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.

February 2010: Cannabinoids affect level of hormone release from the brain. (Universidad de Buenos Aires; Buenos Aires, Argentina)

First some background: Most of the major hormones found in the body are regulated by and released from what is known as the hypothalamic-pituitary axis, involving two distinct but connected areas of the brain, the hypothalamus and pituitary gland. The hypothalamus is responsible for the production and release of hormones such as thyrotropin-releasing hormone, dopamine, growth hormone-releasing hormone, somatostatin, gonadotropin-releasing hormone, and corticotropin-releasing hormone. All of these hormones in turn act on the anterior pituitary gland causing release or inhibiting release at their respective sites of action. The other half of the pituitary gland, the posterior pituitary is responsible for the release of other hormones produced in the hypothalamus, oxytocin and vasopressin. Vasopressin, also known as anti-diuretic hormone, controls the level of hydration in the body. When released, vasopressin acts on the kidneys to increase re-absorption of water, thus decreasing the amount of urine produced. Oxytocin is known for its role in uterine contraction when giving birth and in stimulating the let-down of breast milk. Oxytocin levels also increase in both men and women during sexual arousal and especially during orgasm, which may play a role in mate selection by invoking feelings of contentment and repressing anxiety. Mutations in the gene coding for oxytocin have also been implicated as a cause of Autism.*

The new information: It was found that in hypothalamic magnocellular neurons, which are responsible for the production and release of oxytocin and vasopressin, there were significant numbers of cannabinoid receptors. This indicates that cannabinoids can modulate the production and release of these hormones. Additionally, when the brain was directly exposed to stressors, cannabinoids induced the secretion of oxytocin. The experiment was carried out by injecting lipopolysaccharide (LPS), a component of gram-negative bacterial membranes, into the brain. The LPS invokes an immune response that creates a level of stress in the brain by increasing inflammation. When the LPS was injected, there were increased levels of cannabinoids found in the brain, which lead to enhanced secretion of oxytocin.

What this means: This experiment illustrated one of the mechanisms of cannabis’ well-known anxiolytic effects. By stimulating the synthesis and release of oxytocin, cannabis can be effectively used to treat both general and specific anxiety disorders, mood disorders, as well as some symptoms of Autism. Additionally, because it was shown that cannabinoids have modulatory effects in the pituitary, it may be possible to treat certain forms of hypopituitarism using cannabis.

De Laurentiis, A., et al. “Endocannabinoid System Participates in Neuroendocrine Control of Homeostasis.” Neuroimmunomodulation. 17.3 (2010): 153-156.

*Jacob, S., et al. "Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism." Neuroscience Letters. 417.1 (2007): 6–9.

February 2010: The beneficial effects of cannabinoids in one portion of the brain is fully understood (Goethe Universität Frankfurt am Main; Germany)

First some background: The portion of the brain used in this experiment is called the dentate gyrus. The dentate gyrus is part of the temporal lobe of the cortex, which, in layman’s terms, is the portion of the brain that exists directly on both sides of the head. The temporal lobe is involved in the processing of sounds, as well as the semantics of vision and the formation of memories. Additionally, cell damage and death in the dentate gyrus is known to be one of the etiological causes of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. It has also been well documented that cannabinoids reduce inflammation and have a protective effect in the dentate gyrus.

The new information: Although the end biological effect of cannabinoids in this area of the brain has been known for some time, the molecular events have now been determined. The experiment examined the effects of cannabinoid receptor-mediated activation of ion channels in the brain cells at varying concentrations of cannabinoids. It was found that at lower concentrations (0.01 muM), the cannabinoid most effectively mediated neuroprotection and anti-inflammatory effects, and with higher doses, the cannabinoids were less effective. It was also shown through channel blocking and activation that cannabinoids led to the inhibition of TRPV1 channels, which allow passage of calcium, magnesium, and sodium, as well as the activation of Ca(v)2.2, a voltage-gated N-type calcium channel.

What this means: This study allowed a look at the dosage-dependent effects of cannabinoids. As more is learned about how the concentration of cannabinoids affects their benefits, it will be possible to determine more effective dosages of cannabis itself. Additionally, by elucidating the molecular mechanisms of neuroprotection and anti-inflammation, it could be possible to accentuate these specific actions of cannabinoids by the use of drugs that affect the ion channels whose permeability was shown to be altered. This could lead to more effective treatment of neurodegenerative diseases such as Alzheimer’s of Parkinson’s.

Kock, M., et al. “The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels.” Hippocampus. (2010): preprint.