Pains, Strains, and the Complex Chemistry of Cannabis

A regulated medical cannabis industry needs to evolve to provide users with accurate biochemical information on all cannabis-containing products.

As a Quality Assurance Person (QAP) for Canna Farms Ltd., BC’s first Licensed Producer of medical cannabis under Health Canada’s MMPR, it is my job to ensure that the dried cannabis and cannabis oils that we offer our clients are of high-quality, are safe for consumption, and that the information we provide to our clients is accurate (particularly as it relates to cannabinoid potency). I also have the opportunity to interact with many of our clients on a regular basis, and often hear from them about how cannabis therapy has had a positive impact on their health and overall quality of life.

Current medical research seems to support such anecdotes, at least to some extent. There is some compelling evidence showing that cannabinoids like delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) can be used for the treatment of chronic pain, spasticity, PTSD, anxiety, sleep disorders, and nausea for those undergoing treatment for cancer. Although some studies may support the use of cannabis or purified cannabinoids as an alternative or complementary therapy for the treatment of such conditions, there is still a lot we do not know about the efficacy of cannabis as a medicine, largely because it is hard for scientists to do research on this plant.


The Indica/Sativa Debate

In a recent Lift Cannabis Podcast I spoke about the lack of standardization in the medical cannabis industry, and my skepticism regarding the notion that herbal forms of cannabis can be used to reliably treat or cure specific medical conditions, or that different classes (types) of cannabis can have consistent, reproducible therapeutic outcomes.

For those unaware of the prominent and suspiciously simple cannabis classification system, Cannabis sativa dominant plants are often touted as having stimulating, uplifting effects (best used during the daytime), in contrast to Cannabis indica dominant plants that are alleged to have relaxing, sedating properties (best consumed during the nighttime or right before bed). Hybrids are often said to offer “the benefits of both sativas and indicas”.

Proponents of medical cannabis have fought for legitimacy for decades, and it seems we are nearing an era where medical cannabis is bordering mainstream social and even medical acceptance (at least at some level). However, legitimacy comes at the price of increased scrutiny.

Many have suggested that it is the presence of terpenes (numerous low-molecular weight aromatic compounds responsible for the smells and tastes of different varieties of cannabis) that work synergistically with major cannabinoids, such as THC or CBD, to modulate their effects, known as the “Entourage Effect” (first described by Drs. Mechoulam and Ben-Shabat in 1998). The differences in effects are allegedly a function of the different terpene profiles of each strain or more generally strain-type. Although research regarding the concept of cannabinoid/terpenoid synergy is scant, it is very likely that these different phytomolecules can interact with the endocannabinoid system, and with each other.

Since chemistry is ultimately responsible for the pharmacological effects of cannabis, it is implicit in this indica/sativa dichotomy that such terms can be used to (somewhat) accurately describe the chemical composition of a particular strain of cannabis. However, the terms sativa and indica were originally coined by biologists and taxonomists to describe a cannabis plant’s morphology (size/shape) and geographical origins, and were never intended to provide a precise, quantitative description of its chemical profile. Current scientific research on this topic tells us that strain names often do not reflect a meaningful genetic identity or chemical profile, largely because the source of the strain is unknown and the names themselves are not standardized.

Is there any validity to the indica/sativa classification scheme as it relates to a cannabis plant’s chemistry or medicinal properties?

In a January 2016 interview with Cannabis and Cannabinoid Research, Dr. Ethan Russo (MD) expressed his views on this ubiquitous indica/sativa classification system and its utility in helping those looking to use cannabis as a medicine. Dr. Russo is a neurologist, published psychopharmacology researcher, author, past chairman of the International Association for Cannabinoid Medicines, and is perhaps best known for his 2011 scientific article, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”.

When asked about the different purported effects between Cannabis indica and sativa, Russo unequivocally stated that, “There are biochemically distinct strains of Cannabis, but the indica/sativa distinction as commonly applied in the lay literature is total nonsense and an exercise in futility… It is essential that future commerce allows complete and accurate cannabinoid and terpenoid profiles to be available.”

indica sativa
Cannabis flowers maturing at Hope, BC's Canna Farms

In the absence of evidence to support the notion that the currently accepted indica/sativa dichotomy is even vaguely correct, what has caused this system of classification to become so deeply ingrained into current cannabis culture?

“We would all prefer simple nostrums to explain complex systems, but this is futile and even potentially dangerous in the context of a psychoactive drug such as Cannabis,” says Dr. Russo.

The issue is that cannabis chemistry is incredibly complex. A typical cannabis plant produces hundreds of chemical compounds throughout its lifetime (nearly 100 of which are cannabinoids), many with their own unique medicinal properties. Both the absolute and relative concentrations of the active ingredients in cannabis are controlled by genetics (genotypes and phenotypes), cultivation practices (including growth cycle time), environmental conditions throughout the plant’s lifetime (including light, temperature, humidity, CO2, and nutrient levels), plant stressors (such as pests and disease), and even drying/curing/storage/pasteurization practices. Combined with the numerous ways a cannabis user may opt to ingest cannabis (each with their own dosage efficiencies and absorption pathways), it is clear that we are dealing with enormous potential for chemical variability.

A major tenant of medical research is control, which is why large, randomized, peer-reviewed, double-blinded, placebo-controlled studies are considered to be the gold standard when investigating the efficacy of a new pharmaceutical. Medical research favours the study of isolated molecules of known concentration, largely because it allows researchers to control as many variables as possible, limits drug-drug interactions, and makes the subsequent manufacturing of single-molecule drugs much simpler.

In fact, much of what is known about the medical effects of cannabinoids and terpenes comes from studies done on single molecules, and not standardized, multi-compound formulations. It is unreasonable to assume that we are able to extrapolate sufficient data from studies done on single molecules, especially from those done in a petri dish or using animal models.

So what does the science say about the supposed benefits of multi-compound cannabis formulations?

One study comparing the subjective, behavioral, or therapeutic effects of whole plant cannabis with just THC showed no statistically significant differences between the two. Another clinical study done on dronabinol (trade name Marinol), a gelatin capsule containing synthetic THC, revealed that “dronabinol produced longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana.”

Last year, GW Pharmaceuticals announced that results from three Phase 3 Clinical Trials showed no statistically significant differences between the effects of placebo and of nabiximols (trade name Sativex, a refined cannabis extract that contains a 1:1 ratio of THC and CBD) in reducing pain in the treatment of cancer patients. However, the same company recently announced that its CBD-containing drug, Epidiolex, had shown positive results in a Phase 3 clinical trial in treating children with Dravet Syndrome, an aggressive form of epilepsy. Both Sativex and Epidiolex are highly purified (>99%) cannabis extracts, and contain trace amounts of minor cannabinoids and terpenes.

The Future of Medical Cannabis

Unfortunately, the medical cannabis movement seems to be driven more by anecdotal evidence, politics, and legal precedents than it is by science. Proponents of medical cannabis have fought for legitimacy for decades, and it seems we are nearing an era where medical cannabis is bordering mainstream social and even medical acceptance (at least at some level). However, legitimacy comes at the price of increased scrutiny.

Advocates of herbal cannabis or whole-plant cannabis extracts will often differentiate cannabis from conventional medicines, citing the synergistic benefits of multi-compound formulations, often appealing to nature in the process. However, if the ultimate goal is acceptance of cannabis as a medicine by the mainstream medical community, I would argue that it is extremely important that we study cannabis with the same rigour we study conventional medicines. Quite simply, we must not put the cart in front of the horse.

When asked about the best way to approach medical cannabis in a scientifically-sound manner, Dr. Russo stated that, “Since the taxonomists cannot agree, I would strongly encourage the scientific community, the press, and the public to abandon the indica/sativa nomenclature and rather insist that accurate biochemical assays on cannabinoid and terpenoid profiles be available for Cannabis in both the medical and recreational markets. Scientific accuracy and the public health demand no less than this.”

Dr. Russo is right – public health and scientific accuracy demand a quantitative, evidence-based approach to cannabis as a therapy. But in the absence of high-quality, peer-reviewed studies, and mandated cannabinoid and terpenoid testing, those who are willing to try cannabis therapy in place of (or in addition to) conventional therapies will continue to rely on anecdotes and trial and error in search of relief. It is my hope that a regulated medical cannabis industry will evolve to provide users with accurate biochemical information on all cannabis-containing products, and that barriers to research will be lifted as cannabis laws around the world are relaxed.

-Tom Ulanowski

Tom Ulanowski is a Quality Assurance Person (QAP) at Canna Farms Ltd., a family-owned and operated Licensed Producer of medical cannabis located in Hope, British Columbia. Tom holds an HBSc Degree in Analytical Chemistry & Environmental Analysis and Monitoring from the University of Toronto, and a MSc Degree in Biogeochemistry from Western University.

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  1. Philippe Henry Reply

    Very good article Tom, I think you sum it all up in one well packaged piece! One thing that strikes me when dealing with the incredible complex landscape of cannabis chemistry is that it is compounded by in vivo interactions within each individual's internal environment (dictated by variants in different liver enzymes, diets, or exercise regimes), and that this response is incredibly individualistic. Even two closely related individuals will respond differently to the same cannabis preparation. This poses a serious challenge to scientists and doctors trying to elucidate the effect of a particular strain or preparation type. Do we need a novel paradigm that diverges from the "gold standard" instead of trying to make cannabis fit into the commonly accepted dogmas of western medicine and science?