Much attention has been paid to the emotional and cognitive effects of marijuana. However, we believe that these effects can only be understood in the context of the endocrine interactions which are initiated by marijuana’s ingestion. In this article we will examine the function of both endogenous and exogenous cannabinoids with an emphasis on metabolic functioning.

We will review evidence which points to endocannabinoids as critical components of the body’s energy balance apparatus, and implicates endocannabinoid dysregulation in the development of metabolic syndrome, type 2 diabetes, and mental illness. Finally, we will suggest that cannabis extracts may be useful in the treatment of metabolic dysregulation, and that illicit use of marijuana may in many cases constitute a form of self-medication for the emotional effects of metabolic disorder.

The Metabolic Disorder

The metabolic disorder is a constellation of prediabetes symptoms now recognized by the International Diabetes Federation. Its symptoms include central obesity, hypertension, fasting hyperglycemia, decreased HDL cholesterol, and elevated triglycerides. The metabolic syndrome is associated with the development of type 2 diabetes, gout, non-alcoholic fatty liver disease, polycystic ovarian syndrome, and an irregularity of skin pigmentation known as acanthosis negricans (IDF, 2006).

The etiology of the metabolic disorder is unclear and appears to be extremely complex. Some have argued that insulin resistance brought about by excessive dietary carbohydrate may be a primary cause of the metabolic syndrome, while others have pointed to obesity, chronic inflammation, or excessive uric acid levels caused by dietary fructose.

The Endocannabinoid System

Interest in the biological activity of cannabis sativa and its primary constituent, Delta(9) Tetrahydrocannabinol (THC), led to the discovery of an endogenous cannabinoid system. The endocannabinoids are natural phospholipids which bind to a pair of G-protein coupled cannabinoid receptors known as CB1 and CB2. THC primarily activates CB1 receptors, which are found in the hypothalamic nuclei, the mesolimbic system, and in peripheral tissues including fat cells and gastrointestinal organs (Pagotto, Vicennati, & Pasquali, 2005).

The hypothalamic nuclei is involved in regulating energy balance and body weight, and so it is believed that CB1 plays a role in up- and down-regulating the body’s metabolic rate in order to adjust to the amount of energy available. The mesolimbic system is believed to be involved in regulating the incentive value of food, and so is important for increasing and decreasing appetite as necessary. The peripheral tissues represent the final link in this chain of metabolic regulation, and are responsible for the absorption and release of nutrients. Because CB1 receptors are concentrated in these biological regions, and because THC administration is associated with increased appetite, the endocannabinoids have long been thought to be involved with regulating appetite (Pagotto, Vicennati, & Pasquali, 2005).

Biochemical Effects of Cannabinoids

The function of THC-activated CB1 receptors in adipose tissues has been clarified by laboratory experimentation. A recent study examined the biological effects of cannabis extract on both normal and insulin-resistant adipose tissue cultures. In cell cultures, THC increased insulin-induced glucose uptake, meaning that it essentially countered the effects of insulin resistance. These results support previous findings that smoking cannabis can reduce blood glucose in diabetics (Gallant, Odei-Addo, Frost, & Levendal, 2009). They also lend support to the hypothesis that cannabis and cannabis extracts may be useful in the treatment of type 2 diabetes and prediabetes metabolic disorders, which disorders are characterized by insulin resistance and consequent hyperinsulinemia.

The Metabolic Role of Cannabinoids

It appears that endocannabinoids play a central role in the metabolic process by mediating the effects of insulin and regulating the rate at which cells utilize insulin-induced nutrient uptake. For example, one study found that in healthy subjects who were not insulin-resistant, insulin reduced endocannabinoids levels. This effect was inversely proportional to the level of insulin resistance.  (DiMarzo et al, 2009). The implication of this finding is that the popular understanding of type 2 diabetes as a disorder of insulin sensitivity may be incomplete.

It is well established that endocannabinoids plays a major role in the control of appetite and peripheral metabolism. CB1, which is activated by THC, is responsible for most of these effects. A natural hyperactivation of the endocannabinoid system results in a chronic positive energy balance and obesity. Drugs designed to block endocannabinoid reception reverse this effect, producing not only a decrease in appetite but also weight loss in excess of what could be explained by the reduction in caloric intake. In short, high levels of endocannabinoid activity induce energy storage while low levels induce energy expenditure (Despres, 2007). Further evidence for this relationship can be found in the characteristic accumulation of intra-abdominal fat that is seen in patients with type 2 diabetes and cardiovascular disease. CB1 reception appears to specifically mediate this effect (Cote, 2007).

Emotional Effects of Glucoregulatory Disorders & THC

Emotional distress has been identified as one of the two primary motives for marijuana use in young adults (Brodbeck, Matter, Page, & Moggi, 2007). However, the mechanisms by which marijuana alleviates emotional distress have remained mysterious. A study of high school students found that, among students with high rates of truancy, emotional distress was significantly associated with dysregulation of blood sugar levels. Students with hyperglycemia reported higher levels of distress (Iwatani et al, 1997). Since hyperglycemia is a result of insulin resistance, this study tells us that prediabetic conditions are significantly associated with subjective feelings of emotional distress.

Recent studies have demonstrated that metabolic syndrome is associated with the onset of depression (Takeuchi et al, 2009) and post-traumatic stress disorder (Jin et al, 2009). It is very possible that susceptibility to these disorders may be a result of endocannabinoid dysregulation, and could be treated by cannabis extracts. It is furthermore possible that chronic illicit marijuana use may represent a form of self-medication for metabolic dysregulation and its associated emotional effects.

Conclusion

As we have seen, the endocannabinoid system is intimately involved with the regulation of metabolic functioning. Cannabinoid receptors mediate insulin-stimulated glucose uptake, cellular lipogenesis, and energy balance. Type 2 diabetes and metabolic disorder are brought about by hyperinsulinemia, which in turn brings about insulin resistance and insensitivity to the effects of endocannabinoids.

Cannabis extracts, and specifically THC, exert a direct effect on insulin sensitivity and glucose uptake, resulting in lowered blood sugar. They also result in the alleviation of subjective feelings of emotional distress, although the mechanism for this effect remains unclear. Because the literature increasingly suggests a connection between metabolic dysregulation and emotional distress, we conclude that metabolic correction may be the means by which cannabis extracts provide relief from emotional distress.

Our conclusion is novel. Although others have suggested that cannabis may sometimes be used to self-medicate for symptoms of anxiety or ADHD, we are aware of no other researchers who have connected illicit cannabis use with self-medication for metabolic disorder. Nonetheless, we believe the evidence is compelling enough to warrant serious speculation and to prompt additional research. The evidence we have reviewed in this paper suggests that cannabis extracts may be effective treatments for metabolic syndrome, and may help to moderate the negative physiological, neurological, and psychological effects of glucoregulatory disorders.

The evidence furthermore suggests that treatment programs focusing on chronic marijuana use should give special attention to the medical and dietary implications that this drug use may have. It is possible that certain cases of marijuana dependence may be better conceptualized and treated if full metabolic assessments were performed concurrently with psychological assessments. This may be particularly true of those cases in which the reported reasons for marijuana use relate to emotional distress. The literature provides increasing evidence for mind-body interaction, and therefore suggests that quality of care will improve as medical and psychological treatment programs become more fully integrated.

References

Brodbeck, J., Matter, M., Page, J., & Moggi, F. (2007). Motives for cannabis use as a moderator variable of distress among young adults. Addictive Behavior, 32(8), 1537-1545.

Côté, M., Matias, I., Lemieux, I., Petrosino, S., Alméras, N., Després, J.P., & Di Marzo, V. (2007). Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. International Journal of Obesity, 31(4), 692-699.

Després, J.P. (2007). The endocannabinoid system: a new target for the regulation of energy balance and metabolism. Critical Pathways in Cardiology, 6(2), 46-50.

Di Marzo, V., Verrijken, A., Hakkarainen, A., Petrosino, S., Mertens, I., Lundbom, N., Piscitelli, F., Westerbacka, J., Soro-Paavonen, A., Matias, I., Van Gaal, L., & Taskinen, M.R. (2009). Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. European Journal of Endocrinology, 161(5), 715-722.

Gallant, M., Odei-Addo, F., Frost, C.L., & Levendal, R.A. (2009). Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes. Phytomedicine, 16(10), 942-949.

International Diabetes Federation (2006). The IDF Consensus Worldwide Definition of Metabolic Syndrome. Retrieved from http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf on November 24, 2009.

Iwatani, N., Miike, T., Kai, Y., Kodama, M., Mabe, H., Tomoda, A., Fukuda, K., & Jyodoi, T. (1997). Glucoregulatory disorders in school refusal students. Clinical Endocrinology, 47(3), 273-278.

Jin, H., Lanouette, N.M., Mudaliar, S., Henry, R., Folsom, D.P., Khandrika, S., Glorioso, D.K., & Jeste, D.V. (2009). Association of posttraumatic stress disorder with increased prevalence of metabolic syndrome. Journal of Clinical Psychopharmacology, 29(3), 210-215.

Pagotto, U., Vicennati, V., & Pasquali, R. (2005). The endocannabinoid system and the treatment of obesity. Annals of Medicine, 37(4), 270-275.

Takeuchi, T., Nakao, M., Nomura, K., Inoue, M., Tsurugano, S., Shinozaki, Y., & Yano, E. (2009). Association of the metabolic syndrome with depression and anxiety in Japanese men: a 1-year cohort study. Diabetes/Metabolism Research And Reviews, 25(8), 762-767.

A new study in the APA journal Neuropsychology used a highly controlled sample from Maastricht University’s long-term Aging Study in Holland. These individuals were screened every three years for a wide range of neurological problems, and divided into groups based on level of functioning. Neuropsychological test batteries were used to determine how well participants maintained neural functioning, and MRI scans were used to measure the physical size of seven brain areas important for aging, including hippocampal and parahippocampal areas as well as the frontal and cingulate cortices.

Study participants showed a loss of brain mass in direct relationship to cognitive decline. The researchers conclude that age-related decreases in brain size likely reflect pathological changes in the brain, rather than natural processes of aging.

This is a great example of the need for more cautious and methodical interpretation of clinical research. In attempting to determine what is normal, it is too easy for clinical researchers to miss the mark on what is optimal.

Citation: Burgmans, S., van Boxtel, M.P.J., Vuurman, E.F.M.P., Smeets, F., Gronenschild, E.H.B.M., Uylings, H.B.M., & Jolles, J. (2009). The prevalence of cortical gray matter atrophy may be overestimated in the healthy aging brain. Neuropsychology, 23 (5), 541-550. [PDF]

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