Cannabis Science

Spring 2019 Print Article

The latest news, research, and reports on the therapeutic uses of cannabis from the scientific community

The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: “No Strain,” No Gain

Prolific cannabis researcher Ethan Russo published a report on the entourage effect in Frontiers in Plant Science in January 2019, bringing together a large number of known studies on the subject. He starts by discussing the difficulty of identifying the active ingredients of cannabis. “While labeled “strains” in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or “chemovars.”…Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.”

In this comprehensive overview of the effect, he states, “In 1998, Professors Raphael Mechoulam and Shimon Ben-Shabat posited that the endocannabinoid system demonstrated an ‘entourage effect’ in which a variety of ‘inactive’ metabolites and closely related molecules markedly increased the activity of the primary endogenous cannabinoids, anandamide, and 2-arachidonoylglycerol. …They also postulated that this helped to explain how botanical drugs were often more efficacious than their isolated components. …Although the single molecule synthesis remains the dominant model for pharmaceutical development…, the concept of botanical synergy has been amply demonstrated contemporaneously, invoking the pharmacological contributions of ‘minor cannabinoids’ and Cannabis terpenoids to the plant’s overall pharmacological effect.” With many examples, he lays out the case for botanical medicine. “These studies and others provide a firm foundation for Cannabis synergy and support for botanical drug development vs. that of single components.” He concludes, “The data supporting the existence of Cannabis synergy and the astounding plasticity of the Cannabis genome suggests a reality that obviates the need for alternative hosts, or even genetic engineering of Cannabis sativa, thus proving that ‘The plant does it better.’”

The Contribution of Cannabis Use to Variation in the Incidence of Psychotic Disorder Across Europe (EU-GEI): A Multicentre Case-Control Study

A 5-year study published in The Lancet in May 2019 concludes, “Cannabis use is associated with increased risk of later psychotic disorder but whether it affects the incidence of the disorder remains unclear.” Among the findings, “Use of high-potency cannabis (THC ≥10%) modestly increased the odds of a psychotic disorder compared with never use; this remained largely unchanged after controlling for daily use. Those who had started using high-potency cannabis by age 15 years showed a doubling of risk, without evidence of an interaction.” Researchers were able to come to their conclusions partly due to the wide geographical reach. “Use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where high-potency cannabis was widely available, by contrast with sites such as Palermo where this type was not yet available. In the Netherlands, the THC content reaches up to 67% in Nederhasj and 22% in Nederwiet; in London, skunk-like cannabis (average THC of 14%) represents 94% of the street market whereas in countries like Italy, France, and Spain, herbal types of cannabis with THC content of less than 10% were still commonly used. … Thus our findings are consistent with previous epidemiological and experimental evidence suggesting that the use of cannabis with a high concentration of THC has more harmful effects on mental health than does the use of weaker forms.

The report concludes, “We report what, to our knowledge, is the first evidence that differences in the prevalence of daily use and use of high-potency cannabis in the controls correlate with the variation in the adjusted incidence rates for psychotic disorder across the study sites. Our results show that in areas where daily use and use of high-potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder.” The authors do acknowledge some of the limitations of the study. “Our findings need to be appraised in the context of limitations. Data on cannabis use are not validated by biological measures, such as urine, blood, or hair samples. However, such measures do not allow testing for use over previous years. Moreover, studies with laboratory data and self-reported information have shown that cannabis users reliably report the frequency of use and the type of cannabis used.”

Access to Medical Marijuana Reduces Opioid Prescriptions

In May of last year, Peter Grinspoon, MD posted in the Harvard Medical School blog about the debate over using medical cannabis to mitigate opioid abuse. He writes, “The idea of using marijuana to mitigate the opiate crisis may seem counterintuitive to many people in the medical community. Some healthcare providers ask questions like, “Aren’t we just replacing one drug with another?” and “Doesn’t marijuana present its own set of dangers, such as addiction, dependency, and other health concerns?” To answer these questions, he referenced two studies recently published in JAMA Internal Medicine, which show, “the rate of opiate prescriptions is lower in states where medical marijuana laws have been passed.” One study showed that “when medical marijuana laws went into effect in a given state, opioid prescriptions fell by 2.21 million daily doses filled per year. When medical marijuana dispensaries opened, prescriptions for opioids fell by 3.74 million daily doses per year. These reductions in daily opioid doses were particularly notable for hydrocodone (Vicodin) and morphine prescriptions.” “The other study analyzed Medicaid prescription data from 2011 to 2016, and that analysis showed that states that have implemented medical marijuana laws have seen a 5.88% lower rate of opioid prescribing, and when they implemented adult-use (i.e., recreational use) marijuana laws, there was a 6.38% reduction in opiate prescribing.”

Just as important as the data, Dr. Grinspoon said, are the editorial comments. He quoted the authors of one study who wrote, “We do not know whether patients actually avoided or reduced opioid use because of increased access to cannabis (marijuana).” According to Grinspoon, “However, given that millions of prescriptions for opiates were not written, and consequently there were millions of fewer bottles of prescription opiates consumed, sold, diverted, or abused, it does not seem to be too big a leap to infer that opiate use was avoided, or at least reduced.”

He concluded with a call for more conversations on this subject between doctor and patient. “Healthcare providers, whether they are pro-, neutral, or anti-medical marijuana, need to leave their prejudices outside the exam room. Physicians need to create a climate where patients feel they can be open with us so that we can know if and how they are using medical marijuana. Physicians can be in a position to advise them on the risks and benefits of safe usage and meaningfully contribute to the conversation (assuming that we ourselves have a modicum of education on this issue). Once we are all on the same page, guided by evidence in new studies about reduced opiate use and adding medical marijuana to the pain relief arsenal, we can start helping patients to minimize their use of opiates.”

The Association between Cannabis Product Characteristics and Symptom Relief

A study published in February 2019 by Scientific Reports used data from the Releaf App to overturn ingrained dogma on the therapeutic effects of THC as well as set a new standard of data collection on the real-time data from a wide cross-section of patients on 27 different “measured symptom categories.” Over a 21-month period, “3,341 people completed 19,910 self-administrated cannabis sessions using the mobile device software, ReleafApp to record: type of cannabis product (dried whole natural Cannabis flower, concentrate, edible, tincture, topical), combustion method (joint, pipe, vaporization), Cannabis subspecies (C. indica and C. sativa), and major cannabinoid contents (tetrahydrocannabinol, THC; and cannabidiol, CBD), along with real-time ratings of health symptom severity levels, prior to and immediately following administration, and reported side effects.”

The study lays out the challenges to research so far. “Medical cannabis markets are currently being flooded with thousands of cannabis strains with unique cannabinoid profiles, novel, uninvestigated cannabis-derived formulates and products with little to no clinical references or formal guidance on how fundamental characteristics of the products themselves may affect pharmacodynamics. Federal laws have all but prohibited the use of perspective, pragmatic, naturalistic studies with random treatment assignment for measuring the effects of cannabis consumed in vivo. What little clinical research does exist is mostly limited to randomized controlled trials (RCTs) using synthetic cannabinoids or low quality and potency cannabis obtained from the federal government that is unrepresentative of the cannabis products used by millions of people every day.”

This has led to contradictory research, especially around schizophrenia. Releaf mobile technology is a revolutionary way to collect data. The study says, “…few large-scale investigations to date have measured the relative effects of THC and CBD consumption in real-time under naturalistic conditions among people diagnosed with schizophrenia or any other user group. … Our observational study using mobile app technology was designed to measure these effects in real-time among a large sample of patients using cannabis for treating their medical symptoms under naturalistic conditions.”

The results are notable. “Patients showed an average symptom improvement of 3.5 (SD=2.6) on an 11-point scale across the 27 measured symptom categories.” Further, “Across product characteristics, only higher THC levels were independently associated with greater symptom relief and prevalence of positive and negative side effects. In contrast, CBD potency levels were generally not associated with significant symptom changes or experienced side effects.” The study concludes, “…with preliminary evidence that cannabis may treat an even wider range of conditions than those tracked in this study, including cancer, it is imperative that the scientific community develop innovative strategies such as the use of mobile technology for measuring the multidimensional relationships among cannabis product characteristics, patient health conditions, perceived symptom relief, and side effect manifestation.”