April 2010: A Mechanism by Which Cannabinoids Act as an Antidepressant is Illustrated. (Charles University; Prague, Czech Republic)

Note: Starting in May, there will consistently be two new summaries a week.

First some background: Mood disorders effect approximately 5-13% of the United States population, with major depressive disorder (unipolar depression) reflecting 4-9%.* Although the etiology of depression is not well understood, it is associated with decreased hippocampal volume. Within the hippocampus, a region named the subgranular zone is one of only two areas in the brain where new brain cells can be produced. This area of the hippocampus contains stem cells that form new neurons and differentiate in response to brain-derived neurotrophic factor (BDNF). Antidepressants work by increasing levels of serotonin, dopamine, and norepinephrine in the brain. Increased levels of serotonin and norepinephrine cause an increase in BDNF levels, thus causing an increase in hippocampal volume. Current pharmacological mechanisms for treating depression utilize reuptake inhibitors, which increase levels of these chemicals by inhibiting their reuptake into brain cells. However, older antidepressants, less favored now because of their side effects, are targeted to inhibit the enzyme monoamine oxidase (e.g. isocarboxazid, phelezine). Monoamines refer to a class of molecules which include the aforementioned neurotransmitters serotonin, dopamine, and norepinephrine as well as several others such as histamine. The enzyme monoamine oxidase catalyzes the degradation of these monoamines, thus a monoamine oxidase inhibitor (MAOI) would cause higher levels of these chemicals in the brain. There are two types of monoamine oxidase enzymes found in the human body, MAO-A and MAO-B. MAO-A is found mainly in brain cells that utilize norepinephrine and is able to degrade norepinephrine, serotonin, and dopamine most effectively; while MAO-B is found mainly in brain cells that utilize serotonin and is able to degrade β-phenylethanolamine and dopamine most effectively.

The new information: This experiment tested the effect of three cannabinoids on the activity of both monoamine oxidase enzymes. The three cannabinoids used were ∆9-tetrahydrocannabinol (THC), anandamide (a cannabinoid that occurs naturally in our body), and the synthetic cannabinoid WIN (WIN 55,212-2). The concentrations needed to inhibit 50% of the enzyme activity were then compared with the MAOI medication iproniazid. It was found that the MAO-A enzyme was blocked at lowest concentrations by WIN, followed closely by THC, with a large gap in concentration between THC and anandamide. The MAO-B enzyme was blocked at approximately equal concentrations of THC and WIN, with a large gap in concentrations between them and anandamide. Additionally, the concentrations at which all three blocked the MAOs were much greater than the concentration of iproniazid needed for the same result. The concentrations were measured in micromoles per liter, meaning that they were measured based on number of molecules and not their size or weight.

What this means: The results of this experiment illustrate in detail the dependence of the antidepressant effect of cannabis on concentration of cannabinoids. Because the effect of THC on monoamine oxidase is not as powerful as MAOI medications, there will not be the dangerous drug and food interactions that are notorious side effects of MAOIs. However, marijuana would nonetheless increase the amount of serotonin and norepinephrine in the brain, thus leading to an expansion in the size of the hippocampus. This neurogenerative effect is part of what leads to the antidepressant properties of marijuana. Additionally, damage to the hippocampus is also seen in Alzheimer’s disease, decreases in long-term memory, post-traumatic stress disorder, schizophrenia, and epilepsy caused by hippocampal sclerosis. Thus cannabis may hypothetically be helpful in the treatment of these conditions and more through its action as an inhibitor of the enzyme monoamine oxidase.

*Nestler, E.J., Hyman, S.E., and Malenka, R.C. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. New York: McGraw-Hill, 2009.

Fišar, Z. “Inhibition of Monoamine Oxidase Activity by Cannabinoids.” Naunyn-Schmiedeberg’s Archives of Pharmacology. (2010): preprint.