ECS & the Nervous System

The nervous system can be divided into the central (brain, spinal cord) and the peripheral nervous system (sympathetic, parasympathetic and enteric nervous system (ENS)). Endocannabinoid receptors are expressed in the central and the peripheral nervous system as well as on other associated cell types; the most common receptor is CB1. The main function of the endocannabinoid systems is to suppress the release of other neurotransmitters. The responsiveness of the cannabinoid receptor is dynamic and generates different physiological effects, depending on the region of its expression. Some implications for cannabis as potential candidate for the treatment of neurologic, neurodegenerative and psychiatric disorders are introduced here.

The central nervous system (CNS) is comprised of the nervous structures in the brain and spinal cord that compute sensory stimuli entering from the periphery. Furthermore, the CNS controls voluntary movement and is the seat of unconscious and conscious thought processes (cognition and emotion). The nervous tissue can be roughly divided into grey and white matter due to its macroscopic appearance in organ sections. The grey matter is located in the outer area of the brain and in the inner area of the spinal cord. It primarily consists of neuronal cell bodies. The white matter is mainly comprised of the projections of these neurons (axons, myelinated with glia cells), the) nerve fibers connect the neurons for the transmission of signals.

Topographically distinct from the CNS, the peripheral nervous system (PNS) is located outside of the skull and the vertebral canal. It is primarily comprised of the spinal nerves and connects the CNS with the effector organs. The peripheral nervous systems can further be subdivided into the somatic nervous system (voluntary nervous system; controls skeletal muscles) and the vegetative / autonomic nervous system (involuntary nervous system, controls vital functions such as breathing, digestion, metabolism, sexual organs and reflexes). The vegetative nervous system consists of two antagonistic systems, the sympathetic (puts the body into elevated performance ability, depletion of energy reserves, „fight or flight“) and the parasympathetic nervous system (to regenerate the organism, build-up of energy reserves, „rest and digest“), as well as the enteric nervous system (ENS; „abdominal brain“ or „gut brain“, runs through the entire gastrointestinal tract)1.

The major function of the endocannabinoid system is to inhibit the release of other neurotransmitters (see table 1). Stimuli are transmitted as action potentials from the cell body of a neuron along its axon to the synaptic knob. Presynaptic neurotransmitters are secreted into the synaptic cleft and stimulate postsynaptic receptors. The subsequent neuron processes all incoming stimuli (from various neurons) and “decides” whether it will generate an action potential itself, which again will be transmitted along its axon. Following postsynaptic depolarization or neurotransmitter signaling pathways, endocannabinoids are produced “on demand” and are released postsynaptically. They diffuse across the synaptic cleft and bind to presynaptic CB1 receptors. These inhibit the further release of neurotransmitters.

Excitatory Neurotransmitters Corresponding disorder
Exciting Amino Acids
Glutamate epilepsy, nerve cell death in ischemia and hypoxia (stroke, traumatic brain injury, nerve gas damage)
Inhibitory Amino Acids
GABA (gamma-amino-butyric acid) disorders of spinal cord function, epilepsy
Glycine Hyperekplexie and other syndromes with increased fright
Monoamine
Norepinephrine autonomous homeostasis, hormones, depression
Serotonin depression, anxiety, migraine, vomiting
Dopamine Parkinson's disease, schizophrenia, vomiting, epiphyseal hormones, drug addiction
Acetylcholine neuromuscular disorders, autonomic homeostasis (heart rate, blood pressure), dementia, parkinsonism, epilepsy, sleep-wake cycle
Neuropeptides (endorphins, enkephalins) pain, movement, neural development, anxiety
Table 1. Neurotransmitter function under the control of the endocannabinoid system. Taken from "Cannabis- Arbeitshilfe für die Apotheke" Häußermann, Grotenhermen, Milz

CB1 is by far the most prevalent G protein-coupled endocannabinoid receptor in the CNS. Furthermore, it is also expressed on neurons of the peripheral nervous system and other cell types. In addition, amongst others CB2, GPR55 and vanilloid receptors should be mentioned. CB1 is coupled negatively to adenylate cyclase and is either negatively or positively associated with selective ion channels. CB1 is mainly expressed in the basal ganglia, in the cerebellum and in the limbic system / hippocampus, which explains the known effects of cannabis on emotional condition, motor coordination and short-term memory formation (see Fig. 1). In a similar way CB1 is densely expressed in dorsal and primarily afferent regions of the spinal cord that are important for pain transmission, while being scarcely expressed in the brain stem that controls many vital functions. The responsiveness of the receptor is dynamic and it generates different levels of stimulation / physiologic effects depending on the region where it is expressed. The parasympathic effects (“rest and digest”) of cannabis are predominant which can be exploited in the treatment of eating or metabolic disorders, amongst others3; it is possible that this effect is based on the inhibition of the HPA stress axis.4

Fig. 1 (adapted from Baker et al., 20035)

CB1 expression in the brain varies with location. The concentration of CB1 is highest (intensity of green) in the basal ganglia, globus plallidus (GP), and substantia nigra (SN); moderate in the cerebellum (Cer), hippocampus (H), caudate nucleus (C), putamen (P), hypothalamus (Hy), and amygdala (Am); low in the cortex; and very low (grey) in white matter.

The inhibitory effect of cannabis on memory formation and affect that can be useful i.e. in the treatment of posttraumatic stress, is likely based on stimulation of CB1 in the hippocampus or the amygdala, respectively.6

The dopaminergic system that is important for motor control, motivation, concentration and other higher cognitive functions seems to be modulated by cannabinoids on various levels7; CB1 receptors can be found on excitatory glutamatergic and inhibitory GABAergic neurons that regulate the activity of dopamine neurons.  Dopaminergic neurons can synthesize endocannabinoids that in turn act on (presynaptic) GABAergic and glutamatergic neurons and thereby inhibit them. It is likely that the clinically observed positive therapeutic effects of medical cannabis in conditions such as ADHS, depression and Parkinson´s disease are due to the fine tuning of the dopaminergic systems. Dopamine also promotes blood circulation of the kidneys and modulates intestinal activity.

Cannabinoid receptors in the basal ganglia and the cerebellum are involved in the modulation of fine-motor skills.

An improved control of motor function through THC is clinically proven in neurological diseases such as the Tourette syndrome and Chorea Huntington. Also, epileptic seizures respond in a beneficial way to cannabis treatment.

However, in this case it seems as if the non-psychotropic phytocannabinoid CBD should be preferred as active substance. CBD has been investigated in detail in clinical trials for the treatment of pharmaco-resistant epilepsy even in children.8

The endogenous opiate system is also modulated by the endocannabinoid system which especially plays a role in the treatment of (neuropathic) chronic pain and spasticity, respectively: the effects of cannabinoids and opiates unfold synergistically which can be utilized to reduce the dose of opioid medication or to taper off entirely. Besides the objectively measurable analgesia, cannabis seems to have positive effects on the emotional assessment of pain that leads to an overall improved quality of life.9,10

Tumors (i.e. gliomas) and autoimmune disorders of the nervous system (i.e. multiple sclerosis), as well as neurodegenerative diseases (i.e. Alzheimer´s disease, ALS) show responsiveness to cannabinoid medication in animal models as well as in vitro studies. Medical cannabis (or the active substance THC, respectively) is pharmaceutically approved for the treatment of these diseases to improve pain symptoms, spasticity and cachexia; furthermore, possible curative effects can be explained by anti-inflammatory and neuroprotective properties of various other cannabinoids present in cannabis (i.a. CBD, CBG and CBC).8,11,12,13,14

Especially for dementia, various mechanisms were identified through which THC and CBD from cannabis prevent aggregation of beta-amyloid plaques in the brain, the most prominent pathologic marker of Alzheimer´s disease.13,15,16

In this light it is desirable that neuroscientists further investigate the promising effects of the endocannabinoid system and its plant-based ligands for disorders of the nervous system, in order to allow more patients to benefit from the therapeutic potential of cannabinoid medication, which usually has only moderate side effects.

[1] http://flexikon.doccheck.com/

[2] Cannabis: Arbeitshilfe für die Apotheke von Klaus Häußermann; Franjo Grotenhermen; Eva Milz beim ZVAB.com – ISBN 10: 3769269845 – ISBN 13

[3] Capasso A, Milano W, Cauli O. Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders. Endocrine, Metab Immune Disord – Drug Targets. 2018;18(4):325-332. doi:10.2174/1871530318666180213112406

[4] Micale V, Drago F. Endocannabinoid system, stress and HPA axis. Eur J Pharmacol. 2018;834:230-239. doi:10.1016/j.ejphar.2018.07.039

[5] Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic potential of cannabis. Lancet Neurol. 2003;2(5):291-298. doi:10.1016/S1474-4422(03)00381-8

[6] Principles of Neuropsychopharmacology; Chapter 17: Mind-altering drugs. Robert S. Feldman, Jerrold S. Meyer, Linda F. Quenzer. ISBN-10: 0878931759; ISBN-13: 978-0878931750

[7] http://profofpot.com/thc-effects-dopamine/

[8] Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007;9(4):413-430. http://www.ncbi.nlm.nih.gov/pubmed/18286801. Accessed July 31, 2018.

[9] https://www.aerzteblatt.de/archiv/34138/Chronische-Schmerzen-Cannabis-verhindert-Schmerz-und-Spastik

[10] Sharon H, Goldway N, Goor-Aryeh I, Eisenberg E, Brill S. Personal experience and attitudes of pain medicine specialists in Israel regarding the medical use of cannabis for chronic pain. J Pain Res. 2018;11:1411-1419. doi:10.2147/JPR.S159852

[11] Gugliandolo A, Pollastro F, Grassi G, Bramanti P, Mazzon E. In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-psychotropic Cannabinoid. Int J Mol Sci. 2018;19(7):1992. doi:10.3390/ijms19071992

[12] Velasco G, Hernández-Tiedra S, Dávila D, Lorente M. The use of cannabinoids as anticancer agents. Prog Neuro-Psychopharmacology Biol Psychiatry. 2016. doi:10.1016/j.pnpbp.2015.05.010

[13] Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci. 2015;16(1):30-42. doi:10.1038/nrn3876

[14] Alberti TB, Barbosa WLR, Vieira JLF, Raposo NRB, Dutra RC. (-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int J Mol Sci. 2017;18(4). doi:10.3390/ijms18040691

[15] Eubanks LM, Rogers CJ, Beuscher AE, et al. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol Pharm. 2006;3(6):773-777. doi:10.1021/mp060066m

[16] Esposito G, Scuderi C, Savani C, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151(8):1272-1279. doi:10.1038/sj.bjp.0707337