Mode of ingestion, then, is a big consideration in the cannabis experience. But so too are factors beyond your control. “We're pretty aware that the endocannabinoid system is not a static picture throughout the day,” says Raber. “Why it changes, what causes those changes—those are other levels of complicated questions.” Cannabis might hit you differently during the day than at night, and can also depend on your mood or whether you’ve eaten.
You may have noticed that cannabis’ effects can differ wildly from experience to experience. Eat a weed brownie, for instance, and the THC goes straight to your liver, where it’s metabolized into 11-hydroxy-THC. That metabolite “has five times the activity at the CB1 receptor, the psychoactive one, as THC itself,” says Jeff Raber, CEO of the Werc Shop, a cannabis lab in California.
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It all comes back to the psychoactive CB1 receptor. THC is an agonist that fits nicely into CB1, activating it. “CBD can't do that at the CB1, but it does sort of sit in the pocket,” says Wilson-Poe. “It can compete with THC for the spot in the receptor.” Which means that if you take CBD with THC, there may be fewer receptors available for the THC to activate, thus modulating the psychoactive effects, like paranoia.
But the problem with researching a schedule I drug is that the government doesn’t want you to do it. Yet as more states go legal, cannabis continues to climb out of the scientific dark ages. Because it’s not just about giving people a comfortable high, but about developing cannabis into drugs that could treat a massive range of ills.
At the top of the list of mysteries is how a galaxy of compounds in the plant combine to produce a galaxy of medical (and, of course, recreational) effects. For example, THC feels different when combined it with cannabidiol, or CBD, another naturally occurring compound in cannabis, but the reasons aren’t fully known. It’s called the entourage effect: THC, like a rock star, only reaches its full potential when it rolls with a crew, consisting of hundreds of other compounds in the plant that scientists know about so far.
“But that's probably not the whole story,” Wilson-Poe says, “because CBD has at least 14 distinct mechanisms of action in the central nervous system. So it does a little bit of something at a whole bunch of places, and we probably can't attribute the anti-paranoia or anti-anxiety effects just to CB1 occupancy.”
Decades of ignoring CBD came with some consequences. Cannabis cultivars without any CBD are missing one of the powerful healing properties of the plant.
In cancer research, combining THC and CBD has produced more successful results in preclinical research than either cannabinoid alone in some forms of cancer. In glioblastoma, a type of brain cancer, adding CBD to a high-THC treatment enhanced the anti-proliferative effects of THC in cell cultures. In breast cancer, CBD was more effective in animal models.
Why you should add a little THC to your CBD
However, with all the hype around CBD, it’s important not to forget about its close relative, THC. In fact, there is reason to believe that, for some conditions, CBD may be most beneficial when consumed with a little THC.
Far more research is needed to identify when these cannabinoids are best to use in tandem and when it would be better to keep them separate.
The benefits of whole plant medicine
Unfortunately, this means that many other cannabis compounds, like cannabidiol (CBD), have been phased out over time. In fact, an analysis of 600 cannabis samples reported in 2015 found that as percentages of THC increased over time, levels of CBD decreased.