Fields of application in cannabinoid therapy.
Although cannabinoid therapy has mainly been used in the treatment of pain in recent years, there are numerous other areas of application. Here you will find a brief overview of the possible indications for treatment with cannabinoids.
Glaucoma
Glaucoma
Tourette's
Tourette's
Mental disorders
Mental disorders
Epilepsy
Epilepsy
Opiate
addiction
Opiate addiction
Spasticities
Spasticities
Pain
Pain
Anorexia
Anorexia
ADHD
ADHD
Anorexia
Nausea and vomiting are a kind of emergency system of the human body to effectively remove unwanted substances from the body. Since the human body reacts differently to therapies and drugs, nausea and vomiting can occur as a side effect of serious diseases and their therapies, such as cytostatic chemotherapy1 (CINV). In the case of CINV, science has made a breakthrough with the discovery of synthetic antiemetics, but these act on the serotonergic system and are ineffective in treating acute nausea and ineffective in delayed as well as anticipatory CINV. If inadequately treated, anorexia-cachexia syndrome (anorexia = decrease in appetite and interest in food intake, cachexia = emaciation of the body), a common symptom in palliative patients, develops rapidly. Especially in advanced cancer, severe infectious diseases or other severe diseases in advanced stages (e.g. Alzheimer's) anorexia/cachexia occurs.
The regulatory influences of the endocannabinoid system are medically highly interesting in cases of anorexia/cachexia. Motivational behaviour through the neurotransmitter dopamine, food intake and control of the energy balance are the clearest interfaces here. An appetite-stimulating effect of endocannabinoids is attributed, at least in part, to the activation of CB1 receptors in the hypothalamus and the mesocorticolimbic dopamine system²³.
1] Parker, L. A., Rock, E. M., & Limebeer, C. L. (2011). Regulation of nausea and vomiting by cannabinoids. British journal of pharmacology, 163(7), 1411-1422.
[2] Scherma, M., Satta, V., Fratta, W., & Fadda, P. (2015). The endocannabinoid system: anorexia nervosa and binge eating disorder. In Cannabinoids in neurologic and mental disease (pp. 389-413). Academic Press.
[3] Matias, I. (2007). Di Marzo V. Endocannabinoids and the control of energy balance. Trends Endocrinol Metab, 18, 27-37.
Epilepsy
Epilepsy is the most common severe neurological disorder worldwide, affecting approximately 50 million people1. However, the term "epilepsy" does not describe a single clinical picture, but a collective term for functional disorders in the brain. These disorders are caused by a defective excitation formation in the central nervous system (CNS) which is usually intensified by an additional lack of excitation limitation1. Thus, short episodes of involuntary movement or altered sensory perception occur. These can affect only a part (focal) or the entire body (generalized).
Specifically, epilepsy is diagnosed when any of the following conditions apply²:
- Two or more unprovoked seizures within 24 hours.
- One unprovoked seizure + at least 60% probability of another seizure within the next 10 years
- Diagnosis of epilepsy syndrome
Epilepsy has been repeatedly linked to dysfunction of the endocannabinoid system and specifically to neuroinflammation3,4. One of the main mediators of neuroinflammation are so-called microglia. These immune cells of the CNS react to a wide variety of (chemical) warning signals, which can have a damaging effect on the neuronal networks if activated in an uncontrolled manner.
Expression of both CB1 receptors and the enzyme responsible for the synthesis of one of the two most prominent endocannabinoids, 2-AG (diacylglycerol lipase-α) have a lower incidence in the hippocampus of epileptic patients5. Additionally, lower levels of the endocannabinoid anandamide (AEA) have been found in the cerebrospinal fluid of epileptic patients6.
[1] WHO. Epilepsy. Available online: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy (accessed on 16 May 2019).
[2] Robert S. Fisher et al: A practical clinical definition of epilepsy Epilepsia, 55(4):475-482, 2014 doi: 10.1111/epi.12550
[3] Vezzani, A.; Balosso, S.; Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat. Rev. Neurol. 2019, 15, 459-472.
[4] Rojas, A.; Chen, D.; Ganesh, T.; Varvel, N.H.; Dingledine, R. The COX-2/prostanoid signaling cascades in seizure disorders. Expert Opin. Ther. Targets 2019, 23, 1-13
(5) Ludányi, A.; Er˝oss, L.; Czirják, S.; Vajda, J.; Halász, P.; Watanabe, M.; Palkovits, M.; Maglóczky, Z.; Freund, T.F.; Katona, I. Downregulation of the CB1 cannabinoid receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus. J. Neurosci. 2008, 28, 2976-2990.
(6) Romigi, A.; Bari, M.; Placidi, F.; Marciani, M.G.; Malaponti, M.; Torelli, F.; Izzi, F.; Prosperetti, C.; Zannino, S.; Corte, F.; et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia 2010, 51, 768-772
Spasticities
Spasticities (also: spasticities) are uncontrolled muscle tensions (also: muscle tone), which are triggered by damage to the spinal cord or the brain. If this spinal cord damage leads to complete paralysis of both legs, this is referred to as paraplegia.1,2
Around 50% of all multiple sclerosis (MS) patients are affected by regular spasticities4. This autoimmune disease is characterized by the electrically insulating myelin sheaths of the nerve fibers in the central nervous system being attacked by the patient's own immune system. The exact pathophysiology of these spasticities is still quite unknown, but a loss of inhibitory circuits in the spinal cord is thought to play a major role³.
Since the endocannabinoid system has a modulatory effect on inflammatory and neurodegenerative processes, a possible modulatory effect in spasticity is also suggested.
Different mouse studies administered endocannabinoid receptor agonists, resulting in overall antispastic effects, with the exception of CB1-deficient mice4. This suggests an antispastic effect of endocannabinoids acting through the CB1 receptor. Other studies suggest a neuroprotective effect through activation of both CB receptors. More specifically, activation of CB1 leads to inhibition of excitotoxicity and activated CB2 receptors exert a modulatory effect on neuroinflammation 5,6,7.
[1] Paraplegia, DocCheck Flexicon (retrieved 09/14/20).
[2] Spasticity, DocCheck Flexikon (retrieved 14/09/20)
[3] Pryce G, Baker D (2007) Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br J Pharmacol 150
(4): 519-525 [4] Barnes M, Kent R, Semlyen J, McMullen K (2003) Spasticity in multiple sclerosis. Neurorehabil Neural Repair 17 (1): 66-70
[5] Sanchez A, Garcia-Merino A (2012) Neuroprotective agents: cannabinoids. Clin Immunol 142 (1): 57-67 [6] Kubajewska I, Constantinescu CS (2010) Cannabinoids and experimental models of multiple sclerosis. Immunobiology 215 (8): 647-657
[7] Gowran A, Noonan J, Campbell VA (2011) The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther 17 (6): 637-644
Opiate addiction
Worldwide, the number of people who abuse opiates is approximately 26-36 million. Opiate abuse and dependence is not only caused by the illegal acquisition of opiates, but mainly by their prescription as painkillers. This poses great risks, as the opioidergic system used can cause severe side effects in the respiratory system. Through a similar distribution of the corresponding receptors, it has been proven that synergistic effects can occur between the receptors of the endocannabinoid system and the opioidergic system. Especially through case studies it has already been shown that this synergistic effect can be used to reduce the prescription amount of opiates.
[1] Wiese, B., & Wilson-Poe, A. R. (2018). Emerging evidence for cannabis' role in opioid use disorder.Cannabis and cannabinoid research, 3(1), 179-189.
[2] Nielsen, S., Sabioni, P., Trigo, J. M., Ware, M. A., Betz-Stablein, B. D., Murnion, B., ... & Le Foll, B. (2017). Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis.Neuropsychopharmacology, 42(9), 1752-1765.
[3] Caldera, F. E. (2020). Medical cannibus as an alternative for opioids for chronic pain: A case report.SAGE Open Medical Case Reports, 8, 2050313X20907015.
Pain
Pain is a warning system of the human body to alert us to disorders and problems. Therefore, pain can be an accompanying symptom of various diseases, e.g. cancer, multiple sclerosis or inflammatory rheumatic diseases. A special form of this is so-called "neuropathic pain", which includes pain that occurs after damage to somatosensory nerve structures in the peripheral or central nervous system (including HIV, diabetes, cytostatic treatments). These causes often lead to so-called "chronic pain", which is referred to when
- pain persists 3 months after the appropriate time for the wound to heal, or
- pain is associated with a chronic pathological process that continuously causes pain²
Chronic pain is usually followed by an increase in nociceptive (= "pain-sensitive") neural networks in the central nervous system. As with so many processes in the human body, the endocannabinoid system seems to have a regulating effect, which becomes noticeable as soon as the ECS modulates this effect.
High numbers of cannabinoid receptors have been found in brain areas directly associated with pain processing (periaqueductal gray, dorsal root ganglia, peripheral ends of afferent pathways). Their analgesic effect lies in the activation of descending pain modulating neural pathways and in the inhibition of neurotransmitter release in nociceptive afferent neural pathways. This effectively reduces pain signals in brain centers and the spinal cord and reduces mild inflammation through neuroprotective and anti-inflammatory effects³.
A dysfunctional endocannabinoid system is suspected to be the cause of a wide variety of complaints, such as a clinical endocannabinoid deficit in fibromyalgia4.
(2) Bonica JJ (2001) Bonica's management of pain. Lippincott Williams & Wilkins, Philadelphia.
(3) Zhang J, Echeverry S, Lim TK, Lee SH, Shi XQ, Huang H (2015) Can modulating inflammatory response be a good strategy to treat neuropathic pain? CurrPharmaceut Design (21): 831-839
(4) Russo EB (2008) Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett (29): 192-200
Tourette's Syndrome
Tourette syndrome (TS) is a neuropsychiatric disorder. The main symptoms are motor and vocal tics. The pathophysiology behind Tourette's syndrome is not known, but it usually develops from the age of 7 and is particularly pronounced during puberty. In rare cases, after the age of 25, a regression of symptoms can lead to an improvement in the burden of the disease. Several theories have emerged which attempt to explain the development (aetiology) of TS. Possible causes of TS are therefore:
- Imbalance of the neurotransmitters dopamine and serotonin
- Possible inheritability
- Autoimmune disease: autoantibodies against basal ganglia in the central nervous system
The main role of the endocannabinoid system is the inhibitory modulation of neurotransmitter systems. Since a large proportion of the symptoms of TS are triggered by a dysregulation of these neurotransmitters, a role of the ECS is obvious. Cannabinoid receptor 1 is present with high prevalence in the basal ganglia, suggesting an effect on motor functions here.
[1] Tourette Syndrome, DocCheck Flexikon
[2] Szejko, N., Jakubovski, E., & Müller-Vahl, K. (2018). Possible Role of the Endocannabinoid System in Tourette Syndrome. In Recent Advances in Cannabinoid Research. IntechOpen.
Mental disorders
In today's modern world, a wide variety of mental disorders have a high prevalence within the population. Especially in the early stages of life, this leads to a wide variety of changes in thinking, feeling or acting.
The causes for such limitations can be multifaceted: an individual developmental/learning history, environmental factors as well as the individual (genetic) predisposition of a person can equally exert effects on mental health1. On a neurobiological level, the different influences result in a multifaceted interplay between neurotransmitter and neuromodulator systems. Partly due to this versatility, etiology and pathophysiology are not always clearly identifiable, but in recent years there has been increasing evidence for the involvement of the endocannabinoid system in these processes2,3,4.
1] Leweke FM, Koethe D (2008) Cannabis and psychiatric disorders: it is not only addiction. Addict Biol 13 (2): 264-275. doi: 10.1111/j.1369-1600.2008.00106.x
[2] Marco EM, Garcia-Gutierrez MS, Bermudez-Silva FJ, Moreira FA, Guimaraes F, Manzanares J, Viveros MP (2011) Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front Behav Neurosci 5: 63. doi: 10.3389/fnbeh.2011.00063
[3] Rubino T, Zamberletti E, Parolaro D (2015) Endocannabinoids and mental disorders. Handb Exp Pharmacol 231: 261-283. doi: 10.1007/978-3-319- 20825-1_9
[4] Schaefer C, Enning F, Mueller JK, Bumb JM, Rohleder C, Odorfer TM, Klosterkotter J, Hellmich M, Koethe D, Schmahl C, Bohus M, Leweke FM (2014) Fatty acid ethanolamide levels are altered in borderline personality and complex posttraumatic stress disorders. Eur Arch Psychiat Clin Neurosci 264 (5): 459-463. doi: 10.1007/s00406–013–0470–8
Glaucoma
Glaucoma is the second most common cause of blindness in Germany1 and refers to eye diseases of various causes, which lead to irreversible damage of the optic nerve ('Nervus Opticus') and the loss of retinal ganglion cells. A classical form of prevention is the regular measurement of intraocular pressure. Although there is no direct causality between intraocular pressure and retinal ganglion cell loss, the risk of further progression of the disease is reduced by 10% with every 1mmHg reduction in intraocular pressure².
Receptors of the endocannabinoid system are also found in the eye tissue, the two endocannabinoids 2-AG and AEA are found in the entire eye, except for the lens³.
Current therapies focus on reducing intraocular pressure and animal and clinical studies show that activation of the CB1 receptor leads to this reduction in intraocular pressure4.
[1] RKI: GBE issue on blindness and visual impairment 2017
[2] Nucci, C., Bari, M., Spanò, A., Corasaniti, M., Bagetta, G., Maccarrone, M., & Morrone, L. A. (2008). Potential roles of (endo) cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection.Progress in brain research, 173, 451-464.
[3] J.Chen,I.Matias,T.Dinhetal., "Findingofendocannabinoids in human eye tissues: implications for glaucoma," Biochemical and Biophysical Research Communications, vol. 330, no. 4, pp. 1062-1067,2005.
[4] Cairns, E. A., Baldridge, W. H., & Kelly, M. E. (2016). The endocannabinoid system as a therapeutic target in glaucoma.Neural plasticity, 2016.
ADHD
ADHD is mainly manifested by a reduced ability to concentrate, with a dysfunction of the dopamine system being caused. The endocannabinoid and dopamine systems influence each other. Animal studies have shown that dopamine has a regulatory effect on the endocannabinoid system and that the endocannabinoid system is dysregulated in ADHD cases1.
Mouse studies show dysfunction of the endocannabinoid system in cases of ADHD mice² and also show that dopamine plays a crucial role in regulating the endocannabinoid system³. This suggests that restored CB1 receptor function may be an effective form of therapy for ADHD4.
[1] American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th ed.). doi:10.1176/appi.books.9780890425596
[2] Castelli, M., Federici, M., Rossi, S., De Chiara, V., Napolitano, F., Studer, V., . . . Centonze, D. (2011). Loss of striatal cannabinoid CB1 receptor function in attention-deficit/hyperactivity disorder mice with point mutation of the dopamine transporter. European Journal of Neuroscience, 34. doi:10.1111/j.1460-9568.2011.07876.x
[3] Bracci, E. (2011). The endocannabinoid system misfires in ADHD mice (Commentary on Castelli et al.). European Journal of Neuroscience, 34. doi:10.1111/j.1460-9568.2011.07917.x
[4] Barchel, D., Stolar, O., De-Haan, T., Ziv-Baran, T., Saban, N., Fuchs, D. O., . . . Berkovitch, M. (2019). Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Frontiers in Pharmacology. doi:10.3389/fphar.2018.01521
