How Marijuana Works in the Brain

Medical Marijuana: A Biochemical Approach
Introduction

For thousands of years cannabis sativa and its extracts have been used to treat a variety of illnesses ranging from epilepsy to gastrointestinal issues. Unfortunately, during the early 20th century cannabis came under the attack of yellow journalism, and was renamed marijuana by the media. Through a series of smear campaigns driven by racism, fear, and politics, slogans such as “smoke one joint and you will want to kill your brother” and movies like Reefer Madness marijuana was made illegal. Eventually it reached the status of a schedule I drug, which according to the FDA means that it has a high potential for abuse, no currently accepted medical, value and a lack of safety. This scheduling has been highly controversial, and due to its legal status research has been difficult. Little research has been done and very few clinical trials have ever been conducted on humans in the United States.

Chapter 1: The Endocannabinoid System in the Brain

In order to understand how a cannabinoid receptor agonist like those found in marijuana can have an effect on medical conditions it is important to be familiar with the basics of the endocannabinoid system in the brain. The endocannabinoid system is a recently discovered signaling system. Cannabinoid receptors in the brain were discovered in 1990[1]. These are G-coupled receptors with seven transmembrane regions. There are two known cannabinoid receptors: CB1 and CB2. CB1 is heavily concentrated in the central nervous system and is coupled with ion channels[2]. It is also the most ample G-coupled protein receptor in the mammalian brain although this receptor is also found in other tissues. CB2 on the other hand is more localized, found to be associated with immune cells, the pancreas and the lymphoid system. The two endogenous ligands to which these receptors are agonized were not discovered until 1992. Anandamide was the first endocannabinoid to be classified, followed by 2-arachidonoyl glycerol. Both of these compounds are derivatives of arachidonic acid and both endocannabinoids appear to bind to CB1 and CB2.

The activation of the endocannabinoid system is similar to other G coupled protein receptors in the way it produces a cascade involving protein kinase A, and cyclic AMP[3]. During high levels of neural activity calcium ion concentrations increase in the cytoplasm which promote N-acyltransferase to produce N-arachidonoyl phosphatidyl ethanolamine from phosphatidyl ethanolamine. This intermediate is further processed by phospholipase D to form anandamide. Anandamide, which is now free in the synapse, is subject to degradation by the enzyme fatty acid amide hydrolase (FAAH). However, if it is not degraded anandamide will bind to and activate CB1 . The G-protein dissociates from the receptor and inhibits adenylyl cyclase. Because of this, cytoplasmic concentrations of cAMP decrease, which in turn decrease the levels of PKA. PKA can stimulate the ryanodine receptor, which will mediate the release of Ca2+ from the endoplasmic reticulum. Therefore reducing the amount of PKA will reduce the amount of calcium leaking from the endoplasmic reticulum into the cytoplasm, which will reduce the neurons ability to become depolarized. The bound CB1 receptor activates the extra cellular signal regulated kinase pathway (ERK) which stimulates the transcription of genes encoding transcription factors c-fos, zif268, and BDNF. These transcription factors are known to help ameliorate the effects of excitotoxic damage caused by excessive neural activity[4]. This sequence has the effect of decreasing the likelihood of further neural excitation and putting in motion the creation of gene products that can dampen the effects of excitotoxic events. Furthermore, CB1 receptor stimulation has also been shown to reduce inflammation and promote neurogenesis[5]. The overall view of the endocannabinoid system is that it mediates the effects of over stimulation, reduces inflammation, and promotes growth of new neurons in response to overstimulation.