PCT NO: PCT/US99/08769

Cannabinoids have been found to have antioxidant properties, unrelated to NMDA receptor antagonism. This new found property makes cannabinoids useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia. Nonpsychoactive cannabinoids, such as cannabidoil, are particularly advantageous to use because they avoid toxicity that is encountered with psychoactive cannabinoids at high doses useful in the method of the present invention. A particular disclosed class of cannabinoids useful as neuroprotective antioxidants is formula (I) wherein the R group is independently selected from the group consisting of H, CH.sub.3, and COCH.sub.3. 

Forty-two percent of Minnesota’s patients taking medical cannabis for intractable pain reported a pain reduction of thirty percent or more, according to a new study conducted by the Minnesota Department of Health.

“This study helps improve our understanding of the potential of medical cannabis for treating pain,” said Minnesota Health Commissioner Jan Malcolm. “We need additional and more rigorous study, but these results are clinically significant and promising for both pain treatment and reducing opioid dependence.”

The first-of-its-kind research study is based on the experiences of the initial 2,245 people enrolled for intractable pain in Minnesota’s medical cannabis program from August 1, 2016 to December 31, 2016. Of this initial group, 2,174 patients purchased medical cannabis within the study’s observation period and completed a required self-evaluation before each purchase.

As part of the self-evaluation, patients completed the PEG (pain, enjoyment and general activity) screening tool. On a scale of 0 to 10 (with 0 being no pain and 10 being the highest pain), patients rated their level of pain, how pain interfered with their enjoyment of life and how pain interfered with their general activity.

Using the PEG scale data, 42 percent of the patients who scored moderate to high pain levels at the beginning of the measurement achieved a reduction in pain scores of 30 percent or more, and 22 percent of patients both achieved and maintained a reduction of 30 percent or more over four months. The 30 percent reduction threshold is often used in pain studies to define clinically meaningful improvement.

Health care practitioners caring for program-enrolled patients suffering from intractable pain reported similar reductions in pain scores, saying 41 percent of patients achieved at least a reduction of 30 percent or more.

The study also found that of the 353 patients who self-reported taking opioid medications when they started using medical cannabis, 63 percent or 221 reduced or eliminated opioid use after six months. Likewise, the health care practitioner survey found that 58 percent of patients who were on other pain medications were able to reduce their use of these medications when they started taking medical cannabis. Thirty-eight percent of patients reduced opioid medication (nearly 60 percent of these cut use of at least one opioid by half or more), 3 percent of patients reduced benzodiazepines and 22 percent of patients reduced other pain medications.

The safety profile of medical cannabis products available through the Minnesota program continues to appear favorable. No serious adverse events (life threatening or requiring hospitalization) were reported for this group of patients during the observation period.

About 40 percent of patients reported adverse side effects and of those that did report adverse side effects, about 90 percent said those side effects were mild to moderate. Common adverse effects included dry mouth, drowsiness, fatigue and mental clouding/“foggy brain.”

Fifty-five patients taking medical cannabis for intractable pain reported severe adverse side effects, meaning side effects that interrupted usual daily activities. The assessment of this patient feedback found no apparent pattern in patient age, primary cause of pain or type of medical cannabis product used.

Pain patients also reported improvements related to sleep and reduced anxiety.

“These survey results are a good starting point,” said Dr. Tom Arneson, research manager for the office of medical cannabis. “We need more research into the potential value of medical cannabis in pain management, especially as our communities grapple with the harmful impacts of opioids and other medications now in use for that purpose. We encourage health care providers to read the full report as they consider whether medical cannabis should be part of their strategies for treating patients’ intractable pain.”

Intractable pain, as defined by state law, is a state of pain in which the cause cannot be removed and, according to generally accepted medical practice, the full range of pain management treatments appropriate for the patient have been used without adequate result or with intolerable side effects.

The MDH Office of Medical Cannabis relies on the professional judgment of the certifying health care practitioner as to whether the full range of treatments for an individual patient have been sufficiently used to meet the program’s definition of intractable pain. For example, it is not necessary for a patient to have tried opioid medications.

Neuropsychopharmacology. 2017 Aug; 42(9): 1752–1765.

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Pharmacology. 1980;21(3):175-85.

In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

Biol Blood Marrow Transplant. 2015 Oct;21(10):1770-5. doi: 10.1016/j.bbmt.2015.05.018. Epub 2015 May 30.

Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. ( NCT01385124).

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

Psychoneuroendocrinology. Author manuscript; available in PMC 2014 Dec 1.

Endocannabinoid (eCB) signaling has been identified as a modulator of adaptation to stress, and is integral to basal and stress-induced glucocorticoid regulation. Furthermore, interactions between eCBs and glucocorticoids have been shown to be necessary for the regulation of emotional memories, suggesting that eCB function may relate to the development of post-traumatic stress disorder (PTSD). To examine this, plasma eCBs were measured in a sample (n=46) drawn from a population-based cohort selected for physical proximity to the World Trade Center (WTC) at the time of the 9/11 attacks. Participants received a structured diagnostic interview and were grouped according to whether they met diagnostic criteria for PTSD (no PTSD, n=22; lifetime diagnosis of PTSD = 24). eCB content (2-arachidonoylglycerol (2-AG) and anandamide (AEA)) and cortisol were measured from 8 a.m. plasma samples. Circulating 2-AG content was significantly reduced among individuals meeting diagnostic criteria for PTSD. The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories. Future work will aim to replicate these findings and extend their relevance to clinical pathophysiology, as well as to neuroendocrine and molecular markers of PTSD.

Pain. Author manuscript; available in PMC 2011 Dec 1.

Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Here, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments.

May 2002. Journal of Cannabis Therapeutics 2(3-4):5-35

Cannabis has an ancient tradition of usage as a medicine in obstetrics and gynecology. This study presents that history in the literature to the present era, compares it to current ethnobotanical, clinical and epide-miological reports, and examines it in light of modern developments in cannabinoid research. The author believes that cannabis extracts may represent an efficacious and safe alternative for treatment of a wide range of conditions in women including dysmenorrhea, dysuria, hyperemesis gravidarum, and meno-pausal symptoms

Science. 1992 Dec 18;258(5090):1946-9.

Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named “anandamide,” was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

Conference: Medical Cannabis and Cannabinoids: POLICY, SCIENCE, AND MEDICAL PRACTICE. Prague / 4–7 March / 2015

The substantial therapeutic properties of the Cannabis plant have been known since antiquity, while recently it has been “rediscovered” and applied in many diseases. The most studied active constituent in Cannabis is THC, which was the first cannabinoid to be identified and isolated. This discovery paved the way for research focused on the molecular pathways of various cannabinoids and their receptors. Cannabinoids are divided into phytocannabinoids, endogenous endocannabinoids, and synthetic cannabinoids. More than 60 phytocannabinoids have been identified within the Cannabis plant and these phytocannabinoids mediate their actions mostly through two G-coupled receptors (GPCR), CB1 and CB2 which comprise what is conceived today as the human endocannabinoid signaling system. Cannabinoids have been proposed to have a therapeutic potential for various diseases, including Multiple sclerosis, Alzheimer’s disease, Epilepsy, Glaucoma, Crohn’s disease and has therefore been applied as a therapeutic drug in many countries. Intriguingly, cannabis palliative effects in oncology have been well established and cannabinoids are currently used in cancer patients for inhibition of chemotherapy-induced nausea and vomiting, as well as for appetite stimulation and pain reduction. Additionally, in the last decade accumulating evidence indicates that cannabinoids might have antitumor effects. Several studies demonstrated regression of different cancer types, such as glioma, breast cancer and skin carcinoma. These effects were further investigated in vitro, in various cancer cell lines, and revealed pro-apoptotic and anti-proliferative response to cannabinoids, as well as inhibition of invasion and migration. However, the medical use of Cannabis remains rather limited, due to a large number of active compounds, which together with variability among different strains and cultivation methods impairs our ability to predict the specific clinical effect and determine the recommended dose. Therefore, there great promise lies in investigating the vast number of phytocannabinoids and the distinct antitumor effects they might have. Our lab has developed deep expertise in the areas of GPCR, cancer research as well as drug uptake and resistance mechanisms. Utilizing these techniques and the components available to us we investigate the pharmacological significance of cannabinoids in cancer. In order to select the ideal cannabinoid for each type of cancer, we are launching, a genome wide screen, testing the antitumor activity of distinct cannabinoids monitoring: anti-proliferative effects (cell cycle arrest), decreased viability, apoptosis and migration. The specific mechanism by which this antitumor effect occurs may involve the CB1 and CB2 receptors, as well as other GPCRs. However, using a whole genome silencing approach, we screen for novel receptors and protein candidates, which may regulate the cannabinoid antitumor effects. This research has the capacity to dramatically forward our basic understanding of the Cannabinoid mechanism of action and establish the optimal treatment strategy for cancer patients thus paving the way towards personalized medicine.

Toxicol Lett. 2012 Nov 15; 214(3): 314–319.

Cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, has been reported to possess diverse biological activities, including anti-proliferative effect on cancer cells. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), few studies have investigated whether CBDA itself is biologically active. Results of the current investigation revealed that CBDA inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. It is established that activation of the RhoA signaling pathway leads to inhibition of the mobility of various cancer cells, including MDA-MB-231 cells. The data presented in this report suggest for the first time that as an active component in the cannabis plant, CBDA offers potential therapeutic modality in the abrogation of cancer cell migration, including aggressive breast cancers.

Mayor’s Committee on Marihuana, by the New York Academy of Medicine. City of New York. 1944

Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press.

National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press.

Trends Neurosci. 2012 Jul;35(7):403-11. doi: 10.1016/j.tins.2012.04.006. Epub 2012 May 22.

The ‘thrifty gene hypothesis’ posits that evolution preferentially selects physiological mechanisms that optimize energy storage to increase survival under alternating conditions of abundance and scarcity of food. Recent experiments suggest that endocannabinoids – a class of lipid-derived mediators that activate cannabinoid receptors in many cells of the body – are key agents of energy conservation. The new evidence indicates that these compounds increase energy intake and decrease energy expenditure by controlling the activity of peripheral and central neural pathways involved in the sensing and hedonic processing of sweet and fatty foods, as well as in the storage of their energy content for future use.

Nat Rev Drug Discov. 2018 Sep;17(9):623-639. doi: 10.1038/nrd.2018.115. Epub 2018 Aug 17.

The endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa. The search for new therapeutics that target endocannabinoid signalling is both challenging and potentially rewarding, as endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the endocannabinoid network. The current development of drugs that alter endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article.

Cannabis Cannabinoid Res. 2017; 2(1): 96–104.

Introduction: Cannabis has been used for medical purposes across the world for centuries. As states and countries implement medical and recreational cannabis policies, increasing numbers of people are using cannabis pharmacotherapy for pain. There is a theoretical rationale for cannabis’ efficacy for pain management, although the subjective pain relief from cannabis may not match objective measurements of analgesia. As more patients turn to cannabis for pain relief, there is a need for additional scientific evidence to evaluate this increase.

Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database.

Discussion: Preclinical studies demonstrate a narrow therapeutic window for cannabis as pharmacotherapy for pain; the body of clinical evidence for this indication is not as extensive. A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Recent epidemiological studies have provided initial evidence for a possible reduction in opioid pharmacotherapy for pain as a result of increased implementation of medical cannabis regimens.

Conclusion: With increased use of medical cannabis as pharmacotherapy for pain comes a need for comprehensive risk-benefit discussions that take into account cannabis’ significant possible side effects. As cannabis use increases in the context of medical and recreational cannabis policies, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking.