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Some people just can't seem to get high on marijuana. It doesn't matter if they're smoking, vaping, or nibbling. Regardless of the method and despite large doses, they report feeling none of the effects that weed is famous for. For some, it could be user error that keeps them from ingesting enough to feel anything. And frequent users can develop a tolerance and require larger doses. But studies suggest that some peoples' body chemistry could be different enough that it might give them a naturally high tolerance. So high that they may not be able to get, well, high at all. And this research may have more serious implications than missing out on a good buzz.
[♪INTRO] Now it is possible that people who say they don't get high just don't recognize what being high feels like. So we'll have to start by defining what a high actually is. Which is surprisingly tough. Everyone's different, and laws have historically made marijuana difficult to study academically in the US. But studies from 2023 and beyond have finally been able to survey thousands of people about what they feel post-pot. These studies have identified feeling chill, tingly, and thirsty, along with having dry mouth and red eyes as associated with being high.
Subjects also reported feeling happy, grateful, optimistic, confused, dizzy, and paranoid. So kind of a mixed bag. There are more than 500 different compounds in cannabis, so we're still figuring out what they all do and which ones make us feel what. But the two compounds that anyone who's ever walked past a weed shop has probably heard of are CBD and THC. CBD is a compound called cannabidiol that doesn't appear to play a role in actually getting you "high", but it does contribute to a lot of the medicinal qualities of marijuana. There's evidence that it may help treat anxiety, chronic pain, and seizure disorders. But again, human studies into its therapeutic uses have historically been limited for legal reasons.
Like many compounds, CBD interacts with a lot of different systems in the body. It appears to directly affect a handful of different receptors, including ones involved in inflammatory responses, pain-detecting neurons, depression, and anxiety. On the other hand, THC, AKA delta-9-tetrahydrocannabinol, is what causes a high. It can also make people move less, experience less pain, feel colder, and, of course, hungrier. THC is responsible for the munchies. It does all that by binding to receptors in our nervous system called cannabinoid receptors, which are part of the endocannabinoid system. In the understatement of the year: the brain is complicated!
Basically everything has multiple effects, works on multiple systems, and impacts multiple different brain areas. But one of the big things that happens when endocannabinoid receptors are activated is that they send messages to dopamine neurons telling them to fire. Dopamine plays a role in learning and memory, emotion, sleep, temperature control, pain control, inflammation, and hunger, which is part of why the endocannabinoid system affects all those things too. It's called the endocannabinoid system because there are naturally occurring molecules floating around in our brains that bind with these receptors and activate the system.
Those molecules are what's called endogenous. THC is an exogenous cannabinoid. It's an external molecule that just so happens to fit well into those same cannabinoid receptors and trigger them to do all the memory, pain, sleep, hunger stuff that they do. One of the other things that happens when THC hooks up with a cannabinoid receptor is that it causes the brain to produce more of a steroid called pregnenolone. Scientists don't think that pregnenolone has any direct effects on the brain, but it is a precursor to all other steroid hormones, and those do have effects.
However, one thing pregnenolone can do on its own is bind with some types of cannabinoid receptors to block them from binding with other molecules, like, say, THC. So pregnenolone doesn't seem to have a direct effect, but it can keep other molecules from doing their thing. And when THC does bind with receptors, it can stimulate the production of extra pregnenolone, creating a feedback loop where THC binding means fewer sites for THC to bind to. Before we get to how all these variations might affect a high, we need to take a quick ad break. Thanks for watching SciShow and staying curious with us!
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Click the link below or scan the QR code to try Brilliant for free. You can upgrade to Premium to unlock all courses. And right now, SciShow viewers can save 20% off an annual subscription at brilliant.org/scishow. Because everybody's body chemistry is different, we all naturally have different levels of stuff throughout our endocannabinoid system. So based on this, we could make a guess about why some people can't seem to get high. For example, if you're someone who has naturally low levels of the endocannabinoids that usually bind with receptors, then it just might be that ingesting THC would bring you up to a "normal" amount of activated cannabinoid receptors.
And we don't go around feeling high all the time on that normal amount of endocannabinoids, we just feel normal. So it's possible that these people would need a whole lot more THC to feel high than others, because they're starting from behind. Other people may have naturally higher levels of pregnenolone, which could have the effect that their cannabinoid receptors stay occupied more often, so THC molecules can't link up with them. For these people, maybe it doesn't matter how much THC they consume, because there's nowhere for it to go. They just might not be able to get high. It's tough to say anything about the people in this category with confidence, though, because the literature is really biased toward studying weed users.
And people who don't get high probably aren't regular weed users. Plus body chemistry is always surprisingly complicated. So we can't know for sure whether these guesses are right until we study them. We do suspect that these specific body chemistries do more than just keep someone from eating every chip in the house, though. Researchers are investigating whether low levels of endocannabinoids are a factor in conditions like migraines, fibromyalgia, and IBS.
It makes sense… Low levels of other neurotransmitter systems are associated with conditions like depression, Alzheimer's disease, and Parkinson's, so it's plausible that the same could be true for endocannabinoids. And given that the endocannabinoid system is connected to things like pain and inflammation, it also makes sense that deficiencies could be associated with chronic pain and inflammatory disorders. So in the same way selective serotonin reuptake inhibitors or SSRIs can help treat depression, it's possible that drugs based on cannabinoids could help treat migraines. On the pregnenolone side of the equation, people who have naturally high levels of this steroid precursor
could inspire treatments for cannabis use disorder. Researchers have found that giving rats pregnenolone can stop them from displaying the brain and behavioral effects of THC. So scientists have even suggested that pregnenolone could be a treatment for people locked in a cycle of using the drug. But there's still debate around that. Some scientists hypothesize that since cannabinoid receptors regulate dopamine, any medication that blocks those receptors would also impact dopamine levels. And long-term lowering of dopamine levels would probably not be good for people's reward systems and mood. In fact, a previous drug that blocked endocannabinoid receptors ended up being pulled from the market because it was causing suicidal ideation.
But other researchers argue that while pregnenolone does interfere with some functions of endocannabinoid receptors, other aspects of signaling, including those involved with dopamine levels, aren't impacted, so it's less of a concern. There's clearly a lot more research to be done to figure out these molecules and how we can use their effects to our advantage. Cannabis and its components are already being used for an increasing number of therapeutic purposes. So structured studies about the ways they work in the brain and interact with other systems is critical to figuring out the possible
conditions they can treat with as few side effects as possible. Let's just hope the researchers studying these questions remember to add "snacks" to the study's budget. [♪OUTRO]
