Many of us never thought we’d be working with cannabis. And yet, we’ve found ourselves paying homage to an ancient plant that continues its medicinal mysticism, demonstrating time and again that its ingredients often outperform many synthesized drugs. We’ve been bewitched by the science, the fragrance, the possibilities.
Fortunately, Ethan Russo, MD, found his way to cannabis. Recently, I spoke with Russo about his migration away from traditional medicine and more towards botanically derived remedies.
As a board-certified pediatric and adult neurologist, circa 1990, Russo felt like he was in a rut. He was treating his patients with increasingly toxic drugs with less and less benefit. So, he returned to an interest from his youth — using ethnobotanical plants for medicinal purposes. “I was a fan of Euell Gibbons’ book Stalking the Healthful Herbs as a teenager and had successfully prevented dreaded poison ivy outbreaks utilizing his suggested jewelweed,” Russo explained. “I knew that there were many herbal alternatives to conventional pharmacotherapy.”
Part of this medicinal quest regarded treatments for migraines. Russo wanted to explore the Amazon Rainforest, as he knew that using plants as medicine was commonplace there. “I started taking night classes in Spanish and ultimately made it to Peru in 1994.”
This brief visit provoked Russo to take a three-month sabbatical to cultivate his ethnobotany education while working with an indigenous tribe in Peru in 1995, and, come 1996, Proposition 215 in California made medical cannabis legal. Russo became embroiled in the burgeoning controversy regarding whether cannabis was actually medicine.
“The persistent feeling among some was that cannabis was dangerous and addictive with no medical uses,” Russo added. He was interested in whether cannabis could work for migraines and wanted to evaluate this application using his training and expertise such that the study would exemplify the robustness needed in a clinical trial to make impactful decisions.
“I sought the permission of the federal government,” Russo explained, “and by 1999, I had clearance from the Food and Drug Administration. The National Institute of Drug Abuse, however, refused to provide the material needed for the study.”
Even though the study didn’t happen, Russo’s education regarding the medicinal usage of cannabis proliferated. His extensive contributions to the scientific literature, as author or editor, blossomed. He started the Journal of Cannabis Therapeutics and published a paper on cannabis for migraines in Pain. 
Geoffrey Guy, MD, Founder and Chairman of GW Pharmaceuticals, took note of the paper and offered Russo a position as a scientific advisor, which Russo held for five years before becoming Senior Medical Advisor. GW Pharmaceuticals has developed several cannabis-derived medications, such as Sativex® and Epidiolex® that respectively treat spasticity associated with multiple sclerosis and severe pediatric epilepsy disorders (Lennox-Gastaut syndrome and Dravet syndrome).
Together, We Are Better
As Russo’s journey into cannabis began to unfold, so did his exposure to the medicinal attributes of essential oils and terpenes. “Immediately, the idea of synergy between cannabinoids and terpenoids really resonated,” Russo recalled.
Russo is perhaps most often linked with the powerful paper entitled “Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects.”  Other researchers have hinted at or discussed synergies in the past, including Raphael Mechoulam, Ph.D, who’s group discovered that an endocannabinoid that our bodies make (2-arachidonoylglycerol) works in conjunction with other molecules that help it bind to cannabinoid receptors.  Russo’s paper, however, popularized the notion, putting the entourage effect on the tips of tongues until it was a household term.
So, what’s changed since “Taming THC”’s 2011 publication?
“There have been slow advances,” Russo noted. “We see greater cognizance of the roles terpenes play and their importance in cannabis with possible synergies. Some papers support this; some play it down. We need more ammunition.”
To that end, Johns Hopkins University has begun several clinical trials funded by the National Institute of Health. “They’re looking at THC [tetrahydrocannabinol] in combination with terpenoids in human subjects,” Russo added.
As a trained physician, Russo sees the value in patient feedback strongly supporting of the idea of synergy. However, he noted that it’s only after randomized, controlled studies with follow-up psychometric evaluation that the necessary evidence for proving ensemble effects will become actuality.
“Most studies done with cannabis have utilized sub-optimal preparations,” Russo exclaimed. “Most should be underlined three times. I will challenge anyone on that. The standards need to tighten up so there’s more proof and less skepticism.”
Terpenes = Medicine or “Witchy” Voodoo?
Modern cannabis product development has become more focused on terpenes given the plethora of studies regarding their medical efficacy. Pennsylvania saw fit to require terpenes on product labels, and, no doubt, other states not currently doing so will follow. I was curious as to how Dr. Russo sees future product design.
“Evolved product design focusing on synergies requires that companies doing this have an awareness that this is important,” Russo advised. “We need studies that will really identify the synergies. But we can also provide examples where this has been shown in practice via patient feedback.”
As an example, Russo used situations where terpenoid content played a difference in allaying THC anxiety.
“CBD can help, as can limonene and linalool which are both very good at reducing anxiety,” Russo added. “Limonene is an excellent mood elevator. In fact, historically, lemon was a supposed antidote to cannabis intoxication. Then there’s short-term memory impairment which alpha-pinene allays. Consumers report being able to think more clearly during work or study.”
When we speak about synergy, Russo says there are two potential pathways. One is the potentiation or boosting of the effects of two or more components in treating pain, for example.
“THC is good for pain,” Russo commented. “CBD can be useful, but so can myrcene, pinene, or caryophyllene, the latter of which also comes with anti-inflammatory and analgesic effects too.”
The second synergistic approach regards boosting the therapeutic index.
“This just means that you can use a higher dose of THC without side effects,” Russo explained, “thereby extending the range of what is possible with cannabis medicine.”
I asked Dr. Russo if there were any specific terpenes that he found most interesting and warranting further study.
“Limonene is an obvious place to go,” he responded. “It’s mood-elevating and mood-stimulating but we’ve never identified a specific receptor in the brain where this might be acting. Part of the problem is that the study of essential oils is misrepresented as being akin to witchcraft. There’s credence to the subject of set and setting playing large roles but there are certain effects we can expect with regularity in a specific population. Art and science must apply the practice of cannabis-based medicine.”
A Molecular Commune v. Life in Isolation
It was clear that Dr. Russo values the efficacy of whole-plant cannabis extracts. But he’s seen both sides of the equation via his work with isolated cannabinoids at GW Pharmaceuticals. So, looking back on his journey, where does he stand, which does he prefer?
Russo believes in preserving what a well-bred plant has at the beginning.
“I usually will favor the extracts that most closely resemble the plant,” he answered. “It’s unlikely that any single components will be more efficacious than a properly constituted extract. Single components can act better than a mixture in some situations, but the opposite is also true.”
Russo pointed to a study that evaluated dose response activity for treating pain.  CBD alone produced a biphasic curve where a low dose showed no effect and too high of a dose lost the benefit on pain. When the researchers used an extract, the dose response curve was linear. It went up and stayed up, and the product didn’t lose its effect at higher doses. The difference stemmed from terpenoids in the extract. 
The talk about full-spectrum products, complete with appetite stimulants and suppressants, or molecules that might be anxiolytic (anti-anxiety) and anxiogenic (causing anxiety), makes me wonder what ingredients might “cancel” each other out.
“We need additional studies to see if things come out in the wash,” Russo offered. “If dispensaries provide good cannabinoid and terpenoid profiles, and you couple the analytics with patient feedback, you can see good correlation between what you’d expect and what was observed.”
The Russo/True Terpenes Collaboration
Recently, Russo began working with terpene provider, True Terpenes, as a member of their Scientific Advisory Board (SAB). As per the press release from True Terpenes, “The SAB will provide True Terpenes with external scientific and medical insights, as well as feedback on product and intellectual property development. It will catalyze a long-standing goal of True Terpenes to address the gaps in the science surrounding the entourage effect and create products to optimize these discoveries.”
“I had been aware of True Terpenes for several years,” he explained, “as I had been looking for good botanical terpenes. I had no problem finding terpenes from chemical supply warehouses, but they weren’t really for human consumption, were synthetic, or weren’t the correct stereoisomer.”
Russo’s journey serves as inspiration to many of us captivated by ethnobotany. Cannabis or essential oils might catalyze our own journeys into this realm. Perhaps the curiosity stems from psychedelic plants and the work of scientists like Alexander Shulgin or Terence McKenna. Maybe the knowledge is even ancestral, innate.
I asked Dr. Russo if he could tell someone one overarching thing about cannabis or terpenes, what might it be?
“I’d like people to be more aware that throughout the history of the human race, the natural situation is that plants have provided us with medicine. It’s only been in the last 75 years or so that synthetic chemistry drove pharmaceutical development. Even still, today, 25% of current drugs are derived directly or indirectly from plants.”
So, the silly notion that using plants as medicine is “witchy” at best has demonstrated a reckless path to discontent. Thankfully, scientists like Russo have helped legitimize cannabis by providing the ammunition for what many have been saying all along.
“It’s challenging for consumers to sort out what’s what,” he continued. “As someone who’s had a foot in both camps, cannabis treatments often have had similar or better outcomes with fewer side effects compared to traditional pharmaceutical options. For people who haven’t looked at these alternatives, they have a great deal to offer. This is true for cannabis and for essential oils. We need to eliminate existing roadblocks to research.”
- Russo, E. “Cannabis for Migraine Treatment: The Once and Future Prescription? An Historical and Scientific Review.” Pain, vol. 76, 1998, pp. 3-8. [journal impact factor = 6.029; times cited = 24 (Semantic Scholar)]
- Russo, E. “Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects.” Br J Pharmacol, vol. 163, 2011, pp. 1344-64. [journal impact factor = 6.81; times cited = 449 (Semantic Scholar)]
- Ben-Shabat, S et al. “An Entourage Effect: Inactive Endogenous Fatty Acid Glycerol Esters Enhance 2-Arachidonoyl-Glycerol Cannabinoid Activity.” European Journal of Pharmacology, vol. 353, no. 1, 1998, pp. 23-31. [journal impact factor = 3.170; times cited = 201 (Semantic Scholar)]