by Liz Sutherland, ND, and Jen Palmer, ND
The discovery of the endocannabinoid system (ECS) is one of the most important advances in the history of human medicine, yet very few healthcare practitioners learn anything about it during their training. In the same way that the existence of a planet is often deduced from the influence it has within a larger planetary context, the existence of the ECS was hypothesized in the 1960s when the precise chemical structures of the phytocannabinoids CBD (cannabidiol) and THC (tetrahydrocannabinol) were finally elucidated. Scientists could observe that these phytocannabinoids had effects on physiology, but they didn’t yet know the mechanism that made it possible for this to happen. The identification of the chemical structures of these phytocannabinoids paved the way for the discovery in mammalian brains of endocannabinoids, endogenous cannabinoid chemicals that are made by the body. The search to understand the metabolic pathways by which both phytocannabinoids and endocannabinoids interact with human physiology resulted in the astounding discovery in the 1990s of a previously unknown molecular signaling network, now known as the endocannabinoid system. It turns out, all living organisms, with the possible exception of insects, possess an endocannabinoid system.1
The Role of the Endocannabinoid System
The ECS appears to be nothing less than the master regulator of homeostasis involved with every known physiological system. It modulates an enormous range of biological processes, including neurogenesis, neuroprotection, cell growth, cell proliferation, inflammation, immune function, metabolic balance, vascular tone, smooth muscle contractility, motor control, nociception, learning, memory, appetite, digestion, mood, sleep-wake cycle, and reproduction. It responds to external input such as pain and stress, as well as monitoring energy metabolism and the intracellular flow of biological information necessary for life to function optimally.2,3,4 It has a crucial influence on both embryogenesis and post-natal development,5 including playing a critical role in brain maturation.6
The ECS is a complex, widely distributed system that for the sake of simplicity can be described as consisting of cannabinoid receptors; endogenous ligands known as endocannabinoids; and enzymes for ligand biosynthesis and catabolism.
The two major cannabinoid receptor sites are the G protein-coupled receptors (GPCR) known as CB1 and CB2. Cannabinoid receptors are ubiquitous, but as a general guideline: CB1 is widely expressed in the CNS, adipocytes, hepatocytes, skin, kidney, lungs, reproductive cells, and musculoskeletal tissue; CB2 is located in the peripheral nervous system, lymph tissue, immune system cells (including activated microglia in the CNS), bone, heart, and gastrointestinal tract.7
CB1 is the most highly expressed GPCR in the CNS. The high prevalence of CB2 receptors in immune tissue highlights the significant role of the ECS in regulating inflammation and immune function.8
The most well-characterized endocannabinoids are 2-arachidonoylglycerol (2-AG), and N-arachidonylethanolamine (AEA), commonly referred to as anandamide. Anandamide was the first endocannabinoid neurotransmitter identified. It was given the nickname “bliss molecule” based on the Sanskrit word for “joy,” in part because of its positive effects on mood. Most physiological systems use peptide mediators, but the endocannabinoids are synthesized from essential fatty acids derived from cell membrane phospholipids. As a consequence, virtually every cell possesses the necessary precursors in its membrane to manufacture anandamide and 2-AG.9 2-AG and anandamide have similar chemical structures, but they are synthesized and broken down by different enzyme pathways. In addition, their levels are regulated separately within cells, tissues, and organs, suggesting they likely have different and complementary physiological functions.7
In further contrast to most other signaling systems, anandamide and 2-AG are not synthesized in advance and stored in presynaptic vesicles. Instead, in keeping with the intrinsic role of the ECS in moment-to-moment homeostasis, they are synthesized within seconds and released “on demand,” in response to neuronal activation. Because of their on-demand role, endocannabinoids have a short half-life. They are catabolized quickly by the enzymes monoacylglycerol lipase (MAGL) in the case of 2-AG, and fatty acid amide hydrolase (FAAH) in the case of anandamide.
2-AG is a moderate affinity, full agonist for both CB1 and CB2 receptors.10 Activation of CB receptors by 2-AG is central to multiple biological processes and functions, including neuroinflammation;11
inflammation;12 neuroprotection;13 learning and memory;14 stress, anxiety, and depression;15 food intake;16 and nociception.17 2–AG is the most abundant endocannabinoid in the CNS, with brain levels about 170 times higher than that of anandamide.18 Studies suggest it is a potent neuromodulator, with major influence on synaptic plasticity and CNS development.19 It is possible that 2-AG can have both anti-inflammatory and pro-inflammatory effects depending on the physiological microenvironment and cell type targeted.20 For example, increases in 2-AG such as those observed in the early phases of ischemic stroke may have neuroprotective effects.21
Anandamide is a high affinity, partial agonist for CB1 receptors.10 It has the most powerful anti-inflammatory influence of the endocannabinoids, acting on cells of both the innate and adaptive immune systems (with the exception of NK and B cells). Some scientists consider anandamide to be the master regulator of the innate-adaptive immunity axis, with a pivotal role in resolving the immune response. Anandamide, along with many factors that support its signaling capacity (such as metabolizing enzymes and receptors) may be dysregulated in certain chronic inflammatory conditions.20
Human studies have shown an inverse correlation between baseline circulating anandamide levels and hypothalamic-pituitary-adrenal (HPA) axis reactivity, suggesting that high circulating levels of anandamide may protect against anxiety and stress reactions.22 Anandamide may play an important role in fear extinction, the ability to consciously repress the recall of intrusive thoughts and adverse memories. Animal studies have shown that fear extinction is associated with higher levels or increased signaling of anandamide in the amygdala, a brain region intrinsic to emotional regulation of trauma and fear in humans.23,24 Animal studies have also shown that raising anandamide levels by inhibiting its catabolizing enzyme FAAH can actually reverse anxiety-based behaviors.25,26 CBD is known to inhibit the breakdown and reuptake of anandamide. Anandamide appears to have cardioprotective effects,27,28 and to be involved in mechanisms of motivation and reward reinforcement.29
One of the most important ways that the ECS regulates homeostasis is by modulating the release of both excitatory and inhibitory neurotransmitters via a negative feedback mechanism known as retrograde signaling.30 2-AG, rather than anandamide, is the retrograde messenger in this process.31,32 When inhibition of neurotransmitter release involves GABAergic neurons, the result is suppression of inhibition; when it involves glutamatergic neurons, the result is suppression of excitation.
Most neurotransmitters are synthesized and stored presynaptically, then released into the synapse where they initiate their effects via postsynaptic neurons. The ECS works in the opposite direction. With retrograde signaling (also known as retrograde inhibition), postsynaptic neurons will trigger on-demand production of endocannabinoids that are then released into the synapse. From there, the endocannabinoids travel “backwards” and bind to receptors on the axon terminal of the presynaptic neuron thereby downregulating the intensity of its input. Post-synaptic receptors on the receiving end, for example, of a flood of excitatory neurotransmission, are able to send a signal backwards to presynaptic neurons for assistance in restoring homeostasis. By operating through retrograde signaling, the ECS is uniquely designed to regulate homeostasis. Retrograde signaling also enables the ECS to be neuroprotective by muting the type of excessive neuronal activity that can be present in seizures, pain syndromes, and sometimes in acute anxiety.33,34 In addition, presynaptic inhibition of neurotransmitter release is integral to synaptic plasticity, which is necessary for memory formation and learning.35,36
ECS Effects Beyond CB1 and CB2 Receptors
The extensive and wide-ranging influence of the ECS, especially with regard to pain, mood, and inflammation cannot be entirely accounted for by CB1 and CB2 receptor signaling alone. Mounting evidence indicates that receptor systems beyond CB1 and CB2 may be involved in mediating multiple ECS effects. With ongoing research, the list of receptor systems influenced by the ECS continues to grow as does the list of molecular targets potentially influenced either directly or indirectly by the phytocannabinoids, in particular CBD.
Transient receptor potential (TRP) receptors are a large family of receptors found throughout the body in both neuronal and non-neuronal tissue. A subcategory of this receptor family, TRPV1, was initially identified as a receptor for capsaicin. TRPV1 receptors are mainly expressed in sensory nerves. They are involved in sensing temperature, smell, and taste, as well as in regulating nociception. Both anandamide and 2-AG can activate TRPV1 receptors thereby modulating pain signals to the brain, with the result that pain sensitivity is diminished.37,38This ability to interrupt pain signaling makes the ECS an ideal target for the treatment of neuropathic pain.39 CBD is also an agonist at TRPV1 receptor sites.40
5-HT Serotonin Receptors
5-HT serotonergic receptors are widely expressed physiologically in a variety of tissues including the gastrointestinal tract and the brain, Endocannabinoids interact with the serotonergic system through numerous direct and indirect intracellular pathways, which may play a role in reducing anxiety.41CBD has also been shown to facilitate 5-HT neurotransmission via an indirect mechanism.442
Peroxisome Proliferator-Activated Receptors (PPAR)
The PPAR system is a family of nuclear receptors that consists of transcription factors for specific genes. PPARs are present in most tissues, playing an intrinsic role in optimal metabolic function and energy balance. Endocannabinoids interact with the PPAR system, and are able to activate different isoforms of this receptor family, in particular PPAR-α and PPAR-γ. The ability to interact with the PPAR system may help explain the beneficial impact of endocannabinoids on many processes including immunomodulation, neuroprotection, inflammation, analgesia, and vascular health.43,44,45 Studies show that CBD can directly activate PPAR-γ receptors thereby potentially mediating anti-inflammatory effects.46
GPR55 receptors are sometimes considered to be a third type of CB receptor. They are widely expressed in both the CNS and peripheral tissue, and regulate biological processes involved in numerous functions including motor coordination, nociception, energy balance, blood pressure, bone metabolism, and anxiety.47,48 Both the endogenous cannabinoids and CBD appear to interact with these receptors, but the mechanisms of action are complex and still being clarified.49
The importance of the ECS cannot be overemphasized. It plays a crucial role in areas that integrative physicians, naturopathic physicians, and other holistic practitioners consider to be foundational to their patients’ health. The human brain has more receptor sites for endocannabinoids than for all other neurotransmitter ligands combined, which, among other things, speaks to the importance of the ECS in regulating neuroinflammation.50Interestingly, in contrast to the endogenous opioid system, there are no cannabinoid receptors in the cardiac and respiratory centers of the brain stem, and so exogenous phytocannabinoids will not cause respiratory depression.51
Almost every cell of the innate immune system (such as macrophages, dendritic cells, neutrophils, NK cells, and mast cells), expresses endocannabinoid receptors. The ECS is also intricately involved in gastrointestinal health in multiple ways, including promoting the production of T-regulator cells, which are essential for gut tolerance and the prevention of food allergies and sensitivities.52 Endocannabinoids also interact with receptors beyond the ECS to support a variety of vital physiological processes.
From an evolutionary perspective, the ECS is characterized as being about survival, with its fundamental role in homeostasis summed up as “relax, eat, sleep, forget, and protect.”53
At a basic level this is true, but it’s important to remember that the ECS is interwoven with the ability to experience pleasure and enjoy life. For example, increased endocannabinoid levels from exercise improved mood in women with major depressive disorder.54And singing in a group with people who love to sing raised anandamide levels and improved other factors associated with ECS function.55
A rudimentary ECS is known to have evolved in primitive creatures more than 600 million years ago. This suggests that the ECS has acted as an integral force for species-wide evolution, including that of humans, from the earliest beginnings of animal life on Earth.