By: Christine Milentis
The 2019 International Association for Cannabinoid Medicines (IACM) conference was held in Berlin Oct. 31-Nov. 1. It offered an opportunity for clinicians, researchers, patients, and advocates to learn how different nations’ medical cannabis programs are structured.
The IACM seeks to disseminate reliable information on cannabis and the endocannabinoid system, and to support research and promote information exchange between healthcare practitioners, patients, researchers, and the public. A declaration adopted at the IACM’s founding conference in 2000 stated that it is a doctor’s right to discuss the medicinal use of cannabis with their patients. The pragmatic data presented in many of the clinical sessions were based on patient treatments in real-world settings.
The IACM conference opened with Daniele Eigenmann, a pharmacist from Switzerland, reviewing the history of medical cannabis: from China, where in 2700 BC it was used for rheumatism, malaria, and constipation, to Egypt, which is mention in the Papyrus Ebers, to India, and ancient Greece. In 1841, the Irish physician William O’Shaughnessy returned to England after being stationed in Calcutta, India, where he had been using cannabis therapeutically and published a comprehensive study on the successful use of Indian hemp in the treatment of cholera, tetanus, convulsions, rheumatism and other ailments.
The early 1900s marked a high point of medical cannabis use. Pharmaceutical companies, including Merck and Eli Lilly, were widely manufacturing cannabis preparations to treat pain, convulsions, insomnia, asthma, and many other conditions. In 1937 federal prohibition was imposed in the US. In 1961 a United Nations treaty imposed worldwide prohibition. Research re-emerged in the 1990s when the endocannabinoid system was fully elucidated. From 1945 to September 30, 2019, there have been 25,774 publications on cannabinoids listed in Pubmed; 3-4 new publications are currently being released per day.
With cannabidiol (CBD) products gaining rapid popularity for treating a range of medical problems, a topic of concern at the conference was quality control in the cannabis market, especially the reliability of CBD oils. In his talk, “The Trouble with CBD,” the Dutch chemist Arno Hazekamp addressed the uncertainties that remain about the legality, quality, and safety of this new “miracle cure.” Hazekamp purchased CBD oils from the United States, the Netherlands, and Australia and sent each product to several testing labs. He found very few samples labeled correctly, with CBD products being mislabeled, containing THC, or even testing positive for synthetic cannabinoids such as “K2” and “Spice.” Many CBD products listed a misleadingly low “effective dose” on the bottle. CBD products were found to contain heavy metals, pesticides and other contaminants that put consumers at risk. As the market continues to grow, laboratories will need to develop appropriate tests for analyzing these different modes of administration (edibles, topicals, water-soluble, drinks, etc.). Hazekamp wants to see product standards and audits, a system that disqualifies products that do not meet established regulations, and the opportunity for product-makers to improve their products.
The global interest in CBD has been accompanied by inaccurate information on CBD’s effects and mechanisms of action. Ethan Russo set the record straight, addressing common misconceptions of CBD on the first day of the conference. He reported that CBD alone is not very potent. Given its safety profile, more is better, as higher doses are needed to produce pharmacologic effects. CBD alone is not sedating, but it can have that impact when taken in very high doses, in combination with terpenoid effects (e.g. myrcene), or as a result of drug-drug interactions. CBD upregulates endogenous levels of anandamide, which affects endocannabinoid system expression, but CBD is not converted into THC in the body. Despite CBD products being widely available in the United States, CBD is not legal in all 50 states under federal law. (For a through read on this topic, see Russo 2017, Cannabidiol Claims and Misconceptions, Trends Pharmacol Sci 38(3), 198-201.)
In another talk, Russo discussed the potential of herbal cannabis for Alzheimer’s disease, sharing results from Jeffrey Hergenrather’s study in an assisted-living facility. Using primarily tinctures and confections, Hergenrather found it conferred significant benefits—improved memory and increased appetite—while reducing agitation, aggression, anxiety, insomnia/restlessness, anorexia, pain, and depression. This impact greatly decreased the demand on the nurses.
Lihi Bar-Lev Schleider’s group from Israel presented similar results in their phase II, randomized, double-blinded, placebo-controlled trial investigating CBD-rich oil for dementia. Using Avidekel oil developed by Tikun Olam, a CBD-rich 20:1 whole plant extract (1 cultivar extracted with ethanol), patients received drops of oil applied under the tongue three times per day over the course of 16 weeks (112 days). They found a statistically significant difference in Cohen-Mansfield Agitation Inventory from baseline to after medication between the treatment and placebo groups. The treatment was found to be safe and efficient for reducing agitation and aggression.
Kirsten Muller-Vahl commented on the medical cannabis situation in Germany, where cannabis has been available by prescription since March 2017. It is still illegal to cultivate cannabis, so products are imported from the Netherlands or Canada. Physicians recommend a strain on the prescription (26 are currently available, but the options are constantly changing). Whole-flower vaporization is the most highly recommended method of administration. The future market is predicted to include novel, portable inhalers with preloaded cartridges for metered-dose delivery. In her patients with Tourette syndrome, Muller-Vahl found increases in specific endocannabinoids, but did not identify a change in endocannabinoid receptor genes from Tourette patients compared to healthy individuals. A large trial is being conducted to determine the efficacy of cannabinoid therapy in adult patients with Tourette syndrome. Promising results are coming forth, and Muller-Vahl speculates that the positive effect in children with Tourette syndrome may be even stronger. She has seen the condition of an 8-year-old patient improve greatly, which she attributes to the possibility of the developing brain being altered before the symptoms of Tourette syndrome have taken full effect.
IACM Executive Director Franjo Grotenhermen, discussing interactions and side effects, said that no other molecule on earth had such broad therapeutic potential as tetrahydrocannabinol (THC) except perhaps cannabidiol (CBD). A side effect in one patient may be a therapeutic effect in another (e.g. increased appetite, sedation, muscle relaxation, euphoria, reduction of bowel movements, lowering of blood pressure, dry mouth—could be therapeutic in the case of hypersalivation). Although pharmacokinetic interactions with other medicinal drugs can occur with very high doses of THC or CBD, these are very rare cases. THC and CBD have been given to millions of patients using other drugs without serious side effects.
Special consideration should be given to patients with heart disease, as acute side effects of cannabis consumption may increase heart rate and change blood pressure. A main concern when evaluating cannabis treatment for cancer patients is whether they are undergoing immune therapy. Tomoxiphen binds to both CB1 and CB2 receptors and thus may interfere with cannabis treatment. To avoid disturbing the immune system during this process, physicians may avoid giving THC and CBD during immune therapy treatment.
After opening Canna-Centers in 2008 in Los Angeles, Bonni Goldstein has seen more than 15,000 patients (~900 of them are children). Eighty-five percent of her patients had already tried conventional therapies. Goldstein stated that “with medical supervision, there is clear clinical evidence of significant benefits with no toxicity.” She found that many of her patients who try Epidiolex (CBD) end up switching back to whole plant oils. Epidiolex contains alcohol and sucralose, and as these patients are very sensitive they were getting other side effects from the medication. She also found that CB2 receptors are upregulated in white blood cells of children with autism. This may be a biomarker to diagnose children with autism in earlier stages, more research is needed.
Ilya Reznik (Israel) presented data showing that the passage of medical cannabis laws in Israel has reduced chronic pain in self-assessed health among older adults. Following this observation, Addie Ron presented data from the prospective observational registry study in women and men above 65 years of age who were licensed by the Israeli Ministry of Health to use medical cannabis. Of the 184 patients who initiated treatment, 58.1% were still using cannabis after the six-month treatment period with positive results. All patients were cannabis-naïve, and practitioners utilized slow titration of medication under a safety-first regimen, following the dosing mantra “start low and go slow.” In this cohort, they found sublingual oil to be the preferred route of administration. Ron noted that ameliorating baseline disturbances like pain increases the chances of improving other symptoms, such as depression, trouble sleeping, etc. Caution is warranted in older adults due to polypharmacy, pharmacokinetic changes, nervous system impairment, and increased cardiovascular risk. Cannabinoid receptors may also decrease as we age, and thus cannabis therapies may not always be as effective in older adults.
Ziva Cooper, from the University of California, Los Angeles reported on the first placebo controlled double blind study investigating the role of cannabinoids to decrease or eliminate opioid use for pain management. This study bridges the gap between promising preclinical evidence and population-based studies, testing opioid analgesia, intoxication, and abuse liability in healthy participants. Supported by grants from the US National Institute on Drug Abuse, early findings show the potential for cannabis to enhance opioid analgesia, supporting THC-opioid synergy observed in preclinical investigations. Other cannabinoid constituents including CBD and specific terpenes may similarly reduce or eliminate reliance on opioids for pain relief. The group has a study currently underway to compare the effects of CBD alone, THC alone, and CBD/THC in combination for their ability to reduce or eliminate the use of opioids for pain.
The presentation by Atilla Ollah (Faculty of Medicine at University of Debrecen, Hungary) concerned endocannabinoid signaling system in the skin and the potential role of phytocannabinoids in dermatology. The skin is much more than a passive barrier, and through its diverse signaling capabilities, it can smell, taste, see, talk, listen, and respond to cannabinoid therapy. As he explained in his recently published review on cannabinoid signaling in the skin (Molecules 2019, 24(5), 918; https://doi.org/10.3390/molecules24050918), “although the best studied functions over the endocannabinoid system are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch.” With CB1 and CB2 receptors located in the epidermis, there is clinical translation potential for extracellular-restricted CB1 agonists to alleviate inflammation (J Clin Invest. 2014 Sep;124(9):3713-24). Olah notes that local, topical treatment would be desirable to avoid systemic side effects and that rigorous preclinical testing is still needed.
Javier Fernandez-Ruiz (Professor at Complutense University of Madrid, Spain) reported on cannabinoid-based neuroprotective therapy for neurodegenerative disorders. Living longer means more possibilities for neurodegenerative disorders to be visible, and with aging as the major risk factor for Alzheimer’s, Parkinson’s, and Huntington’s disease, there are higher incidences in countries with higher life spans. In 2005, there were an estimated 4.1 million individuals with Parkinson’s worldwide. This number is expected to double by 2030 to 8.7 million individuals. As current licensed treatments have limited efficacy and frequent activity mainly on symptom relief, the broad-spectrum profile of cannabinoids is well poised to encourage neuronal homeostasis and survival, neuroprotection, and neurorepair. In ALS (amyotrophic lateral sclerosis), cannabinoids can increase trophic support, while reducing toxicity, excitotoxicity, and oxidative stress.
Mario van der Stelt (Professor of Molecular Physiology at Universiteit Leiden, Netherlands) covered mechanisms underlying the endocannabinoid system (ECS) and its modulation, and touched upon emerging drugs based on the ECS. Endocannabinoids modulate communication between nerve cells, are rapidly degraded, and regulate appetite, fear, sleep, and memory. In an attempt to block the endocannabinoid action for the treatment of obesity, rimonabant (Acomplia) was developed by Sanofi-Aventis in 2006 as a selective CB1 endocannabinoid receptor antagonist. However, it was withdrawn from the market in 2008 due to increased prevalence of depression and suicide (data showed a doubling of the risk of psychiatric disorders in patients taking Acomplia in comparison with placebo). As alternatives to rimonabant, Van der Stelt has outlined some potential research categories of interest to exploit the ECS for therapeutic benefit that include peripherally restricted CB1 receptor antagonists, signaling specific CB1 receptor inhibitors, and negative allosteric CB1 receptor modulators.
Exploring future research directions, Russo said cannabis shows promise in limiting damage after concussion and traumatic brain injury and urged more research. Also, cannabinoids have been shown to diminish neuropathic pain associated with endometriosis, and endocannabinoids have been shown to modulate apoptosis in endometriosis and adenomyosis (Dmitrieva et al., Pain. 2010 Dec; 151(3): 703–710, Bouaziz et al., Cannabis Cannabinoid Res. 2017; 2(1): 72–80). Cannabis also has great potential to treat dysmenorrhea, premature labor, hyperemesis, aid in childbirth postpartum hemorrhage, toxemic seizures, and menopause, according to Russo.
Several speakers touched on the topic of cannabis and pregnancy during the conference, noting that cannabinoids have been used most widely in pregnancy for hyperemesis and mental health issues. After thoroughly discussing the risks and benefits with the mother, physicians should consider whether the patient’s health is suffering more by not intaking cannabinoids during pregnancy.
At the closing physician panel, speakers highlighted future strategies for the burgeoning field of medical cannabis. They repeated the need for more clinical trials and strong objective evidence, recognizing that the system is biased towards randomized controlled trials. Observational studies should be included in decisions about medical cannabis and the need to collate clinical data from large databases is strong. Surveys collecting data from patients who self-medicate can be helpful sources of information to lead the development of clinical trials to test the claims. The question of “where will we be in 10 years?” embraced hopes from clinicians of moving medical cannabis into previously forbidden areas such as psychiatry and obstetrics and gynecology, and reducing the regulatory and political obstacles to medical cannabis research.
The 2019 conference concluded with an echo of the IACM’s original declaration: doctors in all countries should be able to recommend and prescribe medical cannabis to their patients without backlash or stigma from the medical establishment.