The Pharmacology of Marijuana

When writing about drugs and how they are used, certain things are taken for granted: an understanding that drugs have an effect, that this effect leads to tolerance, that tolerance leads to addiction, and therefore drugs are bad. But how drugs exert their effects is rarely explored in-depth, and this leaves a huge knowledge gap between the scientists that are working to understand marijuana and the people who wonder why such an effective plant needs to be studied at all. This is an effort to at least partially redress that. It is not an extensive overview of pharmacology, just an overview of the basics. Links to additional resources will be included at the end.

Getting in, getting out

Pharmacokinetics deals with the movement of drugs into, within, and out of the body. How a drug gets into the body can have a major effect on how much of an effect you feel, how long the effects last, and how quickly you recover. Drugs that are ingested, for example, tend to have longer-lasting but less intense effects than drugs that are inhaled. Drugs can also be absorbed through the skin, or injected directly into the bloodstream. But once they are inside, all drugs will, at some point, be processed and cleared by the liver and kidneys.

The rates at which these processes occur can vary somewhat between individuals, but by and large these are purely chemical processes. The differences come down to physical factors, such as body fat content—since fat absorbs some chemicals but not others—size and weight, the amount of drug that was ingested, whether the drug is more soluble in fat, or whether it can be bound by blood proteins, etc. But the basic premise is that all humans, barring a genetic anomaly, operate under the same basic rules of physiology.

Once a drug is inside, though…

Pharmacodynamics

Pharmacodynamics deals with how drugs exert their effects, and while it may start with a question such as “How does this make you feel?” we are rapidly closing in on the exact interactions between different drugs and different receptors, and everything that happens afterwards. It’s common knowledge that not everybody is affected by cannabis in the same way; that the same person may even experience cannabis differently if he eats it as opposed to smoking it. But why is this, if marijuana only interacts with CB1 and CB2 receptors?

Yes, that’s right: of the almost-500-active compounds found in marijuana, most of the effects can be directly linked to the cannabinoid receptors (CB1 and CB2), or which there are only two types in the body. And drugs can’t interact with the body unless they are bound to a receptor, first (there are a few exceptions, such as alcohol and cyanide, which are small enough to pass through the cell membranes). CB1 is found all over the body, but it’s most highly-concentrated in nervous tissue. CB2 is found primarily in immune cells—and there’s still a substantial amount of confusion as to what role it plays there.

Making matters even more confusing is that different compounds can elicit different reactions from the same receptor: a drug can either be an agonist (as THC is for CB1), activating a certain signaling pathway that ultimately results in the user getting high; or an antagonist (Rimonabant), which prevents any signaling from happening. There is also what is known as inverse agonism, where a compound activates a signaling pathway that has the exact opposite effects of an agonist; rather than merely keeping it “off” as an antagonist does, it actively prevents the receptor from turning “on”. It is believed, although it has yet to be proven, that CBD, the other major active compound in marijuana, acts in this way. Furthermore, hormones appear to have a major role in how much of an effect the compounds can have.

So the effects of smoking a joint not only come down to the relative percentages of THC and CBD in the plant, but also how it is delivered, whether you are a man or a woman, and the balance of agonist and reverse-agonist effects in the individual cells—and the interactions with other neural pathways that may or may not be activated at the same time. It is no wonder that the claims of marijuana’s medical usefulness are so varied, and no wonder that it is taking so long to sift through them.

Beyond THC and CBD

Given the shortcomings of plant-based medicine—the inconsistency of the product from batch to batch, plant to plant—it’s should come as no surprise that pharmaceutical companies are looking for alternatives to THC. Many compounds have been created in the lab that are CB1 and CB2 agonists or antagonists, but so far only rimonabant has made it to market—for a grand total of two years before it was withdrawn over concerns for the patients’ psychiatric health. Rimonabant was intended to be an anti-obesity drug, as its main effect was curbing appetite, but it was never approved for use by the FDA, and only saw limited utility in Europe.

Part of the issue is with the basic biology of the endocannabinoid system itself. Unlike, say, cocaine, where the reward center that get acitivated are well-defined, the endocannabinoid system is global, and frequently interacts with other neurotransmitter systems. People with a particular variance in their serotinergic system, for instance, may be more prone to anxiety when they are given a CB1 antagonist. There is also some evidence that suggest that rimonabant could be used to curb nicotine addiction.

But what if you could design a drug that could interact with CB1 or CB2 receptors in the body, but leave the brain alone? This is not as far-fetched as it sounds; the blood-brain barrier is very effective about limiting the passage of substances to the brain. And indeed, some companies are currently trying to do just that.

Moreover—over the past decade, evidence for CB2 receptor pathways in the brain has been accumulating. Binding experiments—where radioactive tracers are used to locate receptors—and immunohistological studies have been inconclusive to date, but the signaling data is highly suggestive, indicating that CB2 receptors may pay a bigger role in cannabinoid signaling that previously believed, and that opens up far more questions about neuronal modulation and how it occurs.

The Real Deal

You might think that these new compounds could one day render marijuana, and the dispensaries, unnecessary, that without the medical pretext there is no longer any reason to buy the plant. But purer is not always better, and it wouldn’t be too difficult to argue that the trace amounts of other compounds present in the whole plant makes the experience what it is. And what if the safety profile of the pills, pure as they may be, includes a limit at which one can overdose? It’s hard to do that with marijuana, no matter what form it’s in. Recreational marijuana is still safer than alcohol and just about every other drug, legal or not, out there. In states where it has been legalized, marijuana literally saves lives as people do not overdose on prescription narcotics as frequently. And it has been demonstrated to be effective against pain and spasticity. Whether it helps veterans cope with PTSD remains to be seen, but even if it’s shown not to, and the placebo effect is what’s driving the relief, is it really ethical not to allow it?

But all this is moot if you can’t get marijuana to begin with. And while most states have made some attempt to decriminalize marijuana, it is only readily available in about half the country. Decriminalizing marijuana will have a far more beneficial effect on society than all of the medicinal effects it may have, though. Yes, there are dangers. We need to acknowledge that a sizeable minority of people can and do become addicted to it, and all of the ensuing complications that follow thereafter. We can’t wish away the increase in calls to the Poison Control center for children that have accidentally eaten mom’s and dad’s pot brownies. Nothing in life is purely good or purely bad, and it’s about time that we recognize that things can get complicated.