Al McDonald started to suspect there was something different about the way his body processed marijuana edibles one night in his early 20s, when he split a strong batch of pot-infused cookies with friends.
“They couldn’t stop laughing — they were all having a great time,” recalled McDonald, a 55-year-old cannabis cultivator from Ontario, Canada. “And I got absolutely nothing from them. I was sitting there with my arms crossed, like, ‘aw man … everybody’s Hoverboard works except for mine.’ ”
To a small number of people, McDonald’s experience will sound familiar. That’s because he’s part of an unknown portion of the population that appears to be functionally “immune” to edibles, or at least has exceptionally high tolerances.
While they experience smoked marijuana normally, McDonald and a half-dozen other such “ediblocked” consumers who spoke to the Globe all insisted they experienced no effects even after eating quantities of marijuana concentrates that would launch the vast majority of people on a long, panicky, and profoundly unpleasant (though not physically toxic) trip.
McDonald, for instance, discovered through a reckless experiment with hash tea that he “starts to feel something” at around 700 milligrams of THC, the compound that causes the drug’s characteristic high. That dose is a staggering 140 times the standard serving in Massachusetts of 5 milligrams.
Leading cannabis doctors and researchers acknowledge the phenomenon is real, but can’t definitively explain it. They called for further research, saying that far beyond the disappointment of recreational marijuana consumers who can’t get high, it has serious implications for dosing in medical marijuana treatment and raises questions about the validity of blood tests that purport to detect pot impairment.
Unraveling the mechanisms at play could also point the way to a better understanding of the human body’s complex system of naturally occurring cannabinoid compounds and receptors, which are thought to play a role in everything from fertility to immunity to mood and cognition.
“We’re only just now starting to understand the cannabinoid system,” said Dr. Staci Gruber, the director of the Marijuana Investigations for Neuroscientific Discovery programs at McLean Hospital. “And it’s already clear that it’s not just about what and how much you’re using; it’s about how you’re wired.”
While no studies have directly examined those with ultra-high tolerances to marijuana edibles, Gruber and other researchers have a compelling hypothesis: People with an unusual variation of a key liver enzyme could essentially be too efficient at processing ingested THC, turning the compound into its “active” high-causing metabolite and then its inactive waste product before the active form can enter the bloodstream or brain. It’s also possible other people’s enzymes make them unusually inefficient at performing this process, with little THC getting metabolized in the first place.
“It’s almost as if they’re skipping the intermediate step,” Gruber said of people with uncommon subtypes of the CPY2C9 gene, which encodes the enzyme that shepherds THC through its three-step metabolic transformation. “You’re breaking it down so fast it doesn’t have an opportunity to create the psychoactive effect.”
Gruber added that other variables such as how easily people absorb and metabolize fat probably play a role, too.
If the hypothesis holds, it would mean “immunity” to edibles can be inherited — and indeed, nearly all of the consumers who spoke to the Globe said they had at least one close family member with a similar condition.
The explanation stems from new studies finding that levels of THC metabolites in people’s blood varied drastically depending on which variant of the enzyme they had.
The research casts doubt on biological marijuana tests widely used by researchers, doctors, police, and employers, which look for those same metabolites but don’t account for the apparently vast and hard-wired variations in metabolic rate between individuals. (In Massachusetts, most suspected stoned drivers are evaluated by officers with so-called “drug recognition expert” certifications, a process that typically includes a saliva or blood test for THC.)
“It underscores the need to understand people’s genetic profiles, and that there are a lot of variables people haven’t considered” when it comes to interpreting such tests, Gruber said.
Besides the social FOMO, being “ediblocked” makes it difficult to benefit from marijuana’s pain-relieving and other medicinal qualities. It’s possible significant numbers of medical marijuana patients who tried but never benefited from edibles could still find relief if they take a high enough dose, or if a supplement could be developed that slows their enzyme action. (There is also the intriguing possibility of a Narcan-like drug for ending unpleasant cannabis highs that exploits the same principle.)
Renata Caines, a 31-year-old cannabis entrepreneur from Roxbury who has the condition, said she’s dreading an upcoming major surgery, knowing she will be largely unable to smoke marijuana and cannot afford the large quantities of potent cannabis tincture it would take for her to feel an effect.
She has also yet to find her breakthrough dose, nervous about overshooting the mark — even as she astounded her family by downing an entire marijuana-infused “space cake” in Amsterdam to no apparent effect.
“I know they’ll prescribe me opioids, but that’s really not something I want to take,” Caines said. “So do I try to see if I can manage with edibles, even knowing I have a high tolerance? My insurance won’t cover that.”
People who cannot easily get high from edibles are accustomed to skepticism, with most saying they first discovered their condition in a social setting, then gradually tried higher and higher doses to prove it wasn’t a fluke.
“At first, my friends assumed I was high and just sort of didn’t realize it, but I’m an experienced smoker — I know whether I’m high or not,” said one Massachusetts resident in her late 20s who asked to be referred to only by her common last name, Patel, to candidly discuss her cannabis consumption. “Now they’re just utterly perplexed. They think I’m some sort of freak of nature.”
While being “ediblocked” is usually just a minor nuisance, Patel said, it’s frustrating to not have the option of consuming edibles instead of smoking when she’s sick, traveling, or staying with her family.
Dr. Peter Grinspoon, a Harvard Medical School instructor and cannabis expert, said that Patel and others who think they may be unusually tolerant of edibles should proceed cautiously.
“There’s still a risk of taking too high a dose, and then you’re stuck with it for eight hours,” he said.
Grinspoon said the phenomenon illustrates how little we understand the body’s cannabinoid system, thanks in part to longstanding federal restrictions on studying marijuana. “This is something that, with appropriate research and smart people working on it, we could understand and maybe even fix,” he said.
In the meantime, McDonald will stick to consuming weed the old-fashioned way.
“Just give me a joint and I’ll try to keep up,” he said with a laugh.
Dan Adams can be reached at email@example.com. Follow him on Twitter @Dan_Adams86.