The Brain and Cannabinoids

By Amabelle Dela Cruz

The brain is known to be the most complex of human organs—said to contain 100 billion neurons, which is nearly as many stars as said to be in the Milky Way galaxy. But as far as we know, unlike the neurons in our brain, the stars in our galaxy don’t have hundreds of thousands of connections to all of the other stars for coordination of the entire system. Those connections between neurons – known as synapses – may equate to as low as 100 trillion, but may also be as high as 1,000 trillion. Thus, as far as today’s science currently posits, the human brain is the most complex object in the known universe. 

More surprisingly, human brain tissue is not much more complex than that of other creatures, like the fruit fly. Many researchers use the fruit fly as a model in brain research because almost every cell can be mapped to the human brain. One most interesting similarity that has been found is that the brains of mammals (including humans) and fruit flies communicate in the same way and use one key system to maintain brain homeostasis: the endocannabinoid system (ECS). First discovered in the early ‘90s, the ECS is the reason endocannabinoids evolved so early within the history of life and why they are a key field of study in brain health today. 

The first clue to the widespread nature of the endocannabinoid system began when Dr. Allyn Howlett first discovered the CB1 receptor in 1989. It was a technical triumph that answered a question neurochemists had been working on for a decade: How did the THC molecule of cannabis affect everyone in such different ways? 

Unlike most psychoactive plants consumed by people, cannabis brought forth a wide array of effects – from sleepiness and introspection to excitement, sadness, and joy – and the same plant could cause a different effect on the same person, if consumed on a different day.

When Dr. Howlett first applied her radioactive cannabinoid to the brains of pigs and took an X-ray, she thought something must’ve be wrong. All of the highest parts of the brain were highlighted, which made her question the possibility for the cannabinoid receptor to be that widespread. It turns out, the CB1 receptor is the most widespread G-protein coupled receptor (GPCR) in the brain, as well as the largest and most diverse class of receptors. To fully understand their importance, half of all approved pharmaceutical drugs on the US market are aimed at a GPCR, making the discovery of the endocannabinoid system one of the biggest breakthroughs for brain health.

The CB1 receptors found on the basal ganglia and the globus pallidus  regulate movement, while the ones in the hippocampus are key for learning, memory, and stress. There are CB1 receptors in the hypothalamus that control appetite, some in the medulla where nausea and vomiting are triggered, in the spinal cord, and in the cerebral cortex where higher-level thinking occurs.

Not long after the discovery of the CB1 receptor, the CB2 receptor was identified. It was found to be present on the immune cells in almost every organ of the body. When a brain experiences an insult or damage, CB2 receptors activate as part of one’s protection system. 

There are two key sources of cannabinoids in our brain: the endocannabinoids that we create ourselves and phytocannabinoids from the cannabis plant (CBD and THC are the most studied) that we can ingest. The first endogenous neurotransmitters found are called anandamide and 2-arachidonoylglycerol (2-AG). Now, six of them have been identified along with a host of cellular machinery to help regulate the endocannabinoid system. While the body has its own supply of cannabinoids, supplementing with phytocannabinoids, like CBD, can optimize this balancing act when needed.  

But how exactly do these cannabinoids work in the body?

The CB1 receptor is activated by THC and is the main pathway responsible for the ‘high’ effect of cannabis. Anandamide also activates the CB1 receptor and gained its reputation as our ‘neurotransmitter of bliss’. Curiously, CBD does not directly activate the CB1 receptors. Instead, it does something called negative allosteric modulation. When CBD is present, it binds to a side pocket of the CB1 receptor and slightly changes the receptor’s shape, preventing other molecules (such as THC) from creating strong connections to the CB1 receptor and protects the brain from an overwhelming psychoactive experience. CBD can also prevent or reduce the intoxicating effects of THC.

The CB1 and CB2 receptors have also both been found to be important for maintaining the blood brain barrier. More recently, activation of the CB2 receptor has been shown to promote neurogenesis – the creation of new brain cells. This is especially intriguing because brain scientists weren’t even sure that neurogenesis was real until an experiment in 1998. Before that, it was thought that by the age of 2 or so, all the cells in the brain would be complete and developed and the only thing that changed would be the strength of synaptic connections between them. However, it was discovered that the creation of new brain cells is a vital process in a healthy brain – especially in the hippocampus, a key part of memory storage.  

In his review, The Endocannabinoid System and the Brain, Dr. Mechoulam lays out the many ways the endocannabinoid system is involved in the creation of new brain cells. CB1 is expressed in many developing areas of the brain, the activation of CB1 is necessary for the growth of new axons between neurons, the endocannabinoid system drives the creation of brain stem cells, and the endocannabinoids promote neurogenesis. However, neurogenesis is a complicated process still undergoing intense study and is not solely regulated by the cannabinoids.

While the discovery of the ECS has taken us far in research, science has discovered that cannabinoids from the plant may interact with more parts of the brain than the cannabinoid receptors and their associated endocannabinoid machinery. One rather unique property of THC and CBD is that they effect many molecular targets. Most drugs only interact with one or two receptors or enzymes – but THC and CBD cause a huge range of changes in addition to the ones caused in the cannabinoid receptors. They interact with serotonin receptors, dopamine receptors, opioid receptors, as well as the two key neurotransmitters for excitation and inhibition: glutamate and GABA.

While phytocannabinoids like CBD have shown great potential, there is still much we cannot say about the benefits of hemp CBD supplements. More clinical trial research is needed to find out exactly how these phytocannabinoids can be harnessed for human health. 

We may not truly solve the complexity of the human brain, just as we cannot accurately count the vast number of skies in our galaxy. But we can posit certain activities that help us – like making health and nutritious food choices, getting an appropriate amount of exercise, and taking our CBD. As research continues on the involvement of the endocannabinoid system and the brain, it’s an exciting time to learn how we can live longer, richer, more fulfilled lives. 

NOTE: If you read the online version there will be links to references, reviews and research.

Other Articles by this Author: