CANNABIS CULTURE – The ultimate goal of the endocannabinoid system ECS is homeostasis – the maintenance of a constant internal environment. Endocannabinoids are neurotransmitters – chemical messengers that send instructions to cells.
The endocannabinoid system (ECS) is involved in the regulation of a variety of physiological and cognitive processes, including appetite, pain-sensation, mood, memory, fertility, pre- and postnatal development, immune system function, motivation (especially voluntary exercise and exercise-induced euphoria), body temperature and, of course, mediating the pharmacological effects of cannabis. They can even influence our taste, and activating CB1 receptors may actually make sweet things taste sweeter!
The ECS is made up of three main parts:
- “Endocannabinoids” – so called because the body produces its own cannabinoids – anandamide (aka arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG). AEA is analogous to tetrahydrocannabinol (THC), whilst 2-AG is analogous to cannabidiol (CBD). THC and CBD are often called “phytocannabinoids”, as they are produced outside of the body. The term “cannabinoids” refers to all cannabinoids, endo- or phyto-. Cannabinoids are ligands, meaning they are molecules that bind to form a complex that produces a specific chemical signal or neurotransmission.
- The cannabinoid receptors CB1 and CB2, which are G protein-coupled receptors. This means that they can detect molecules outside of the cell and can activate signal transduction pathways and cellular responses. CB1 receptors are found mostly in the brain and nervous system, as well as peripheral organs and tissues. There is much debate as to where CB2 receptors are expressed, but they may be found in the brain (to a lesser degree than CB2 receptors), immune system and gastrointestinal system. There could be other cannabinoid receptors – research is still needed in this area. Cannabinoid receptors are found on the cell membrane, and cells may contain either one or both cannabinoid receptors, depending on their function.
- The enzymes that synthesize and degrade cannabinoids, like fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL).
THC, CBD, cannabigerol (CBG), and the endocannabinoid system was first discovered by Dr. Raphael Mechoulam and his students, postdoctorals and collaborators, although 2-AG was first discovered by Shimon Ben-Shabat. Much of Dr. Mechoulam’s work continues at the Hebrew University of Jerusalem, and other doctors and scientists like Ethan Russo, M.D. are carrying on their work.
What Endocannabinoids Does the Body Produce?
There are 5 recognizable endocannabinoids. They are:
- Arachidonoylethanolamide (anandamide) – derived from the Sanskrit word ananda, meaning “joy” or “bliss”. Anandamide is broken down by the enzyme FAAH, which converts anandamide into ethanolamine and arachidonic acid. Inhibition of FAAH leads to higher levels of anandamide in the body. THC mimics anandamide. Anandamide plays a role in memory, reward, feeding behavior and even the earliest stages of human pregnancy. Anandamide is also found in chocolate. Anandamide may also inhibit human breast cancer cell proliferation, as well as be a target for treating depression and anxiety.
- 2-Arachidonoyl Glycerol (2-AG) – endogenous agonist of the CB1 agonist, meaning 2-AG will bind to CB1 receptors to produce a response (an antagonist blocks the action of an agonist, whilst an inverse agonist has the opposite reactive of an agonist). 2-AG is found in high concentrations in the central nervous system (CNS). 2-AG mimics CBD, and is involved in heat and pain detection, as well as immune response and inflammation.
- 2-Arachidonoyl Glyceryl Ether (noladin ether, 2-AGE) – CB1 and CB2 agonist. Partial agonist for the heat-detecting protein, TRPV1. Regulates calcium uptake in the body, as well as the uptake of gamma-Aminobutyric acid (GABA), which regulates neuronal excitability. 2-AGE also lowers intraocular pressure. There is still some debate as to the extent 2-AGE occurs in the human body.
- Virodhamine (O-AEA) – CB1 receptor antagonist and CB2 receptor agonist. May act to regulate body temperature and pain.
- N-Arachidonoyl-Dopamine (NADA) – CB1 AND TRPV1 receptor agonist. Plays a regulatory role in both the central and peripheral nervous system (CNS/PNS), and displays both antioxidant and neuroprotective properties. May also work as an anti-inflammatory.
How Does the ECS Work?
To explain this, we need to look at the synapses, in particular the presynaptic neuron (medical definition: “a neuron from the axon terminal of which an electrical impulse is transmitted across a synaptic cleft to the cell body or one or more dendrites of a postsynaptic neuron by the release of a chemical neurotransmitter”) and the postsynaptic neuron (medical definition: “a neuron to the cell body or dendrite of which an electrical impulse is transmitted across a synaptic cleft by the release of a chemical neurotransmitter from the axon terminal of a presynaptic neuron”).
In English, the presynaptic neuron is where the message is being sent from, and the postsynaptic neuron is where the message is being sent to. The presynaptic neuron releases neurotransmitters (endocannabinoids) into the synaptic cleft, which is the space in between two neurons. These neurotransmitters may trigger effects on the postsynaptic neuron, specifically excitation, inhibition or the initiation of second messenger cascades.
Phytocannabinoids act as “mimics” of endocannabinoids, and have similar effects to them. Different cannabinoids act on different parts of the ECS in different ways. 2-AG, for example, works on presynaptic CB1 receptors and can reduce depression. Anandamide, meanwhile, triggers autocrine signalling (when a cell secretes a hormone or chemical agent – called the autocrine agent – binding autocrine receptors to the cell and changing its structure) in TRPV1 receptors. This induces long-term depression. Autocrine signalling is also a huge factor in the development of cancerous cells and tumors, and cannabinoids may help prevent them from developing.
What Other Receptors Do Cannabinoids Effect?
The ECS seems to be a hugely important part of homeostasis as a whole, perhaps the most important part. Modulating the ECS tends to affect other receptors in the body. We’ve already mentioned the TRPV1 receptor (aka the vanilloid receptor) above, and CBD’s influence on sodium and calcium channels seems to have potential therapeutic effects for the detection of pain, reducing inflammation, preventing seizures in epilepsy sufferers, and potentially provide relief for those who suffer from disorders that affect the gastrointestinal tract like irritable bowel syndrome (IBS) and Crohn’s disease.
The ECS also seems to have an effect – whether directly or indirectly – on the serotonergic and adrenergic receptors. Alpha-adrenergic receptors, which are responsible for the uptake of the neurotransmitter norepinephrine, are responsible for the vasoconstriction of veins and decreasing the motility of smooth muscle in the gastrointestinal tract. The alpha-2 adrenergic receptor can inhibit insulin production when activated. Learning how to modulate this receptor via the ECS may help us treat diabetes and obesity.
Cannabinoids’ and terpenoids’ effects on serotonin, meanwhile, mean that it could be used to treat depression and anxiety, as well as pain. It seems as if cannabinoids can increase serotonin production, but this very much depends on the cannabinoid-terpenoid profile used and what type of depression is being treated. Again, we have noted above that anandamide might induce depression in some, as it causes drastic changes on the cellular level, and potentially reducing the amount of serotonin found in the brain and the body.
The precise ins- and outs- of the ECS and the way in which endocannabinoids and phytocannabinoids function is not fully known yet. The ECS was discovered around 27 years ago, and most of the mechanisms are not anywhere near understood fully. Part of the reason for this is because of the federal government’s stance on cannabis research, but another factor is the fact that the discovery of the ECS is relatively recent, and researchers are effectively trying to make sense of it all with the limited resources (and illegality) at their disposal.
However, many doctors and scientists are very excited at the discovery of the ECS and how it may help us manage conditions in the future. For many people, the discovery of the ECS made sense of the view “marijuana could very well be medicine”. We never had the science , language and the explanations to truly back this view up in the past. Now we do, and the idea of “medical marijuana” is no longer a realm for fantasists.