By Cannabis Training University (Own work) [CC BY-SA 3.0
Source: By Cannabis Training University (Own work) [CC BY-SA 3.0

I have several requests from patients every week for information about using cannabis for various disorders, such as chronic pain, but most often for insomnia. I have been surprised by the number of patients who are already using cannabis for insomnia, either through the state sponsored medical marijuana program or through the illicit market that still exists. Connecticut state law does not provide for the prescription of medical marijuana for insomnia. It is a frequent symptom of disorders such as PTSD and chronic pain and is a major reason why patients are using the program. The medical marijuana program has grown significantly in Connecticut and nationally the legal marijuana business has been growing at a very rapid clip.

Understanding more about this extremely complex plant and its chemical constituents can help illuminate its potential for treating insomnia. In this post, I am going to explore some aspects of the pharmacology of marijuana in order to lay the foundation for considering its potential role in the treatment of insomnia.

Cannabis is a plant that has been used by humans for thousands of years. It was probably one of the first plants to be domesticated as a part of the agricultural revolution that began about 10,000 years ago during the Neolithic period. Evidence has long existed that it has been used for fiber, food, and for its psychoactive properties for at least 6,500 years (Fleming & Clarke, 1998). Humans found ways of cultivating plants and taming animals that were useful so that human populations were able to set up permanent settlements and no longer needed to move constantly in search of food and shelter as they had in hunter gatherer societies. Grains such as wheat and barley provided steady food sources and cannabis served as a plant source of fiber, food, and medicine. Domesticated animals such as cattle and goats provided a high protein food source. Dogs and cats were domesticated (in the case of cats, perhaps it is best to say “semi-domesticated”) for their value to human societies. The excellent hunting skills of cats helped protect grain stores from consumption by rodents.

In recent history, cannabis that is cultivated primarily for its fiber content is known as hemp, and when cultivated to maximize its psychoactive properties, as marijuana. As an agricultural crop hemp has many uses. Its fiber can be used to make twine, rope, and canvas. It has been said that the world was explored on hemp as the sails of the ships that crossed from Europe to all parts of the planet from the 1400s on were made of it (e.g., Deitch, 2003, p 8 - 9). Modern uses for hemp include animal feed such as bird seed as well as seed sprouts and hemp milk for human consumption, oils for cosmetics and soaps, oils for biodiesel fuels and biomass for bioethanol, fibers for use in the manufacture of plastics and building materials, and so on.

As a drug, marijuana has been used for thousands of years both for its medicinal and psychoactive qualities. Historically it was used for pain control, and is currently being explored for use in the treatment and control of epileptic seizures, anorexia in patients with cancer and wasting diseases, management of inflammatory diseases such as Crohn’s, and for control of pain in disorders such as complex regional pain syndrome. Psychotherapeutically it is being investigated for use in management of disorders such as PTSD.

A number of concerns exist about the potential risk of using cannabis for medical or psychological purposes. Regular use can lead to a form of dependency (American Psychiatric Association, 2013) and there is some evidence that it may increase the risk of the onset of psychosis in vulnerable individuals (Fergusson, Poulton, Smith, & Boden, 2006). It is capable of inducing significant anxiety and panic in even regular users (Zvolensky, Cougle, Johnson, Bonn-Miller, & Bernstein, A., 2010). Concern has been raised that it could increase cardiac risk in some individuals (Franz, & Frishman, 2016). When considered against other legal and illegal substances currently used in our society, however, it has an extremely high safety margin (Lachenmeier, & Rehm, 2015). There is no known lethal dose for humans and most people will recover rapidly from the anxiety and panic that it can cause.

It is important to note that marijuana is an extremely complex and variable plant material and is thus not comparable to a pharmaceutical drug. Even with pure strains and constant growing conditions there will be batch to batch variability in the nature of the plant material produced. The slightest differences in growing environment from one crop to the next can cause significant differences in the amounts of the various phytochemicals present and the ratios of them. Slight differences in the chemical makeup of each crop could alter the potency and effect of the final product.

Modern growing techniques employed by the legal cannabis industry are intended to minimize these differences so that patients and consumers can count on a relatively consistent product. This is, however, different from a pharmaceutical substance that is manufactured to a high degree of precision from one run to the next. It is more like the situation faced by consumers of wine and single malt scotch. Despite the efforts of the vineyards, brewers, and distillers to create a consistent expression of the beverage, there will always be differences from one batch to another.  For example, it is well known that there is considerable variability in each bottling of single malt scotch. A bottle produced in one year may be quite different from that produced in another year despite the best efforts to maintain a consistent presentation. Variations in growing conditions produced by year to year variability in weather, the type of barley used, the strain of yeast used, the quality of water used, the nature of the barrels that the distillery was able to obtain, and the storage conditions in various warehouses will all affect the final product. Any natural product produced to date will have this variable nature. In contrast to a natural product, we do not expect our pharmaceutical drugs to vary in strength or quality from one batch run to the next. Conditions for making a pharmaceutical drug can be much more rigorously managed and the product itself is much less complex than a plant.

Two major constituents of cannabis give rise to its known medicinal and psychological effects. These are THC (tetrahydrocannabinol) and CBD (cannabidiol) and are two of over one hundred unique chemicals isolated to date from the cannabis plant and are known as cannabinoids. THC is the psychoactive component with some reputed medicinal qualities and CBD is non-psychoactive and may provide medicinal benefits by having anti-inflammatory and other qualities. Interestingly, these two are not present in significant quantities in raw plant material. THCA (tetrahydrocannabinolic acid) and CBDA (cannabidiolic acid), both of which are derived from the precursor chemical cannabigerolic acid (CBGA), are present in the fresh plant. They are produced by the plant, possibly because of some kind of defensive property such as being unpalatable to insects.  Heating THCA and CBDA to the proper temperature results in decarboxylation causing them to be converted into THC and CBD respectively. Some of this occurs during the curing or drying process. Most is accomplished during cooking or smoking of the plant material. Indeed, most of the THCA present in the raw plant material is converted to THC during the process of smoking. Eating a raw salad of marijuana leaves would therefore cause little in the way of psychoactive effects.

THC and CBD have the effects that they do because they are very similar to regulatory chemicals already present in the body in the endocannabinoid system.  This system is found in the brains of mammals, including humans (Acharya et al, 2017). Cannabinoid receptors appear to be evolutionarily very old and have been found to be important components of the systems that maintain homeostatic balance in the body. Homeostasis is the maintenance of an optimal biochemical balance. When disturbed, homeostatic systems work to restore that balance. For example, if you become dehydrated, the nervous system will detect this and a sensation of thirst will be experienced. This leads to seeking and consuming water that will in turn restore the proper hydration level.

The endocannabinoid system regulates homeostasis by allowing downstream cells to have some control over the input to them. This occurs through a process known as retrograde neurotransmission (Stahl, 2013). In addition to the endocannabinoids, a number of other retrograde signaling molecules have been discovered such as NO (nitric oxide) and NGF (nerve growth factor). This type of neurotransmission is different from the classical downstream signaling we learned about in high school or college biology. Several endocannabinoids (naturally occurring chemicals that bear a strong resemblance to the chemicals produced by the cannabis plant) have been found including anandamide and 2-AG (Purves et al, 2012). The endogenous cannabinoids are produced from materials in the nerve cell membrane and are fatty acids. They exert their effects through interaction with the CB1 (found in the central nervous system) and CB2 (mostly found in the immune system) receptors. THC has its effects because of its close chemical similarity to anandamide. THC is, however, a more robust molecule and so persists longer in its interaction with the CB1 receptors and thus has a more powerful and long lasting effect than anandamide.

The endocannabinoid system is extensively distributed throughout the brain. Of the G-protein-coupled receptors in the brain, CB1 is one of the most common (Alger, 2013).  These receptors are found in the neocortex, hippocampus, basal ganglia, amygdala, striatum, cerebellum, and hypothalamus of the brain (Alger, 2013). They are involved in numerous self-regulatory activities and impact sleep, the experience of pleasure, and food seeking. They seem to exert neuroprotective effects through regulation of upstream input to downstream cells. Their widespread distribution most likely accounts for the remarkably variable effects of THC. Of note, despite being so widely distributed in the brain and being involved in so many important physiological and psychological processes, they are not involved with basic life support systems such as respiratory control. This accounts for the lack of a known lethal dose and is very different from other common drugs like alcohol and the opiates that at certain doses become extremely dangerous by suppressing respiration or the gag reflex.

A number of synthetic cannabinoid derivatives such as WIN 55,212.2 and rimonabant have been developed for research and pharmaceutical purposes (Purves, 2012). The number of synthetic cannabinoids has grown over time with many being developed by grey market producers for sale as “synthetic marijuana”. The pharmaceutical industry is working to take advantage of the potential medicinal value of the cannabinoids and has developed a number of drugs including dronabinol (synthetic THC) as well as extracts derived from the plant, such as Sativex (containing natural THC and CBD). The Multidisciplinary Association for Psychedelic Studies (MAPS), a private, nonprofit research organization, is actively pursuing research to see if botanical marijuana can be used as a prescription medicine. In order to do this, they will need to overcome some of the problems noted above with regard to a plant material being quite different from the typical pharmaceutical drug, which has much greater consistency across batches.

The “entourage effect” has been described (Russo, 2011) and may significantly affect any medicinal or psychotherapeutic effects of cannabis. That is, the THC in cannabis will have its effect moderated and modified by other chemicals in the plant preparation. As the balance of these chemicals varies so will the effects. In addition to the cannabinoids in cannabis, there are other chemical classes including the terpenes, which are the flavor chemicals that are prized by consumers of cannabis. Consumers of cannabis think of the terpenes as being the major contributors to the smell and taste of marijuana and yet they may also affect the medicinal properties of the plant. A related example of the entourage effect that has been investigated by scientists is in the difference between taking vitamins in a pill versus absorbing them from food. The nutritional value to the body of vitamins absorbed in relatively pure form may be quite different from that of absorbing them from whole foods where the entire evolutionarily produced complex of chemicals in the food is available. It seems likely that pure sources of vitamins may be processed by and have potentially less value to our bodies than the complex sources found in food. In a similar vein, it appears that many patients find the effects of whole marijuana superior to the effects of dronabinol (synthetic THC), even though the primary active chemicals are nearly the same.

A number of issues with regard to the use of cannabis as a treatment for insomnia emerge from the above considerations. The first is that, while marijuana is not like a pharmaceutical drug, it will be most reliable and effective if grown under controlled conditions so that a relatively consistent product is available to users. This is clearly a situation in which an unregulated illicit product will be unable to compete with a professionally grown and properly regulated legal material. When depending on a medication for help, the patient does not want to have to wonder what the effect of this or that batch will be. Second, the effects of cannabis are dependent on the interaction of cannabinoids with other chemicals in the plant and with the remarkably complex endocannabinoid system within the brain. This means cannabis will have many effects besides helping a patient relax into sleep. Will this be of little concern to patients, will it enhance the sleep inducing effect, or will it render the effect useless? Third, although there has been a recent explosion of new findings about cannabis, it continues to be a difficult drug to research, in no small part because the government strictly limits research and pharmaceutical companies have a difficult time finding ways to make money off a product that can be grown in almost anyone’s home. Do we, nevertheless, have enough data to address concerns about safety and effectiveness? These are issues I will address further in the next several posts.

Resources:

Acharya, N., Penukonda, S., Shcheglova, T., Hagymasi, A. T., Basu, S., & Srivastava, P. K. (2017). Endocannabinoid system acts as a regulator of immune homeostasis in the gut. PNAS, May 9, 2017, 114 (19), 5005–5010.

Alger, B. E. (2013). Getting high on the endocannabinoid system. Cerebrum: The Dana Forum on Brain Science, 2013, 14.

American Psychiatric Association, (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association.

Deitch, R. (2003). Hemp: American History Revisited. New York: Algora Publishing.

Fergusson, D. M., Poulton, R., Smith, P. F., & Boden, J. M. (2006). Cannabis and psychosis. BMJ : British Medical Journal, 332(7534), 172–175.

Fleming, M. P. and R. C. Clarke 1998. Physical evidence for the antiquity of Cannabis sativa L. (Cannabaceae). Journal of the International Hemp Association, 5(2), 80-92.

Franz, C.A. & Frishman, W.H. (2016). Marijuana use and cardiovascular disease. Cardiology in Review, Jul-Aug; 24(4), 158-62. doi: 10.1097/CRD.0000000000000103.

Holland, J. (Ed.), (2010). The Pot Book: A Complete Guide to Cannabis. Santa Cruz, CA: Multidisciplinary Association for Psychedelic Studies.

Lachenmeier, D. W., & Rehm, J. (2015). Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports, 5, 8126. http://doi.org/10.1038/srep08126

Purves, D., Augustine, G. J., Fitzpatrick, D., Hall, W. C., LaMantia, A., White, L.E. (2012). Neuroscience, Fifth Edition. Sunderland, MA: Sinauer Associates, Inc.

Russo, E. B. (2011).  Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163, 1344–1364.

Stahl, S. M. (2013). Stahl’s Essential Psychopharmacology, Fourth Edition. New York: Cambridge University Press.

Zvolensky, M. J., Cougle, J. R., Johnson, K. A., Bonn-Miller, M. O., & Bernstein, A. (2010). Marijuana Use and Panic Psychopathology Among a Representative Sample of Adults. Experimental and Clinical Psychopharmacology, 18(2), 129–134. http://doi.org/10.1037/a0019

"Yin and Yang" by Klem - This vector image was created with Inkscape by Klem, and then manually edited by Mnmazur.. Licensed under Public Domain via Wikimedia Commons
Source: "Yin and Yang" by Klem - This vector image was created with Inkscape by Klem, and then manually edited by Mnmazur.. Licensed under Public Domain via Wikimedia Commons

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