Cannabis Scientists Are Chasing the Perfect High

Article by Gary Greenberg, New York Times

Cannabis Scientists Are Chasing the Perfect High

The retail showroom of INSA, a farm-to-bong cannabis company in western Massachusetts, is a clean industrial space on the first floor of a four-story brick building in the old mill town Easthampton. When I visited recently, before the coronavirus shut down recreational sales and forbade crowds, the crew of eight behind the glass display cases looked a lot like the staff you’d see dispensing lattes at Starbucks or troubleshooting iPads at the Genius Bar: young, racially diverse, smiling. They were all wearing black T-shirts with the INSA motto, “Uncommon Cannabis.” Standing in line with me were a white-haired couple leaning on canes; a 40-something woman in a black pantsuit, who complained that the wait would be longer than her lunch break; a bald man in a tweed jacket; and a pair of women in perms and polyester discussing the virtues of a strain called Green Crack. We were all waiting at a discreet distance from the counter, as you would at the bank, for the next available “budtender.”

I got Ben, who described for me the wares that fill the cases like rings and watches in a jewelry store: waxes and dabs and oils and buds and edibles, most of them, he said, processed in a lab and kitchen on the other side of the wall behind him, using weed grown on the upper three floors. He sounded a little apologetic when he told me that while he knew why the bud I was pointing to was called Peyote Critical — “It speaks a little bit to its parentage, Peyote Purple and Critical Kush” — he hadn’t tried it, so he wasn’t entirely sure how it would affect me.

Ben took me around a corner to another glass case, this one displaying vaporizers in different shapes and sizes. He pulled a box off a shelf behind him. It was a $35, 350-milligram disposable vape pen loaded with Jack Herer, a strain named for a legendary grower. If I bought this, he said, I should “resist the temptation to take big rips — four seconds at the max, then pull that pen away and inhale to get a nice full set of lungs.” Ben felt more certain about the effects of Jack Herer than Peyote Critical, especially after he took a look at the label. “The primary terpene in here is limonene,” he said, which should make me “energetic and uplifted.” But there were more terpenes at work, Ben said. “You’ve got pinene coming in at 2.83 percent, good for memory retention and alertness, and then myrcene, which should help balance out some of the raciness from the limonene. Myrcene is good for your brain’s absorption of metabolizing THC but also has relaxing, sedating qualities.”

Terpenes are the compounds that give the different strains of cannabis their distinctive aromas. According to Ben, they are also what “modulates the high”; each variety of weed has its own terpene profile, which helps account for one of the riddles of cannabis: that even if two strains share the same psychoactive molecule — 9-delta tetrahydrocannabinol, or THC — one can make its users collapse in gales of laughter while the other produces paranoia and yet another seems (at least for a moment) to reveal the secrets of the universe. INSA is confident enough that it has figured out which kind of high each of its products will deliver that it offers a customer-satisfaction guarantee if the experience it advertises doesn’t match what the user gets.

The company, which was founded in 2013, was named for the two main varieties of cannabis: indica and sativa. Before budtenders and black-market dealers knew anything about terpenes, they told their customers that indica strains were sedating and sativa strains euphoric. But scientists have shown that while indica plants tend to be short and bushy and quicker to mature and sativas tall and spiky and slower, those differences do not correspond to any kind of consistent differences in the chemical profiles of the plants. “We’ve been trying to re-educate our consumers,” Peter Gallagher, chief executive of INSA, told me.

His firm isn’t the only one changing the way cannabis is marketed. Wherever weed is legal, companies are claiming that they have figured out how to produce a bespoke high. The promises are specific — one California company, MedMen, offers its customers “a surefire explosive orgasm” — and backed by scientific-sounding terminology like “terpene profile” and “cannabinoid breakdown.” Some of the research these companies cite to support what they are advertising has been published and peer-reviewed, but much of the recent work on the effects of cannabis has been conducted privately, and the companies are guarding their results as trade secrets. MedMen canceled my interview with its chief executive when it learned that I wanted to talk about the science behind its claims.

The cannabis business, then, has arrived at a critical moment. Now that pot has become something like a regular consumer product, customers are increasingly seeking the same “proven consistency” they expect from potato chips and soap. The financial stakes are clear: Despite lingering prohibitions in 17 states, legal cannabis is already an $8 billion industry in the United States. Domestic sales of alcohol, humankind’s other favorite intoxicant, topped $200 billion last year. But to make cannabis as popular as booze requires solving that original problem: It’s hard to imagine millions of people becoming new recreational users without being able to promise them that the product they’re spending money on — the average purchase at INSA is around $90 — will give them the effect they want.

Companies like MedMen and INSA may have decided that they’ve already cracked the code, but it remains to be seen whether that’s even possible with a plant as complex as cannabis. What those companies know for certain, however, is that the billion-dollar race to find out has already begun.

Cannabis has been consumed in one form or another for thousands of years, but it wasn’t until 1964 that a team led by the Israeli researcher Raphael Mechoulam identified THC as the molecule that got users high. By then, cannabis prohibition had been widespread for more than 25 years, creating formidable bureaucratic obstacles to researchers who wished to work with the plant. But Mechoulam kept at it, isolating another cannabinoid, cannabigerol (CBG), and mapping the structure of cannabidiol (CBD). All these chemicals, it turned out, had a role to play in the body’s response to cannabis. In 1998, Mechoulam coined the term the “entourage effect” to describe the complicated interplay between cannabinoids and the body’s own neurotransmitters in determining the drug’s effects.

While Mechoulam was still conducting his research, an American neuro­logist named Ethan Russo was zeroing in on terpenes as a major source of the variability in the effects of different strains of weed — or “chemovars,” as he prefers to call them. Not long ago, I went to visit him at his home on an island in Puget Sound, where he walked me through his past two decades of trying to conduct conventional research on this unconventional subject.

Russo told me that while he had been interested in botanical treatments since reading Euell Gibbons’s “Stalking the Healthful Herbs” while still in his teens, he knew little about cannabis as a medicine. That began to change when patients in his private practice in Montana began to report success with plant remedies, including cannabis, for chronic conditions like migraines. Intrigued by the results they reported, he began to study herbal medicine in earnest. Eventually, he wrote a textbook on the subject, which included a chapter on cannabis.

In 1996, while writing the book, Russo was introduced to aromatherapy with essential oils. “I realized how evocative they were,” he told me. He also knew that the same molecules that gave essential oils their punch — the terpenes — were present in cannabis, and that aficionados often said that “the nose knows,” meaning that a strain that smelled good to a user was likely to yield felicitous results. He began to suspect that the terpenes “were having a major modulatory effect on THC” and thus held a key to understanding the wildly variable effects of the drug.

He received Food and Drug Administration approval to run a clinical trial of cannabis as a treatment for migraines, but the National Institute on Drug Abuse, which must approve such research with illegal drugs, refused to sign off. The bureaucratic resistance “really stimulated my sense of adolescent rebellion,” he told me, and he decided to investigate terpenes’ role in the entourage effect on his own — legally, but using a method that, while once the backbone of medical research, had fallen into disrepute: self-experimentation.

He ordered terpenes from chemical-supply houses and, along with a few friends, began to blind-test them by transferring small amounts of them from coded bottles into a vaporizer designed to minimize odors and keeping track of their effects. In 2004, he went to Amsterdam, where he was able to obtain pure THC legally, pair it with different combinations of terpenes and record the effects they had on a group of volunteers.

Russo’s research was not without its problems. Scents could not be totally eliminated, the effects of THC couldn’t be successfully blinded and the prodigious daily cannabis intake of at least one participant made him a poor judge of the effects of individual THC/terpene combinations. Still, Russo found consistent correlations. THC alone, he found, lowered mood and distorted perception, and proved over all to be “really hard to function on.” He recalled one session in which, as it turned out, he had inhaled pure THC. “It was my turn to make dinner that night, and it was like: ‘Oh, God, I’m not sure I can do this. Where’s the knife? What do I need to do next?’ Everything was so hard.” But throw in pinene, the terpene that gives a pine woods its scent, and “all of a sudden that’s gone. You’re clear. You have no problem remembering anything.” Limonene, one source of citrus’s distinctive odor, also cured the THC blues, “making this unpleasant thing vibrant and alive and electric.” On the other hand, some terpenes just made things worse — like myrcene, an oil that smells a little like cloves and is present in high concentrations in hops, on which, Russo recalled, “I can’t function, I can’t think, I can’t move.”

In 2010, at a conference honoring Mechoulam, Russo presented a paper called “Taming THC,” which compiled more than 400 studies that strengthened the case for the role terpenes played in the variable effects of pot. It did not directly mention Russo’s D.I.Y. research, but a careful reader could find observations about the effects of specific combinations on memory, cognition and mood — that myrcene-heavy strains may produce “couchlock,” that pinene might be an “antidote” to the negative effects of THC — that were at least as indebted to Russo’s experiments in Amsterdam as to anything in the scientific literature. The paper was published the following year in the prestigious, widely read British Journal of Pharmacology.

Russo was not the only cannabis researcher studying terpenes, and “Taming THC” was not the first scientific article to speculate about their role in cannabis intoxication. It was also meant to be the starting point for more rigorous research into terpenes, not the final word on their effects. But the article, with its concise charts of correlations between terpenes and drug effects, came along at a crucial moment in the history of pot: By 2011, 15 states had approved medical marijuana, and Colorado and Washington were on the verge of making the drug legal for recreational use.

A new industry was ready to burst into being, and here, in the legitimate academic press, was a paper providing a map to what Russo called a “pharmacological treasure trove.” If the paper’s promises held up, a company could even take aim at the most tempting prize of all: the vast number of Americans who had never tried weed before, and others who had aged out of it but might be brought back on board. For that market, it wasn’t enough for cannabis to be legal; the drug had to be as predictable as a pre-dinner martini.

“Taming THC” laid out an ambitious scientific agenda for anyone seeking to further test the paper’s claims: “high throughput pharmacological screening,” animal experiments to specify mechanisms of action, molecular studies to establish just how terpenes and cannabinoids interact, animal-behavior studies, brain-imaging research and human clinical trials. Nearly a decade later, this agenda, which is modeled on pharmaceutical drug development, remains unfulfilled.

Recently, however, a few companies in the United States and Canada have begun an aggressive investigation into the entourage effect, though they are forgoing many protocols of the pharmaceutical industry. Last year, I met Jon Cooper, the founder of a company called Ebbu, at a co-working space in Denver. Cooper had been toying with the idea of a cannabis start-up ever since Colorado legalized the drug, but he was deterred by his own history with pot. “I’d had some awesome experiences that I wished I could have all the time,” he told me. But he’d also had “some completely horrific experiences that I never ever wanted again.” Cooper says he couldn’t sell something he didn’t believe in; but what if he could figure out how to “capture in a bottle the awesome experience, so every store I walk into, I could get that same experience. Wouldn’t that be amazing?”

A year after Cooper started Ebbu in 2013, he approached Brian Reid, who was running a lab at the University of Colorado’s school of pharmacy, hoping they could collaborate. Reid’s specialty was exactly the “high throughput” screening Russo had called for, in which algorithms are used to quickly determine which potential drugs would interact with which cellular targets. The university’s lawyers, worried about a possible loss of federal funding, nixed the deal, but Reid eventually decided to go to work for Ebbu directly; in 2016, he became its chief science officer.

Reid began to, in Cooper’s words, “crank data.” As long as he did not ask for government money, he could do high-grade pharmaceutical research using human subjects without the usual regulatory scrutiny. Ebbu went straight into human trials of the most likely drivers of the entourage effect. That’s not as reckless as it might appear. Reid points out that no one is known to have ever died from an overdose of cannabis.

Colorado law forbids cannabis companies to give away products, so Ebbu offered samples for $1 to people who agreed to fill out an online questionnaire about their experiences. Their responses were correlated with the chemical profiles of the extracts in order to gather evidence about which combinations produced which effects. In June 2016, the company announced that it had identified eight terpenes and three cannabinoids that modify the effect of THC in a predictable way. The company said this was a “significant milestone” in its quest to develop formulations that would “enable consumers to choose a desired experience.”

Read the full article here.

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