by Kevin Rostam
art by Hailey Kopp
What is a high? And what are the neural processes that underlie psychoactivity? You likely just reflected on those first two sentences and thought back to your experiences with cannabis; not to worry, I hypothetically did too. With cannabis legalization quickly sweeping the globe and increasing discourse about federal legalization in the United States, growing attention is being paid to the implications of this puzzling plant that has been with us for over one million years .
What Is Cannabis, and What Is Its History?
What exactly is happening in the human body when cannabis is introduced? The answers to this question are heavily sought after, and research over the past 35 years has revealed much about these processes. The psychoactivity, or altered mental state, induced by cannabis can be attributed to the absorption of a highly concentrated element called tetrahydrocannabinol, more commonly referred to as THC, into the bloodstream . The interactions between this psychoactive molecule and the nervous system induce sedation, relaxation, euphoria, and appetite stimulation . Additionally, THC is known to cause feelings of anxiety and paranoia for some .
Another term you may hear being thrown around is cannabidiol, more commonly referred to as CBD, which is another high-concentration constituent of cannabis that is commonly credited for alleviating pain, reducing anxiety, and acting as an anticonvulsant by preventing epileptic episodes . What makes CBD so promising as a possible therapeutic is that unlike THC, it does not induce psychoactivity . Due to these acclaimed therapeutic benefits and a general lack of side effects, CBD oils and capsules are widely available and utilized by those who choose to self-medicate.
The wide array of physiological responses of the human body to these cannabis compounds nods to a functional importance that has been evolutionarily conserved. In alignment with this notion, THC and CBD were isolated from cannabis and had their chemical structures revealed in the 1960s [5, 6]. Twenty-five years later, significant research interest was fueling the push for the discovery of these molecules’ internal targets, also known as endogenous targets. In the late 1980s, the first endogenous target of THC was discovered and named cannabinoid receptor 1, or CB1 . With this discovery, researchers wisely presumed that CB1 must be modulated by an endogenous, naturally synthesized molecule that activates this receptor in the human body. A few years later, anandamide was discovered and identified as the first endocannabinoid—or internally produced cannabinoid—shown to modulate CB1 . This groundbreaking discovery confirmed that the human body naturally produces molecules that function similarly to those found in cannabis . The molecular pathway that regulates activity between cannabinoid receptors such as CB1 and naturally synthesized endocannabinoids has come to be known as the endocannabinoid system . Since the mid-1990s, a plethora of endocannabinoids and cannabinoid receptors have been identified. This is an ongoing process that has opened the door to investigating the role of these elements in standard biological functions, which is a crucial next step toward the detection of therapeutic targets.
The Cannabis Funding Complication
In the past twenty years alone, over $1.5 billion have been subsidized to support cannabis research in the United States by NIDA, the U.S. National Institute on Drug Abuse . The total funding allocated towards cannabis research has nearly quintupled from just over $30 million in the year 2000 to nearly $150 million in 2018. This budget goes toward both the study of the harmful effects of cannabis and the task of uncovering mechanisms that underlie the therapeutic potential of cannabis-derived compounds . A major constraint to the turnover of cannabis research boils down to marijuana’s Schedule-I drug status. It has been classified as a substance with high potential for abuse with no medical utility, on par with illicit substances such as heroin and ecstasy. This has made it more tightly regulated than highly addictive, yet medically operational Schedule II drugs such as cocaine, methamphetamine, oxycodone, and fentanyl . Despite the clear therapeutic potential indicated by scientific literature and discussed later in this article, cannabis researchers must endure a lengthy regulatory approval process by institutional review boards, departments in state governments, academic institutions, and funding sources because of the drug’s scheduling status. In addition to the hindrance imposed on researchers, the moral ambiguity of current drug policy has spurred a presidential directive issued to the Department of Health and Human Services to produce a review into whether marijuana is appropriately listed as a Schedule-I substance .
Endocannabinoids and Synaptic Plasticity
One of the primary mechanisms neurons utilize to communicate with each other is synaptic transmission, which occurs in the space between two neurons known as the synapse . When a neuron sends an impulse down its axon, the axon terminal releases chemicals called neurotransmitters that cross the synapse and reach the neighboring, postsynaptic neuron . These neurotransmitters then bind to receptors and convey the desired message from the presynaptic neuron. In doing so, neurons can send and receive information via these signaling molecules . The ability of synapses to undergo modifications that alter signaling strength is referred to as synaptic plasticity . Changes in synaptic plasticity can induce changes in nervous system processes such as cognition, mood, motor control, and a plethora of others . In the case of the endocannabinoid system, postsynaptic neurons can initiate the synthesis of endocannabinoids, a class of neurotransmitters, in response to the signal of their presynaptic partners . These newly created endocannabinoids then travel backward through the synapse (from the postsynaptic neuron to the presynaptic neuron) and inhibit the release of other neurotransmitters, demonstrating the efficacy of the endocannabinoid system in modulating “short-term” synaptic plasticity . These endocannabinoid signaling mechanisms have also been linked to long-term plasticity, where they have the ability to affect both presynaptic and postsynaptic architecture. In other words, they actively change the types and quantities of receptors and neurotransmitters released, which in turn alter synapse strength . These permanent changes to neural circuit function explain their “long-term” denotation, which occur in contrast to temporary changes to dynamics such as the induction of neurotransmitter release, a
“short-term” effect . The ability of endocannabinoid signaling to affect neural circuit architecture in a permanent manner is what makes understanding this system so vital for the development of therapies.
Since the endocannabinoid system (ECS) is modulated by cannabis pharmacology, it has received increasing attention as a therapeutic target. The ECS is a known participant in several physiological processes such as learning, memory, neuropathic pain, inflammation, appetite, metabolism, stress regulation, and addiction [17, 18]. The following sections will be centered around the potential of cannabis to address two of these physiological processes: pain and metabolism, with research on the latter having increased exponentially in the past few years.
Cannabis and Neuropathic Pain
Whether it’s from a vigorously long workout or from getting out of your chair after studying all afternoon, we are all familiar with pain. Pain signals are transmitted from the peripheral nervous system via specialized cell clusters known as dorsal root ganglia, which then relay this information to the brain, resulting in the familiar pain sensation . While pain is an important, evolutionarily conserved experience that communicates an imminent risk of injury to the individual, it is also a byproduct of devastating neurological disorders and other afflictions such as cancer . An abnormal increase in pain sensation due to disease states is referred to as neuropathic pain, or pain caused by damage to nerve cells. Neuropathic pain is a central element of neurological diseases such as multiple sclerosis, an autoimmune disorder in which myelin, an insulating coating around the branches of neurons, is effectively removed and makes neuronal signaling slower within the nervous system . This “demyelination” is caused by an immune system response to a specialized group of neurons known as oligodendrocytes, which are the supporting cells responsible for myelin production . Significant amounts of research support the notion that the activation of CB1 in oligodendrocytes improves their survivability and population growth . Since THC is an extremely reliable activator of CB1 receptors, a natural next question is: “Can cannabis be used as a treatment for multiple sclerosis?” THC has in fact been used to alleviate muscle spasms, rigidity, and pain in afflicted patients, wholly bypassing clinical trials and being approved for medical use in a subset of countries . The scientific literature on the therapeutic benefits of this compound is rather clear, rendering claims of a lack of therapeutic potential blatantly unfounded.
Let’s consider the effects of cannabis on another unfortunate, but common, neurological disorder—Alzheimer’s disease. This disease causes a malfunction of neurons in the brain and is the primary cause of dementia . The neuronal malfunction is caused by a buildup of a protein known as amyloid beta. Although many variants of this protein exist and contribute to a buildup in the brain collectively referred to as plaques, the scientific literature indicates that the accumulation of amyloid beta 42 is the primary culprit underlying neurodegeneration . Neural functions that are disrupted commonly include the pain circuit, and dysregulation of such often leads to chronic pain . We have been talking a lot about THC, the primary psychoactive constituent of cannabis; however, CBD has also been implicated to be of therapeutic potential. In an Alzheimer’s disease model, the administration of CBD demonstrated a neuroprotective effect, preventing axonal degeneration and maintaining proper neuron structure .
Cannabis and Metabolism: The Munchies Paradox
Although research on the therapeutic potential of cannabis has largely been centered on its implications surrounding pain, research on its involvement in metabolism is stirring the pot in regard to renewed interest for its clinical potential. An increased appetite is a common experience when people consume cannabis of moderate THC dosage . But what makes this so paradoxical is that despite causing a craving for foods that are high in sugar and fat content, THC dosages result in weight loss both anecdotally in humans and in rodent studies . A scientific term of interest that has risen in popularity as of late, the “gut microbiome'' (referring to the microorganisms that live in our digestive tract), is being increasingly implicated in metabolic health. For this reason, researchers have started investigating the relationship between gut bacteria and THC-induced weight loss. One study specifically investigated a bacterium known as A. muciniphila and noted that its population increased in response to a THC dosage in mice . The same population of mice demonstrated a weight loss of 12.5 percent total body weight in males and 15.7 percent total body weight in females . These findings point to the possibility that THC-induced weight loss may be occurring independently of the endocannabinoid system and interacting with other biological systems. Just last year, a significant paper was published demonstrating that cannabinoids affect food preferences and consumption in drosophila, more commonly known as fruit flies, but there’s a catch—drosophila do not have an endocannabinoid system and lack CB1 and CB2 receptors . In fact, endocannabinoids such as anandamide were shown to affect feeding behavior in these organisms, again bolstering the notion that cannabinoids have roles outside of the endocannabinoid system, and that the extent of their interactions in other biological processes is unknown .
The Clinical Standing of Cannabis
The therapeutic upsides of cannabis modulation of the endocannabinoid system through THC and CBD are clear, but a variety of research has also implicated negative side effects of the THC modulation. One of the primary downsides is that this compound may induce excessive psychoactivity . The effects of THC usage have been characterized based on dosage during specific developmental stages, where the literature indicates that marijuana usage is most detrimental when used heavily during adolescence . In fact, marijuana use in adolescents with a genetic predisposition to develop schizophrenia increases the likelihood of falling victim to this neuropsychiatric disorder over time, and accelerates the timeline to experiencing the first psychotic episode . During this stage of development, heavy marijuana usage is also linked to cognitive impairment and lower educational attainment, although other factors such as socioeconomic status are important to consider in this argument . Most compelling, however, is the comparison of marijuana addiction rates: 17 percent of those who use cannabis during adolescence fight addiction during adulthood, whereas only nine percent of the total population of cannabis users face this dilemma . These findings indicate that the possible consequences of THC usage, primarily the psychoactive side effects imparted by interactions with CB1 receptors, are a risk factor for many. These are the primary obstacles preventing THC from advancing further as a lone pharmacological candidate.
These barriers were a primary point of discussion in a personal interview with Dr. Allyn Howlett, a full professor of physiology and pharmacology at the Wake Forest School of Medicine and the pioneering researcher who discovered the CB1 receptor, who also shed light on her groundbreaking work and the potential of cannabinoid therapies. The discovery of CB1 began with a correspondence to a team of chemists at Pfizer, who agreed to send Dr. Howlett a few cannabinoid compounds of interest . The data from experimentation with these compounds demonstrated a convincing relationship between an unknown endogenous receptor and the cannabinoid compounds that had been sent. According to Dr. Howlett, by the time she went back to report the findings, the company had moved on and pronounced that “there were no therapeutic uses for cannabinoids” . In addition to her lab’s data, Pfizer had produced their own set of data in regard to other aspects of the activity of these cannabinoid molecules. As a biochemical neuropharmacologist, Dr. Howlett’s expertise on the relationship between receptor structure and its interactions with various biomolecules led her to realize the importance of having both datasets to test correlation and clarified that because the company didn’t care about cannabinoid compounds therapeutically anymore, they were willing to publish the data. Having both pieces of the puzzle led Howlett and her team to draw the conclusion that cannabinoid compounds had high affinities with the
receptor now known as cannabinoid receptor 1, or CB1. “It was a boon to mankind that they decided not to do that [proceed with cannabinoid research] because now we have a wealth of information about cannabinoids, but on the other hand, just envision what life would be like if they did have a cannabinoid compound on the market for pain relief,” said Howlett, addressing the reality that a cannabinoid pain reliever achieving FDA approval and hitting the market would have driven other larger companies to do the same. In alignment with much of what has been discussed about the unwanted side effects associated with THC usage, Dr. Howlett noted that Pfizer’s decision to step away from cannabinoids research “was based on the safety profile. The side effects would have made it difficult for at-home use” .
The second significant constituent of cannabis, CBD, has been implicated as a valuable therapy for a plethora of neuropsychiatric conditions, primarily as a mild sedative for anxiety, and has found potential as an adjunctive treatment to THC . As discussed above, a negative side effect of THC is that it induces excess psychoactivity that may be undesirable, but when co-administered with CBD, it has been shown to reduce psychoactivity. In multiple sclerosis patients, for example, the co-administration of CBD allows for higher doses of THC to be prescribed, leading to more promising clinical outcomes than the administration of THC alone . CBD interacts differently with the endocannabinoid system and also targets a variety of other signaling systems, which explains why it does not alter one’s mental state .
When asked about the potential of THC in combination with CBD, Howlett noted that “drug companies tend to stay away from combination compounds, back in the olden days there were efforts to develop combinations, but I don’t know that it has taken off” . The same story holds for the potential of CBD alone as a therapy, as Howlett noted that “those pieces of information have fallen by the wayside, and maybe that’s partly because when it was obvious that THC was correlating with CB1 receptor interactions for pain relief, everyone jumped on that,” which took attention away from other candidates such as CBD . That being said, the realm of cannabinoids research remains novel and with many discoveries in the queue, especially as clinicians continue to search for high efficacy treatments for the issues of pain and metabolic disease.
The Future of Cannabis as a Therapy
Although this article only begins to introduce the therapeutic potential of cannabis and its constituents, a wide array of ongoing research is attempting to further reveal the mechanisms of action of cannabinoids. Additional efforts are being employed to develop therapies that evade the psychoactive properties of THC while still taking advantage of the endocannabinoid system. An example of this is the chemical synthesis of molecules that resemble THC, but are structurally modified to successfully circumvent side effects . In a second personal interview with Dr. Heather Bradshaw, a full professor of psychological and brain sciences at Indiana University Bloomington, discussion revolved around approaches researchers are taking to tap into the body’s synthetic processes . When asked about whether there are ways to alter production levels of endogenously produced cannabinoids, Dr. Bradshaw stated that “the machinery that makes one endocannabinoid is the same machinery that makes other endocannabinoids. It’s messy and difficult to modulate on that level. We don’t have that specificity” . Targeting receptors as opposed to directly regulating levels of endocannabinoids seems to be the most productive strategy for harnessing the power of cannabinoids. According to Dr. Bradshaw, “Figuring out which receptors that cannabinoids like THC, CBD, and others are targeting for these effects” is the next step that needs to be taken . One of the problems with a receptor-based approach is that any single molecule likely interacts with a plethora of receptors, making it difficult to isolate the effects of a biomolecule to a specific receptor type, which has led to interest in the development of better molecules that only target individual receptors.
When asked about scientific philosophy, Dr. Bradshaw clarified that “my pharmacological goal is not to come up with a drug that somebody would take forever, it’s to try to help them get back into homeostasis and allow their body to start signaling properly again. That is the goal of pharmacology really, to understand the system, exploit the system, and put it back in balance” . As discussed in this article, cannabis and the endocannabinoid system have effects on a variety of systems, meaning that there have to be compounds in cannabis that interact with specific receptors that drive changes in those systems, and not just through CB1. We just don't know what the perfect targets are yet. Along these lines, Dr. Bradshaw shed light on the combinatorial mechanisms of cannabis, specifically that “there must be situations in which mixtures of cannabis are optimized for symptom relief, it doesn’t help to have any cannabis, it goes back to which molecules interact with which signaling systems in the body, and exploiting all these different compounds in cannabis and their ratios” .
Looking to the future, Dr. Bradshaw takes the position that as more is understood about pharmacology, the more obvious it becomes that there are no on/off switches . The issues researchers are addressing are not single-cause issues—a multitude of systems are dysregulated, leaving the door wide open for a generation of scientists looking to identify the systems at play and discover how to correctly regulate their interactions. Due to its novelty in the scientific realm, cannabinoid research will be of increasing utility throughout the coming years and garner further attention as the grips of the bureaucratic regulation of cannabis begin to weaken. Opening our minds to all the possibilities cannabis has to offer is a logical next step for both scientific researchers and the general population who have all to gain from a trip down a new therapeutic avenue.
1. Ren, G., Zhang, X., Li, Y., Ridout, K., Serrano-Serrano, M. L., Yang, Y., … Fumagalli, L. (2021). Large-scale whole-genome resequencing unravels the domestication history of Cannabis sativa. Science Advances, 7(29), eabg2286. https://doi.org/10.1126/sciadv.abg2286
2. Wachtel, S., ElSohly, M., Ross, S., Ambre, J., & de Wit, H. (2002). Comparison of the subjective effects of Δ 9 -tetrahydrocannabinol and marijuana in humans. Psychopharmacology, 161(4), 331–339. https://doi.org/10.1007/s00213-002-1033-2
3. Hindley, G., Beck, K., Borgan, F., Ginestet, C. E., McCutcheon, R., Kleinloog, D., … Howes, O. D. (2020). Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis. The Lancet Psychiatry, 7(4), 344–353. https://doi.org/10.1016/S2215-0366(20)30074-2
4. Pisanti, S., Malfitano, A. M., Ciaglia, E., Lamberti, A., Ranieri, R., Cuomo, G., … Bifulco, M. (2017). Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacology & Therapeutics, 175, 133–150. https://doi.org/10.1016/j.pharmthera.2017.02.041
5. Gaoni, Y., & Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society, 86(8), 1646–1647. https://doi.org/10.1021/ja01062a046
6. Mechoulam, R., & Gaoni, Y. (1967). The absolute configuration of δ1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Letters, 8(12), 1109–1111. https://doi.org/10.1016/S0040-4039(00)90646-4
7. Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S., & Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology, 34(5), 605. https://molpharm.aspetjournals.org/content/34/5/605.long
8. Devane, W. A., Hanuš, L., Breuer, A., Pertwee, R. G., Stevenson, L. A., Griffin, G., … Mechoulam, R. (1992). Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. Science, 258(5090), 1946–1949. https://doi.org/10.1126/science.1470919
12. Roubein, R. (2022, October 10). Biden’s directive on marijuana faces a Catch-22. The Washington Post. Retrieved October 12, 2022, from https://www.washingtonpost.com/politics/2022/10/10/biden-directive-marijuana-faces-catch-22/
17. Aizpurua-Olaizola, O., Elezgarai, I., Rico-Barrio, I., Zarandona, I., Etxebarria, N., & Usobiaga, A. (2017). Targeting the endocannabinoid system: future therapeutic strategies. Drug Discovery Today, 22(1), 105–110. https://doi.org/10.1016/j.drudis.2016.08.005
18. Silvestri, C., & Di Marzo, V. (2013). The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders. Cell Metabolism, 17(4), 475–490. https://doi.org/10.1016/j.cmet.2013.03.001
20. Nesse, R. M., & Schulkin, J. (2019). An evolutionary medicine perspective on pain and its disorders. Philosophical Transactions of the Royal Society B: Biological Sciences, 374(1785), 20190288. https://doi.org/10.1098/rstb.2019.0288
21. Ilyasov, A. A., Milligan, C. E., Pharr, E. P., & Howlett, A. C. (2018). The Endocannabinoid System and Oligodendrocytes in Health and Disease. Frontiers in Neuroscience, 12, 733. https://doi.org/10.3389/fnins.2018.00733
24. Wang, Z., Zheng, P., Xie, Y., Chen, X., Solowij, N., Green, K., … Huang, X. (2021). Cannabidiol regulates CB1‐pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models. The FASEB Journal, 35(5). https://doi.org/10.1096/fj.202002724R
25. Cluny, N. L., Keenan, C. M., Reimer, R. A., Le Foll, B., & Sharkey, K. A. (2015). Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol. PLOS ONE, 10(12), e0144270. https://doi.org/10.1371/journal.pone.0144270
26. Rusling, M., Lampeter, T., Fung, C., Love, C., Dhopeshwarkar, A., Mackie, K., & Yuan, L. (2021). A. Muciniphila; a Microbiome Mediator of Tetrahydrocannabinol Induced Weight Loss? The FASEB Journal, 35(S1), fasebj.2021.35.S1.04364. https://doi.org/10.1096/fasebj.2021.35.S1.04364
27. He, J., Tan, A. M. X., Ng, S. Y., Rui, M., & Yu, F. (2021). Cannabinoids modulate food preference and consumption in Drosophila melanogaster. Scientific Reports, 11(1), 4709. https://doi.org/10.1038/s41598-021-84180-2
28. Volkow, N. D., Baler, R. D., Compton, W. M., & Weiss, S. R. B. (2014). Adverse Health Effects of Marijuana Use. New England Journal of Medicine, 370(23), 2219–2227. https://doi.org/10.1056/NEJMra1402309
29. Howlett, A. (2022, November 3). Personal Communication.
30. Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., … Friedman, D. (2014). Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6), 791–802. https://doi.org/10.1111/epi.12631
31. Bloemendal, V. R. L. J., van Hest, J. C. M., & Rutjes, F. P. J. T. (2020). Synthetic pathways to tetrahydrocannabinol (THC): an overview. Organic & Biomolecular Chemistry, (17). https://doi.org/10.1039/D0OB00464B