Marijuana has been considered medicinal for almost as long as it’s been smoked—which is quite a long time. But the pharmacology behind it—the active compounds, how they work—has only been established since the last century, and like many things to do with the human body, each question answered about how it works has opened up ten more.
<p style="text-align: left;">We know a lot more about marijuana now than we did in the past. We understand the pharmacology, and the chemistry behind how it works its magic. The primary active compound of marijuana is THC, more specifically delta-9 tetrahydrocannabinol. In lay terms, it’s what gets you high and gives you the munchies. Medically, it’s interesting as a nausea suppressant and appetite stimulant; while a purified form is available for cancer patients, its usefulness is limited by the unpleasant side effects of THC at high doses. The other active compound, CBD (cannabidiol) is the one that makes you sleepy and mellow. This is the compound at the heart of most of the research being done on marijuana today. Its effects on the body at various doses are enormously varied and the research is only now beginning to scratch the surface about quantifying what it can and can’t do, and separating fact from fiction.</p>
Where there’s smoke, there’s fire, as the saying goes, and with marijuana it can be hard to separate what’s fact from what’s just smoke being blown. A lot of the studies that are cited are too small-scale to be meaningful, and there is too much variability in the supply—to say nothing of the discrepancies with labeling—to draw any meaningful conclusions about whether smoking a joint will help you, specifically, with your problem. Nevertheless, the data that is available supports the use of medical marijuana for spasticity and chronic, neuropathic pain.

<strong>What is Pain?</strong>

At the heart of it, the question “What is pain?” seems a bit ridiculous. We all know what pain is: it’s a way of letting the body know that there is something wrong. It is mostly unpleasant, and, well, painful.

But how the body registers pain is a lot more complicated than just “ow!” The nerves in the body are broadly divided into two types: sensory neurons, which carry signals to the brain, and motor neurons, which carry commands from the brain. Of the sensory neurons, a special subtype called nociceptors are dedicated to sensing painful things. The pain signal travels up the nerve to the dorsal root ganglion (DRG), where the neuron makes the decision whether to send it through to the brain.

It turns out that not only are special nerves dedicated to sensing pain, there are special receptors for different kinds of painful inputs. Mechanoceptors trigger a pain sensation when, for instance, you prick yourself with a pin; chemoceptors alert your brain that you’ve just eaten chili peppers; thermoceptors get activated when you touch something that’s too hot or too cold. THC and CBD interact with cannabinoid receptors, of which there are two main types in the body: CB1 and CB2. CB1 receptors are found primarily in the nervous system, while CB2 receptors are believed to be present on immune cells and some nerves; due to the difficulty in finding CB2 and proving its presence it is not entirely certain what the function of CB2 is. But using cannabinoids, whether it’s smoking a joint or taking an extract like Sativex, doesn’t really do much for the kind of pain you get when you stub your toe. And the reason why seems to have something to do with what happens after the the THC hits the receptor. There is substantial proof that cannabinoids are involved in long-term functions such as neuronal plasticity and remodeling, so the effects wouldn’t be seen right away.

Closer to the spinal cord lies the dorsal root ganglion, or DRG. Anatomically, the DRG is a little bulge in the nerve as it enters the spinal cord—this is where the sensory nerve cell bodies are concentrated. The DRG is not just a through point for these sensory signals—a surprising amount of neural processing happens here, too. When you touch a hot stove and find your hand jerking back before you’ve realized it’s hot, it’s because the DRG has registered the hot stove and sent a relay directly to the motor neurons controlling your arm—the signal to your arm, having less of a distance to travel, reaches your arm before the sensation of pain hits your brain. Additionally, different sensory inputs from different parts of the body meet in one DRG, so pain that’s actually coming from one area can feel like it’s coming from another. The sensory inputs from internal organs are notorious for this. This is why some people who are having heart attacks feel the pain in their shoulder or jaw.

<strong>Neuropathic pain</strong>

Acute, bodily pain is relatively straightforward and reasonably well-understood. But a different kind of pain, called neuropathic pain, has been baffling pain scientists, doctors, and long-suffering patients since the dawn of mankind.

The primary causes of neuropathic pain are nerve injury: spinal cord injury, diabetes (the increase in blood glucose damages the nerves), and <em>varicella zoster </em>(when chicken pox becomes shingles). Severe cases of alcoholism can also lead to nerve damage, and the immune system can also have a role in either causing the injury, or maintaining an inflammatory state that leads to nerve damage. But regardless of the cause of the injury, the end result is the same: pain that is chronic, often unrelenting, and difficult if not impossible to treat. It can also be accompanied by allodynia, where normal sensations become painful, and hyperalgesia, where minor injuries cause a disproportionate amount of pain.

In other words, something happens that changes the way neurons process pain sensations. What that is, exactly, is still up for debate. Neuromas—tangled messes of nerve fibers that form after a nerve is damaged, as part of the healing process—are known culprits for producing the unwanted sensations, but (in rats) signs of neuropathic pain persist even after the nerve is completely severed. Some studies suggest that other nearby nerves become hypersensitive when a fiber gets damaged. There is also evidence that changes in the spinal cord can occur to enhance the pain signal that reaches the brain. The compounds in marijuana might be involved in preventing this remodeling from happening, or at least mediating it.

It is likely that more than one mechanism contributes to cases of neuropathic pain. On a molecular level, scientists have just shown that stress to the endoplasmic reticulum is involved in neuropathic pain: blocking the enzyme that degrades certain bioactive lipids (such as endocannabinoids, the body’s natural feel-good chemical) can reverse the pain. As endocannabinoids and marijuana are both lipid-like and capable of interacting with the same kind of receptors, it’s not too much of a stretch to assume that the compounds in marijuana can also prevent stress to the ER and mediate neuropathic pain, though the study did not specifically address marijuana. The compounds in marijuana, as well as a few synthetic compounds have been shown to quiet nerve firing as well, lessening the overall amount of pain that someone experiences. It is not entirely clear how THC and CBD work, but the evidence is mounting that they do. More importantly, that they do so without the risks of death and addiction that hamper the use of more conventional narcotics.

Traditionally, neuropathic pain has been treated most successfully with tricyclic antidepressants, followed by narcotics. Tricyclics may be effective against the pain but they are not without a fair amount of risk and unpleasant side effects, including elevated blood pressure and cardiac toxicity. Opiates, such as Oxycontin and morphine, are considered secondary drugs owing to the risk of overdose and addiction when treating neuropathic pain cases. One surprising benefit seen in states with legalized marijuana was that the number of deaths due to prescription narcotic overdoses dropped dramatically, by as much as 30%. One can only surmise that patients prefer getting high to risking an overdose. And indeed, with relatively few side effects and comparatively little risk, it is easy to see why smoking a joint would be preferable to taking a medication that is famous for its lethality and addictiveness.

To date several papers have shown that marijuana and compounds derived from marijuana can be used to relieve neuropathic pain. Sativex, an oral spray that is approved for pain and spasticity in Europe and is currently in the middle of getting approval from the FDA, has been used successfully, albeit in a limited number of cases.

It’s clear that marijuana and the compounds derived from it are medically useful for neuropathic pain, but the risks involved make it very much a <em>caveat emptor</em> treatment. Not only is it still illegal in many places, but the THC content is often under-estimated (assuming that it’s even known at all) and as a natural product, inconsistencies in the supply are a given. Nevertheless, with the decreasing social stigma and the increase in awareness for what it can and cannot do, it is likely that more and more patients will make use of it in the future, and it behooves doctors to be aware of this when managing paint patients, and patients to mention marijuana usage to their doctors.

References

<a href="http://time.com/3931863/medical-marijuana-benefits/">Time</a> summary of JAMA

<a href="http://time.com/3931863/medical-marijuana-benefits/">http://time.com/3931863/medical-marijuana-benefits/</a>

<a href="http://jama.jamanetwork.com/article.aspx?articleid=2338266">Link</a> to Hill’s paper

<a href="http://jama.jamanetwork.com/article.aspx?articleid=2338266">http://jama.jamanetwork.com/article.aspx?articleid=2338266</a>

<a href="http://jama.jamanetwork.com/article.aspx?articleid=2338266">Causes</a> of neuropathic pain

<a href="https://en.wikipedia.org/wiki/Neuropathic_pain">https://en.wikipedia.org/wiki/Neuropathic_pain</a>

Neuroapthic pain primer

<a href="http://cell.uchc.edu/pdf/fein/nociceptors_fein_2012.pdf">http://cell.uchc.edu/pdf/fein/nociceptors_fein_2012.pdf</a>

<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810425/pdf/nihms17723.pdf">Cannabinoid</a> receptors and what they do

<a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2826.2008.01671.x/epdf">http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2826.2008.01671.x/epdf</a>

<a href="http://cell.uchc.edu/pdf/fein/nociceptors_fein_2012.pdf">Cannanbinoid</a> receptors and pain

<a href="http://onlinelibrary.wiley.com/doi/10.1002/wmts.83/pdf">http://onlinelibrary.wiley.com/doi/10.1002/wmts.83/pdf</a>

<a href="http://cell.uchc.edu/pdf/fein/nociceptors_fein_2012.pdf">Mechanisms</a> of neuropathic pain paper

<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810425/pdf/nihms17723.pdf">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810425/pdf/nihms17723.pdf</a>

Endoplasmic reticulum stress and neuropathic pain

<a href="http://www.sciencedaily.com/releases/2015/07/150707093353.htm">http://www.sciencedaily.com/releases/2015/07/150707093353.htm</a>

Papers for neuropathic pain

<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950205/">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950205/</a>

<a href="http://files.iowamedicalmarijuana.org/science/pain/Wilsey%20Cannabis%20Cigarettes%20in%20Neuropathic%20Pain%20J%20Pain%202008.pdf">http://files.iowamedicalmarijuana.org/science/pain/Wilsey Cannabis Cigarettes in Neuropathic Pain J Pain 2008.pdf</a>

Protocol for handling neuropathic pain

<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844007/">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844007/</a>

<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844007/">Paper</a> showing reduced opiate mortality

<a href="http://archinte.jamanetwork.com/article.aspx?articleid=1898872">http://archinte.jamanetwork.com/article.aspx?articleid=1898872</a>