotes cancer cell proliferation, both in cell cultures and in xenografted mice, through the overactivation of the extracellular signal-regulated kinase cascade. These findings reveal the importance of GPR55 in human cancer, and suggest that it could constitute a new biomarker and therapeutic target in oncology.

Citation Details

Authors: Lauren S. Whyte, Erik Ryberg, Natalie A. Sims, Susan A. Ridge, Ken Mackie, Peter J. Greasley, Ruth A. Ross, and Michael J. Rogers.

Citation:  Whyte LS, Ryberg E, Sims NA, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(38):16511-16516. 

Doi: 10.1073/pnas.0902743106

Abstract

GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and by lysophosphatidylinositol (LPI). However, the physiological role of GPR55 remains unknown. Given the recent finding that the cannabinoid receptors CB1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarization and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55−/− macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55−/− mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light an effect of both the endogenous ligand, LPI, on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo.

Chronic Pain

Citation Details

Authors: Alexia Blake, Bo Angela Wan, Leila Malek, Carlo DeAngelis, Patrick Diaz, Nicholas Lao, Edward Chow, Shannon O’Hearn

Citation: Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017 Dec;6(Suppl 2):S215-S222.

Doi: 10.21037/apm.2017.08.05.

Abstract

Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic options. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7–43.2 mg/day THC and 0–40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7–10.8 mg THC in combination with 2.5–10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neuropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.

Citation Details

Authors:Kevin F. Boehnke, Evangelos Litinas, Daniel J. Clauw

Citation: Boehnke KF, Litinas E, Clauw DJ. Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. J Pain. 2016 Jun;17(6):739-44.

Doi: 10.1016/j.jpain.2016.03.002

Abstract

Opioids are commonly used to treat patients with chronic pain (CP), though there is little evidence that they are effective for long term CP treatment. Previous studies reported strong associations between passage of medical cannabis laws and decrease in opioid overdose statewide. Our aim was to examine whether using medical cannabis for CP changed individual patterns of opioid use. Using an online questionnaire, we conducted a cross-sectional retrospective survey of 244 medical cannabis patients with CP who patronized a medical cannabis dispensary in Michigan between November 2013 and February 2015. Data collected included demographic information, changes in opioid use, quality of life, medication classes used, and medication side effects before and after initiation of cannabis usage. Among study participants, medical cannabis use was associated with a 64% decrease in opioid use (n = 118), decreased number and side effects of medications, and an improved quality of life (45%). This study suggests that many CP patients are essentially substituting medical cannabis for opioids and other medications for CP treatment, and finding the benefit and side effect profile of cannabis to be greater than these other classes of medications. More research is needed to validate this finding.

PERSPECTIVE:

This article suggests that using medical cannabis for CP treatment may benefit some CP patients. The reported improvement in quality of life, better side effect profile, and decreased opioid use should be confirmed by rigorous, longitudinal studies that also assess how CP patients use medical cannabis for pain management.

Citation Details

Authors: Manzanares J, Julian M, Carrascosa A.

Citation: Manzanares J, Julian M, Carrascosa A. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. Current Neuropharmacology. 2006;4(3):239-257.

PMCID: PMC2430692

Abstract
Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB1mediated suppression of mast cell activation responses, CB2-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.

Citation Details

Authors: Patrick H. Finan, Ph.D. and Michael T. Smith, Ph.D.

Citation: Finan PH, Smith MT. The Comorbidity of Insomnia, Chronic Pain, and Depression: Dopamine as a Putative Mechanism. Sleep medicine reviews. 2013;17(3):173-183.

Doi: 10.1016/j.smrv.2012.03.003

Abstract

Epidemiological, cross-sectional, and prospective studies suggest that insomnia, chronic pain, and depression frequently co-occur and are mutually interacting conditions. However, the mechanisms underlying these comorbid disorders have yet to be elucidated. Overlapping mechanisms in the central nervous system suggest a common neurobiological substrate(s) may underlie the development and interplay of these disorders. We propose that the mesolimbic dopamine system is an underappreciated and attractive venue for the examination of neurobiological processes involved in the interactions, development, exacerbation, and maintenance of this symptom complex. In the present article, studies from multiple disciplines are reviewed to highlight the role of altered dopaminergic function in the promotion of arousal, pain sensitivity, and mood disturbance. We argue that studies aiming to elucidate common factors accounting for the comorbidity of insomnia, chronic pain, and depression should evaluate functioning within the mesolimbic dopaminergic system and its effect on common processes known to be dysregulated in all three disorders.

Citation Details

Authors: Josée Guindon and Andrea G. Hohmann

Citation: Guindon J, Hohmann AG. The Endocannabinoid System and Pain. CNS & neurological disorders drug targets. 2009;8(6):403-421.

PMCID: PMC2834283

Abstract

The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB(1) and CB(2) receptor subtypes. Endocannabinoids, the brain’s own cannabis-like substances, share the same molecular target as Delta(9)-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide and 2-arachidonoylglycerol, the two best characterized endocannabinoids identified to date, in controlling nociceptive responding. The roles of anandamide and 2-arachidonoylglycerol, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of endocannabinoid levels through inhibition of endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.

Citation Details

Authors: Perry G. Fine, M.D., and Mark J. Rosenfeld, M.S., Ph.D.

Citation: Fine PG, Rosenfeld MJ. The Endocannabinoid System, Cannabinoids, and Pain. Eisenberg E, Vulfsons S, eds. Rambam Maimonides Medical Journal. 2013;4(4):e0022.

Doi: 10.5041/RMMJ.10129

Abstract

The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB1 receptors) and in the periphery (primarily but not exclusively CB2 receptors) are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids) and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking), as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.

CINV

Citation Details

Authors: Melissa E. Badowski

Citation: Badowski ME. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics. Cancer Chemotherapy and Pharmacology. 2017;80(3):441-449.

Doi: 10.1007/s00280-017-3387-5

Purpose
Oral cannabinoids (i.e., dronabinol, nabilone) containing the active component of marijuana, delta(Δ)9-tetrahydrocannabinol (THC), are available for the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who have failed to adequately respond to conventional antiemetic therapy. The aim of this article is to provide an overview of the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of oral cannabinoids for patients with CINV.

Methods
A PubMed search of the English-language literature available through 4 January 2017 was conducted to identify relevant articles for inclusion in the review.

Results
Oral cannabinoids have been shown to have similar or improved efficacy compared with conventional antiemetics for the resolution of nausea and/or vomiting in patients with cancer. However, oral THC has high PK variability, with variability in oral dronabinol peak plasma concentrations (C max) estimated between 150 and 200%. A new oral dronabinol solution has decreased intraindividual variability (area under the curve) vs oral dronabinol capsules. Further, oral THC has a slower time to C max compared with THC administered intravenously (IV) or by smoking, and a lower systemic availability than IV or smoked THC. The PD profile (e.g., “high”) of oral THC differs from that of IV or smoked THC in healthy individuals. Oral cannabinoids are associated with greater incidence of adverse effects compared with conventional antiemetic therapy or placebo (e.g., dizziness, hypotension, and dysphoria or depression).

Conclusions
A new formulation of oral cannabinoids (i.e., dronabinol oral solution) minimized the PK/PD variability currently observed with capsule formulations.

Citation Details

Authors: Erin M. Rock and Linda A. Parker

Citation: Rock EM, Parker LA. Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting. Frontiers in Pharmacology. 2016;7:221.

Doi: 10.3389/fphar.2016.00221

Abstract
Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic. If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea—a conditioned response to the contextual cues associated with illness-inducing chemotherapy—can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options. One of the first documented medicinal uses of Δ9-tetrahydrocannabinol (Δ9-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV. Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.

Conclusions
Animal models suggest that, in general, Δ9-THC, THCA, CBD, and CBDA, and manipulations of the endogenous cannabinoid system, have anti-emetic and anti-nausea properties. However, 2-AG and AEA’s role in emesis is inconsistent across species. Further investigation is needed regarding the potential role of TRPV1 receptors in the anti-nausea effects produced by treatments that elevate AEA. It is time to take some of the preclinical findings (in particular CBDA, FAAH, and MAGL inhibition) into clinical trials for the treatment of acute and anticipatory nausea.

Citation Details

Authors: Lesley A Smith, Fredric Azariah, Verna TC Lavender, Nicola S Stoner, Silvana Bettiol

Citation: Smith LA1, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev. 2015 Nov 12;(11):CD009464.

Doi: 10.1002/14651858.CD009464.pub2

MAIN RESULTS:

We included 23 RCTs. Most were of cross-over design, on adults undergoing a variety of chemotherapeutic regimens ranging from moderate to high emetic potential for a variety of cancers. The majority of the studies were at risk of bias due to either lack of allocation concealment or attrition. Trials were conducted between 1975 and 1991. No trials involved comparison with newer anti-emetic drugs such as ondansetron. Comparison with placebo People had more chance of reporting complete absence of vomiting (3 trials; 168 participants; RR 5.7; 95% CI 2.6 to 12.6; low quality evidence) and complete absence of nausea and vomiting (3 trials; 288 participants; RR 2.9; 95% CI 1.8 to 4.7; moderate quality evidence) when they received cannabinoids compared with placebo. The percentage of variability in effect estimates that was due to heterogeneity rather than chance was not important (I(2) = 0% in both analyses).People had more chance of withdrawing due to an adverse event (2 trials; 276 participants; RR 6.9; 95% CI 1.96 to 24; I(2) = 0%; very low quality evidence) and less chance of withdrawing due to lack of efficacy when they received cannabinoids, compared with placebo (1 trial; 228 participants; RR 0.05; 95% CI 0.0 to 0.89; low quality evidence). In addition, people had more chance of ‘feeling high’ when they received cannabinoids compared with placebo (3 trials; 137 participants; RR 31; 95% CI 6.4 to 152; I(2) = 0%).People reported a preference for cannabinoids rather than placebo (2 trials; 256 participants; RR 4.8; 95% CI 1.7 to 13; low quality evidence). Comparison with other anti-emetics There was no evidence of a difference between cannabinoids and prochlorperazine in the proportion of participants reporting no nausea (5 trials; 258 participants; RR 1.5; 95% CI 0.67 to 3.2; I(2) = 63%; low quality evidence), no vomiting (4 trials; 209 participants; RR 1.11; 95% CI 0.86 to 1.44; I(2) = 0%; moderate quality evidence), or complete absence of nausea and vomiting (4 trials; 414 participants; RR 2.0; 95% CI 0.74 to 5.4; I(2) = 60%; low quality evidence). Sensitivity analysis where the two parallel group trials were pooled after removal of the five cross-over trials showed no difference (RR 1.1; 95% CI 0.70 to 1.7) with no heterogeneity (I(2) = 0%).People had more chance of withdrawing due to an adverse event (5 trials; 664 participants; RR 3.9; 95% CI 1.3 to 12; I(2) = 17%; low quality evidence), due to lack of efficacy (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; very low quality evidence) and for any reason (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; low quality evidence) when they received cannabinoids compared with prochlorperazine.People had more chance of reporting dizziness (7 trials; 675 participants; RR 2.4; 95% CI 1.8 to 3.1; I(2) = 12%), dysphoria (3 trials; 192 participants; RR 7.2; 95% CI 1.3 to 39; I(2) = 0%), euphoria (2 trials; 280 participants; RR 18; 95% CI 2.4 to 133; I(2) = 0%), ‘feeling high’ (4 trials; 389 participants; RR 6.2; 95% CI 3.5 to 11; I(2) = 0%) and sedation (8 trials; 947 participants; RR 1.4; 95% CI 1.2 to 1.8; I(2) = 31%), with significantly more participants reporting the incidence of these adverse events with cannabinoids compared with prochlorperazine.People reported a preference for cannabinoids rather than prochlorperazine (7 trials; 695 participants; RR 3.3; 95% CI 2.2 to 4.8; I(2) = 51%; low quality evidence).In comparisons with metoclopramide, domperidone and chlorpromazine, there was weaker evidence, based on fewer trials and participants, for higher incidence of dizziness with cannabinoids.Two trials with 141 participants compared an anti-emetic drug alone with a cannabinoid added to the anti-emetic drug. There was no evidence of differences between groups; however, the majority of the analyses were based on one small trial with few events. Quality of the evidence The trials were generally at low to moderate risk of bias in terms of how they were designed and do not reflect current chemotherapy and anti-emetic treatment regimens. Furthermore, the quality of evidence arising from meta-analyses was graded as low for the majority of the outcomes analysed, indicating that we are not very confident in our ability to say how well the medications worked. Further research is likely to have an important impact on the results.

AUTHORS’ CONCLUSIONS:

Cannabis-based medications may be useful for treating refractory chemotherapy-induced nausea and vomiting. However, methodological limitations of the trials limit our conclusions and further research reflecting current chemotherapy regimens and newer anti-emetic drugs is likely to modify these conclusions.

Citation Details

Authors: Megan Brafford May and Ashley E Glode

Citation:May MB, Glode AE. Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Management and Research. 2016;8:49-55.

Doi: 10.2147/CMAR.S81425

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common symptoms feared by patients, but may be prevented or lessened with appropriate medications. Several antiemetic options exist to manage CINV. Corticosteroids, serotonin receptor antagonists, and neurokinin receptor antagonists are the classes most commonly used in the prevention of CINV. There are many alternative drug classes utilized for the prevention and management of CINV such as antihistamines, benzodiazepines, anticonvulsants, cannabinoids, and dopamine receptor antagonists. Medications belonging to these classes generally have lower efficacy and are associated with more adverse effects. They are also not as well studied compared to the aforementioned agents. This review will focus on dronabinol, a member of the cannabinoid class, and its role in CINV. Cannabis sativa L. (also known as marijuana) contains naturally occurring delta-9-tetrahydrocannibinol (delta-9-THC). The synthetic version of delta-9-THC is the active ingredient in dronabinol that makes dronabinol an orally active cannabinoid. Evidence for clinical efficacy of dronabinol will be analyzed in this review as monotherapy, in combination with ondansetron, and in combination with prochlorperazine.

Conclusion
Current guidelines as well as the FDA-approved indications consider dronabinol’s role to be in the management of breakthrough CINV. Dronabinol has a unique mechanism of action and adverse effect profile that should be considered when treating a patient with this medication. Unfortunately, there are few ongoing studies evaluating the role of dronabinol in the management of CINV. Two completed, yet unpublished, studies have evaluated dronabinol in combination with a 5-HT3 RA as a prophylactic strategy. At this time, there is insufficient data to support the routine use of dronabinol as an antiemetic in all chemotherapeutic regimens. Data do support the beneficial effects of dronabinol in the breakthrough CINV setting. Further study of the scope of dronabinol’s potential efficacy is warranted.

Citation Details

Authors: Keith A. Sharkey, Nissar A. Darmani, and Linda A. Parker

Citation:Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. European journal of pharmacology. 2014;722. 

Doi: 10.1016/j.ejphar.2013.09.068

Abstract

Nausea and vomiting (emesis) are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances. However, these neurally-mediated responses are at times manifested as symptoms of disease and they are frequently observed as side-effects of a variety of medications, notably those used to treat cancer. Cannabis has long been known to limit or prevent nausea and vomiting from a variety of causes. This has led to extensive investigations that have revealed an important role for cannabinoids and their receptors in the regulation of nausea and emesis. With the discovery of the endocannabinoid system, novel ways to regulate both nausea and vomiting have been discovered that involve the production of endogenous cannabinoids acting centrally. Here we review recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system, and we discuss the potential to utilize the endocannabinoid system in the treatment of these frequently debilitating conditions.

Citation Details

Authors: Linda A Parker Erin M Rock Cheryl L Limebeer.

Citation:Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. British Journal of Pharmacology. 2011;163(7):1411-1422.

Doi: 10.1111/j.1476-5381.2010.01176.x

Abstract

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9-THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.

Epilepsy

Citation Details

Authors: Luciano R. Vilela Daniel C. Medeiros Antonio Carlos P. de Oliveira Marcio F. Moraes Fabricio A. Moreira

Citation: Vilela, L. R., Medeiros, D. C., Oliveira, A. C., Moraes, M. F. and Moreira, F. A., Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual Fatty Acid Amide Hydrolase Enzyme and Transient Receptor Potential Vanilloid Type‐1 (TRPV1) Channel Blocker, on Experimental Seizures: The Roles of Cannabinoid CB1 Receptors and TRPV1 Channels. Basic Clin Pharmacol Toxicol. 2014. 115: 330-334.

Doi: 10.1111/bcpt.12232

Abstract
Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N‐arachidonoyl‐serotonin (AA‐5‐HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)‐induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA‐5‐HT. In the first experiment, injection of AA‐5‐HT (0.3–3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)‐induced seizures in mice. These effects were reversed by pre‐treatment with the CB1 antagonist, AM251 (1.0–3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1–1 mg/kg), did not entirely mimic AA‐5‐HT effects. In conclusion, AA‐5‐HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA‐5‐HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.

Citation Details

Authors: Marco Colizzia, Philip McGuire, Roger G.Pertwee, Sagnik Bhattacharyya

Citation: Colizzi M, McGuire P, Pertwee RG, Bhattacharyya S. Effect of cannabis on glutamate signalling in the brain: A systematic review of human and animal evidence. Neurosci Biobehav Rev. 2016 May;64:359-81.

Doi: 10.1016/j.neubiorev.2016.03.010

Abstract
Use of cannabis or delta-9-tetrahydrocannabinol (Δ9-THC), its main psychoactive ingredient, is associated with psychotic symptoms or disorder. However, the neurochemical mechanism that may underlie this psychotomimetic effect is poorly understood. Although dopaminergic dysfunction is generally recognized as the final common pathway in psychosis, evidence of the effects of Δ9-THC or cannabis use on dopaminergic measures in the brain is equivocal. In fact, it is thought that cannabis or Δ9-THC may not act on dopamine firing directly but indirectly by altering glutamate neurotransmission. Here we systematically review all studies examining acute and chronic effects of cannabis or Δ9-THC on glutamate signalling in both animals and man. Limited research carried out in humans tends to support the evidence that chronic cannabis use reduces levels of glutamate-derived metabolites in both cortical and subcortical brain areas. Research in animals tends to consistently suggest that Δ9-THC depresses glutamate synaptic transmission via CB1 receptor activation, affecting glutamate release, inhibiting receptors and transporters function, reducing enzyme activity, and disrupting glutamate synaptic plasticity after prolonged exposure.

Citation Details

Authors: María Rodríguez-Muñoz, Pilar Sánchez-Blázquez, Manuel Merlos, and Javier Garzón-Niño

Citation: Rodríguez-Muñoz M, Sánchez-Blázquez P, Merlos M, Garzón-Niño J. Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction. Oncotarget. 2016;7(34):55840-55862.

Doi: 10.18632/oncotarget.10095

Abstract
Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs. In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. The efficacy of such control depends on HINT1/σ1R assisting in the physical coupling between cannabinoid type 1 receptors (CB1Rs) and NMDARs to dampen their activity. Subsequently, the calcium-regulated HINT1/σ1R protein tandem uncouples CB1Rs to prevent NMDAR hypofunction. Thus, early recruitment or a disproportionate cannabinoid induced response can bring about excess dampening of NMDAR activity, impeding its adequate integration with GPCR signaling. Alternatively, this control circuit can apparently be overridden in situations where bursts of NMDAR overactivity provoke convulsive syndromes. In this review we will discuss the possible relevance of the HINT1/σ1R tandem and its use by endocannabinoids to diminish NMDAR activity and their implications in psychosis/schizophrenia, as well as in NMDAR-mediated convulsive episodes.

Citation Details

Authors: Megan Brafford May and Ashley E Glode

Citation: W. B. VeldhuisM. van der SteltM. W. WadmanG. van ZadelhoffM. MaccarroneF.FezzaG. A. VeldinkJ. F. G. VliegenthartP. R. BärK. NicolayV. Di Marzo. Neuroprotection by the Endogenous Cannabinoid Anandamide and Arvanil against In Vivo Excitotoxicity in the Rat: Role of Vanilloid Receptors and Lipoxygenases. 

Doi: 10.1523/JNEUROSCI.23-10-04127.2003

Abstract

Type 1 vanilloid receptors (VR1) have been identified recently in the brain, in which they serve as yet primarily undetermined purposes. The endocannabinoid anandamide (AEA) and some of its oxidative metabolites are ligands for VR1, and AEA has been shown to afford protection against ouabain-induced in vivo excitotoxicity, in a manner that is only in part dependent on the type 1 cannabinoid (CB1) receptor. In the present study, we assessed whether VR1 is involved in neuroprotection by AEA and by arvanil, a hydrolysis-stable AEA analog that is a ligand for both VR1 and CB1. Furthermore, we assessed the putative involvement of lipoxygenase metabolites of AEA in conveying neuroprotection. Using HPLC and gas chromatography/mass spectroscopy, we demonstrated that rat brain and blood cells converted AEA into 12-hydroxy-N-arachidoylethanolamine (12-HAEA) and 15-hydroxy-N-arachidonoylethanolamine (15-HAEA) and that this conversion was blocked by addition of the lipoxygenase inhibitor nordihydroguaiaretic acid. Using magnetic resonance imaging we show the following: (1) pretreatment with the reduced 12-lipoxygenase metabolite of AEA, 12-HAEA, attenuated cytotoxic edema formation in a CB1 receptor-independent manner in the acute phase after intracranial injection of the Na+/K+-ATPase inhibitor ouabain; (2) the reduced 15-lipoxygenase metabolite, 15-HAEA, enhanced the neuroprotective effect of AEA in the acute phase; (3) modulation of VR1, as tested using arvanil, the VR1 agonist capsaicin, and the antagonist capsazepine, leads to neuroprotective effects in this model, and arvanil is a potent neuroprotectant, acting at both CB1 and VR1; and (4) the in vivo neuroprotective effects of AEA are mediated by CB1 but not by lipoxygenase metabolites or VR1.

Inflammatory Bowel Disease

Citation Details

Authors: Rudolf Schicho and Martin Storr

Citation: Schicho R, Storr M. Cannabis finds its way into treatment of Crohn’s disease. Pharmacology. 2014;93(0):1-3.

Doi: 10.1159/000356512

Abstract
In ancient medicine, Cannabis has been widely used to cure disturbances and inflammation of the bowel. A recent clinical study now shows that the medicinal plant Cannabis sativa has kept its expectancies proving to be highly efficient in cases of inflammatory bowel diseases (IBD). In a prospective placebo-controled study, Naftali and coworkers (Clin. Gastroenterol. Hepatol. 11,1276-1280. e1., 2013) have shown what has been largely anticipated from anectodal reports, that Cannabis produces significant clinical benefits in patients with Crohn’s disease. The mechanisms involved are not clear yet but most likely include peripheral actions on cannabinoid receptors 1 and 2, and may also include central actions.

Neurodegenerative Diseases

Citation Details

Authors: Teresa Iuvone Giuseppe Esposito Daniele De Filippis Caterina Scuderi Luca Steardo

Citation: Iuvone, T. , Esposito, G. , De Filippis, D. , Scuderi, C. and Steardo, L. (2009), Cannabidiol: A Promising Drug for Neurodegenerative Disorders?. CNS Neuroscience & Therapeutics, 15: 65-75.

Doi: 10.1111/j.1755-5949.2008.00065.x

Abstract
Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.

Citation Details

Authors: Simone Tambaro and Marco Bortolato

Citation: Tambaro S, Bortolato M. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent patents on CNS drug discovery. 2012;7(1):25-40.

Doi: 10.2174/157488912798842269

Abstract
Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. In addition the article presents some promising patents on cannabinoid-related agents.

Citation Details

Authors: Raphael Mechoulam, PhD, Natalya M. Kogan, MSc.

Citation: Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues in Clinical Neuroscience. 2007;9(4):413-430.

PMCID: PMC3202504

Abstract
Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable – instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and – in cases where it is impossible to separate the desired clinical action and the psychoactivity – just to monitor these side effects carefully.

Spasticity in Multiple Sclerosis

Citation Details

Authors: Anna Maria Malfitano, Maria Chiara Proto, and Maurizio Bifulco

Citation: Malfitano AM, Proto MC, Bifulco M. Cannabinoids in the management of spasticity associated with multiple sclerosis. Neuropsychiatric Disease and Treatment. 2008;4(5):847-853.

PMCID: PMC2626929

Abstract
The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS). In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Citation Details

Authors: Uwe K. Zettl, Paulus Rommer, Petra Hipp, and Robert Patejdl

Citation: Zettl UK, Rommer P, Hipp P, Patejdl R. Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis. Therapeutic Advances in Neurological Disorders. 2016;9(1):9-30.

Doi: 10.1177/1756285615612659

Abstract
Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented.

Citation Details

Authors: Eva Eljaschewitsch, Anke Witting, Christian Mawrin, Thomas Lee, Peter M. Schmidt, Susanne Wolf, Heide Hoertnagl, Cedric S. Raine, Regine Schneider-Stock, Robert Nitsch, and Oliver Ullrich

Citation: Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron. 2006 Jan 5;49(1):67-79.

Doi: 10.1016/j.neuron.2005.11.027

Summary
Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB1 receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB1/2receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage.

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