How did you first become interested in cannabis research? What challenges have you faced in doing such research? Ethan Russo: I have always been interested in psychopharmacology, which is critical to the disciplines of neurology and psychiatry that I have practiced and researched. After a sabbatical in the Amazon rainforest in Peru studying the medicinal plants of the Machiguenga, I became embroiled in the cannabis controversy in 1996, the same year that medicinal cannabis became legal in California. I spent the next four years attempting to gain U.S. government approval to study cannabis treatment in migraines, to no avail despite the U.S. Food and Drug Administration’s (FDA) approval of my Investigational New Drug application in 1999. To this day, the study that I had planned on migraines has never been done.

Cannabis has been used as a medicine for centuries. However, because of political interference and prohibition in current times, research has been limited about the benefits and applications of this plant to a variety of health problems and diseases. Dr. Ethan Russo, Director of Research and Development for the International Cannabis and Cannabinoids Institute (ICCI), has dedicated much of his career to changing that by conducting medical research with cannabis and bringing attention to the benefits of cannabis and the need for more studies through his own research, published work, and conference presentations. Dr. Russo recently spoke with us about some of his recent research efforts, cannabis dosing, and his continued push to change the stigma against cannabis as a medicine.

The greatest challenge in cannabis research remains political and institutional opposition to its performance. Only reforms in the laws will change that status.

What has been the most surprising discovery for you so far regarding cannabis research?

Russo: My answer may be a surprise, that being the discovery that cannabis research and therapeutics remain so controversial in the U.S. despite the incredible body of evidence surrounding the discovery of the endocannabinoid system and the many successful clinical trials of cannabis-based medicines demonstrating their safety, efficacy, and consistency. This is the simple explanation of why I have worked for foreign companies for most of the last 23 years, currently as Director of Research and Development for the International Cannabis and Cannabinoids Institute (ICCI), a European Centre of Excellence in Prague.

In a recent article (1), you discussed the potential use of cannabis-based medicine to treat a variety of neurological disorders such as intractable epilepsy, brain tumors, Parkinson disease, Alzheimer disease, and traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). Can you tell us about the research in those areas?

Russo: I will address each area briefly; full details are available in the first reference, which is available to everyone on open source.

Epilepsy has been treated with cannabis for more than 1000 years in the historical literature, but has only had scientific investigation in the last 40 years, culminating in the 2018 approval by the FDA of Epidiolex (GW Pharmaceuticals), a 97% pure cannabidiol preparation. However, cannabis contains numerous other anticonvulsant substances including tetrahydrocannabinol (THC), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid (THCA), and the terpenoid linalool. There is a great opportunity for the development of additional cannabis-based anticonvulsants.

Brain tumors remain very difficult to treat effectively, but cannabinoids show great promise as agents that complement conventional chemotherapy and radiation, prolonging survival, and, in some instances, produce long-term remissions. A recent clinical trial showed striking results in glioblastoma multiforme, the most deadly brain cancer, with extended life spans in people taking Sativex (GW Pharmaceuticals) oromucosal cannabis spray in conventional doses along with temozolomide. On a theoretical basis, it may be possible to treat “benign” brain tumors that are normally unresponsive to chemotherapy with other cannabis components such as THCA.

Parkinson disease remains a difficult degenerative brain condition to treat. It is caused, in part, by a deficiency of the neurotransmitter, dopamine. However, it is much more complicated than that, and available drugs fail to halt its progression of various symptoms such as tremor, rigidity, and progressive dementia. Therapeutic trials to date have had mixed results in treating its signs and symptoms, but long-term treatment with THCA and cannabidiol (CBD) may show promise. Formal randomized controlled trials are necessary.

Even more common is Alzheimer disease, the number one cause of dementia, and a tremendous public health burden. Current drugs aim to replace acetylcholine, the memory molecule of the brain that becomes deficient, but none halt the degenerative process. Available research indicates that both THC and CBD can interfere with the buildup of beta-amyloid and neurofibrillary tangles that are part of the pathological processes in Alzheimer disease. Additionally, THC and cannabis calm the agitation of the disorder and allow better sleep patterns. Further research, some currently underway, may help answer whether cannabis-based drugs can actually produce neuroprotective effects that slow or even arrest the disease process.

Traumatic brain injury (TBI) is an important cause of morbidity and mortality from accidents, warfare, and even contact sports. The most common form is concussion, which produces a constellation of problems including headache, fatigue, nausea, dizziness, and cognitive impairment. Repetitive head trauma has been linked to a degenerative condition now called chronic traumatic encephalopathy (CTE) especially associated with American football, in which years later people develop degenerative dementia, personality change, violent behavior, and even hallucinations. The neuroprotective effects of cannabis are well established in the literature, and there is a tremendous amount of anecdotal literature that cannabis benefits symptoms in both syndromes. Formal clinical trials are necessary.

Are there any other neurological disorders that cannabis might be able to help treat?

Russo: Cannabis-based medicines are well studied in treating symptoms of multiple sclerosis (MS), whether it be spasticity, for which Sativex is approved in 30 countries, but also for associated pain, sleep disturbance, and lower urinary tract symptoms.

Cannabis has benefitted patients with Tourette syndrome in several studies and has a strong theoretical basis in treating amyotrophic lateral sclerosis (ALS). A clinical trial in the latter is underway in Australia.

Numerous other neurological syndromes are currently being treated with cannabis and deserve formal investigation.

In another recent article (2), you addressed the practical considerations in administering and dosing medical cannabis. One of the biggest challenges is the lack of education for physicians in this area, how do you think that problem can be solved? Is there a resource that doctors can use to learn more about various cannabis treatment options and recommended dosing?

Russo: My colleague Caroline MacCallum and I recognized that while certain doctors in the world are experienced in advising patients on cannabis formulations and their use, and such information has been available in books, until 2018, there was no peer-reviewed scientific journal article that directly addressed the issue. We felt that this was a serious deficiency producing a knowledge gap that impeded progress in supplying patients and their doctors with the foundations necessary to inform proper approaches to cannabis therapeutics. Our article (2) is available on open source and we hope that it will be widely shared. Additional excellent books are available and are listed below (3–5).

What are some of the other major considerations for dosing?

Russo: THC is the limiting factor in cannabis dosing. In general, 2.5 mg of THC is a threshold dose for people who are not tolerant to its effects, 5 mg is a moderate dose, and 10 mg at once is too much for most patients not accustomed to the effects. I recommend that the total daily dose of THC not exceed 20–30 mg after a slow titration (adjustment of dose upwards), preferably in conjunction with a lot more CBD and terpenoids that buffer the effects of THC. The best adage is: “Start low and go slow!”

What cannabis research projects are you currently working on?

Russo: ICCI provides aid to the cannabis industry in all facets, whether it be identification of novel chemovars (chemical varieties), planning clinical trials, developing cannabis standards for cultivation, extraction and production, investigating new distribution networks, and everything hemp related, whether it be for nutrition or industrial applications. We are also directly involved in research on wound healing, treatment of Alzheimer disease, and cancer, among others. We have in-house projects that will investigate new diagnostic tests and development of nonprescription cannabis-based products for different common conditions.

What do you think is the biggest problem facing the medical cannabis industry and do you have any plans to solve it?

Russo: The biggest problem facing the cannabis industry is ignorance amongst physicians and the politicians that make the rules for the rest of us. I have been battling this every day for the last 23 years! All that I can do is to keep trying.

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