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Cannabis Science: State of the Research

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The passage of marijuana ballot measures in three states a few weeks ago signifies more than just Michigan residents getting to enjoy a non-criminal joint for recreational purposes and residents in Utah and Missouri being allowed legal access to medicinal marijuana. Perhaps the most significant thing about these states easing up the restrictions on cannabis is that it’s another chip of progress in the effort to decriminalize the wonder-plant nationwide. Federal decriminalization would open the floodgates of new research into potential uses for cannabis and cannabinoids, the active compounds found within the plant. Already the state-by-state legalization train has created opportunities for research that have led to some fascinating and exciting discoveries.

Any scientist worth her salt will tell you that good research always leaves further questions in the wake of its conclusions. One of the most fascinating aspects of cannabis research that is creating some very good questions is the discovery that cannabinoids act on each other to create specific outcomes. For example, THC, the psychoactive cannabinoid responsible for the “high” users feel, affects the body differently depending on the levels of cannabidiol (CBD) and other cannabinoids that are present. In fact, they’ve recently found that THC only reaches its full potential when other cannabinoids are present. They’ve dubbed this the “entourage effect.” That the interaction between these and other cannabinoids is critical to the effect on the user is apparent, but researchers have only just begun to study how these compounds interact with one another.

Research up to this point has been hindered by cannabis’ classification as a schedule 1 narcotic by the federal government. The steady wave of states voting in favor of legalization is helping to change attitudes, however, and the likelihood of federal rescheduling is higher than ever before. At the forefront of the legalization movement is the potential for medical advances from cannabinoids. In fact, earlier this year, the FDA approved Epidiolex, the first CBD-derived drug to gain such approval, for the treatment of certain types of childhood epilepsy.

So now let’s get into the basics of cannabis science a bit. The whole reason that THC, CBD, and all of the other cannabinoid crew have an effect on us is a neuroreceptor system called the endocannabinoid system. The specific receptors involved are the CB1 and CB2 receptors, which were only discovered by researchers in the 1990’s; so there’s still a lot to learn about this system, but it does seem to affect things like mood and immunity.

The way that the cannabinoids are delivered to these receptors can have a huge effect on the overall experience. For example, if ingested, THC’s first stop is in the liver, where it metabolizes and turns into a new molecule, 11-hydroxy-THC. When that specific metabolite hits the psychoactive CB1 receptor, it is five times more active than THC alone, according to Jeff Raber, CEO of Werc Shop, a California cannabis lab.

That’s one reason so many people tend to overdo it a bit on edibles. When THC is smoked, it is absorbed by the bloodstream without going through the liver and is five times less active, and therefore five times less potent than the metabolized 11-hydroxy-THC that comes from the liver. So as an example, one 10mg dose of edible THC should be as potent as smoking 50mg.

The way the cannabinoids are introduced to the system is just one example of a variable that researchers are eager to understand. Because the endocannabinoid system is not a static system, many factors can affect user experience, Raber says, including time of day, mood, and whether or not one has eaten.

Add into that mix of variables the fact that THC works differently depending on the levels of other cannabinoids hitting the receptors, and it’s easy to see why research in this field is so enticing and so complicated. Take the relationship between THC and CBD. In anecdotal terms, it’s long been believed that CBD can moderate the paranoia and anxiety associated with too much THC. Now that CBD is seen as a legitimate medication by the FDA, researchers are beginning to understand how the relationship between it and THC works.

Aside from anecdotal evidence of brownies containing pure THC distillate being anxiety producing, there is also the case of Marinol, which is a synthetic form of THC used to stimulate appetite. It’s very good at its intended purpose, but it also carries psychoactive and anxiety-producing side-effects. Stimulating the CB1 receptor with Marinol alone has extreme intoxicating effects that are not tolerated well by patients, according to Adie Wilson-Poe of Washington University in St. Louis.

Wilson-Poe says that a drug like Sativex, on the other hand, which is made with both CBD and THC, is tolerated much better by patients, as is pure flower extract. Specifically, the anxiety, heart-rate increase, and paranoia associated with pure THC are mitigated, the researcher said. Again, it has to do with the CB1 receptor, which is the psychoactive one. If you give it THC, it fits perfectly into that receptor, which is what activates the high. But even though CBD only sort of fits into those receptors, it still competes with THC, leaving fewer receptors for the THC to attach to and activate. This means less anxiety, paranoia, and other adverse effects.

According to Wilson-Poe, the list of variables and ways that CBD interacts with the nervous system is so complicated that we can’t attribute these anti-anxiety properties to it alone. CBD and THC are also not the only cannabinoids with potential medicinal properties. Wilson Poe says that a vaporized flower, for instance, can have up to two dozen different anti-inflammatory molecules. So the “entourage effect,” of THC may be a bit of a misnomer, as some researchers who prefer the term “ensemble effect” instead suggest. They argue that “entourage” makes it sound like THC is the most important cannabinoid, but that in reality, all of the cannabinoids play an important part in the overall effect of cannabis use.

There are also, however, times when THC alone works better than an ensemble cast. In the case of glaucoma treatment, for example, CBD can hinder THC from relieving pressure on the eyes, making the treatment less effective. CBD can have some helpful effects for treating the eye condition, but it does not help THC do its job in this case.

Keep in mind also that we’ve mostly been talking about the CB1 receptor here. There are a lot of other types of receptors in the endocannabinoid system that are interacting with these cannabinoids in ways that we are not close to understanding yet.

It seems, then, that the future of medical cannabis use will be to understanding the ensemble effect. Researchers will be working toward figuring out in which cases the combination of cannabinoids is better than the application of one alone.

The last piece of the puzzle is the one in which anecdotal evidence claims a different user experience based on the different strain of cannabis consumed. Because most North American strains are very high THC and low to zero CBD, the only real explanation for the difference in effect between strains is terpenoids.

Like THC and CBD, these terpenes are a member of our ensemble cast. Terpenes are found in all plants. They are used to protect the plant from insects, and in the case of some plants, like cannabis, pine, and lemon, they have a characteristic smell. They also interact pharmacologically with the brain, and in some cases, that effect is already known. Linalool, for example, is known to have anti-anxiety and sedative properties. It’s reasonable to assume, then, that when you combine it with CBD, those effects would be enhanced.

This new frontier of science is bursting with questions and new avenues for discovery. The interaction of cannabinoids and the different combinations that are possible could be perfected in the very near future to provide new, more effective treatments for everything from inflammation to cancer. Public opinion and shifting attitudes among legislators is creating new opportunities for research, and investment in the cannabis industry continues to grow. The future is bright for cannabis, and it only remains to be seen where the potential of this latest cash crop can lead us.

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