How cannabinoids reduce neuronal excitability is not exactly known but the following options are possible:
- Neuronal activity induces a Cl- influx through 2AG/Anandamide and CB2 (den Boon et al., 2014).
- Anandamide reduces burst-firing in neurons (Evans et al., 2008).
- cannabinoids reduce the number of neurotransmitter vesicles available for fusion (García-Morales et al., 2015).
So far, the only cannabinoids proven to be effective against epilepsy in clinical trials are CBD and THC (see below), but other cannabinoids like CBDV and THCV are likely to follow. In rats, THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011).
Similarly, CB1 activation decreases synchrony in cortical neurons (Sales-Carbonell et al., 2013) suggesting THC (like substances) can be used to suppress seizures. In healthy human volunteers, 10 mg oral THCV reduced functional network connectivity in the brain (measured by fMRI)(Rzepa et al., 2015). Although this does not prove anything in itself, it does support the idea that cannabinoids can reduce network synchronization. In heterologous cells (HEK293), THC and CBD were found to inhibit T-type calcium channels with an IC50 of approximately 1μM (Ross et al., 2008). THC-mediated inhibition was frequency dependent where CBD-mediated inhibition was not.
THCV significantly reduced epilepsy seizure incidence starting with doses of 0.25 mg/kg in animal models. THCV shows antiepileptiform and anticonvulsant properties, probably related to its activity in CB1 receptors (Gaston & Friedman, 2017; Hill et al., 2010).
CBDV, as well as CBD, have a huge potential to treat epilepsy (Gaston & Friedman, 2017; Rosenberg, Patra, & Whalley, 2017, Wallace et al., 2001). CBDV showed anticonvulsant properties in three different models of seizure, with additive effects when it was co-administered with CBD. Anticonvulsant properties of CBDV were not CB1 mediated (Hill et al., 2013). In vitro studies also support the anti-epileptic properties of CBDV (Amada, Yamasaki, Williams, & Whalley, 2013; A. J. Hill et al., 2012).
As T-type calcium channels function in thalamus-mediated synchronization of brain regions and are implicated in various types of epilepsy, THC and CBD are likely to suppress seizure generation. In human neuroblastoma cells (SH-SY5Y) and mouse cortical neurons CBD and CBG both blocked sodium channels Nav1.1, 1.2 and 1.5 (Hill et al., 2014). Interestingly, CBD but not CBG protected against pentyleneterzole (PTZ)-induced seizures in rat, suggesting that the anti-convulsant effect of CBD is not just through blocking sodium channels. Interestingly, cannabis was also shown to prevent the development of seizures/epilepsy (Brust et al., 1992), suggesting a prophylactic effect of cannabinoids. In mice, stimulating CB1 receptors (ACEA) or blocking TRPV1 receptors (capsazepine) protected against PTZ-induced seizures (Naderi et al., 2015). Interestingly, co-administration of both compounds attenuated the anti-convulsive effect, suggesting an interaction between CB1 and TRPV1 mediated signaling. In rats, the synthetic CB1 agonist WIN 55-212-2 was protective against the development of epilepsy when administered after an episode of status epilepticus (induced by pilocarpine)(Di Maio et al., 2014).
Cultured HEK293 cells carrying human epilepsy-associated mutations in Nav1.6 display increased resurgent sodium currents and increased excitability. 1 μM CBD reduced resurgent sodium currents and increased the refractory period. In cultured mouse striatal neurons CBD reduced overall action potential firing suggesting therapeutic potential (Patel et al., 2016).
Sub-acute treatment with WIN 55-212-2 for 15 days dramatically reduced the frequency of spontaneous seizures, their duration and intensity and the incidence of neuronal oxidative damage. In rats, WIN 55-212-2 delayed the onset of audiogenic epilepsy by two weeks suggesting a preventive effect of cannabinoid on the development of epilepsy as well as a curative effect (Vinogradova and van Rijn, 2015).
In a mouse model of epilepsy (Maximal Electro Shock), the following cannabinoids were found to be anti-convulsive (ED50)(Devinsky et al., 2014): CBD 120 mg/kg Δ9THC 100 mg/kg 11-OH-Δ9THC 14 mg/kg 8β-OH-Δ9THC 100 mg/kg Δ9THCA 200-400 mg/kg Δ8THC 80 mg/kg CBN 230 mg/kg Δ9α/β-OH-hexahydro-CBN 100 mg/kg Apart from that the doses reported above are incredibly high, it does provide a proof of principle that many cannabinoids exert anti-convulsive effects.
Amada, N., Yamasaki, Y., Williams, C. M., & Whalley, B. J. (2013). Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ, 1, e214. https://doi.org/10.7717/peerj.214
den Boon, F.S., Chameau, P., Houthuijs, K., Bolijn, S., Mastrangelo, N., Kruse, C.G., Maccarrone, M., Wadman, W.J., and Werkman, T.R. (2014). endocannabinoids produced upon action potential firing evoke a Cl(-) current via type-2 cannabinoid receptors in the medial prefrontal cortex. Pflüg. Arch. Eur. J. Physiol. 466, 2257–2268.
Brust, J.C., Ng, S.K., Hauser, A.W., and Susser, M. (1992). Marijuana use and the risk of new onset seizures. Trans. Am. Clin. Climatol. Assoc. 103, 176–181.
Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W.G., et al. (2014). Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791–802.
Di Maio, R., Cannon, J.R., and Timothy Greenamyre, J. (2014). Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiol. Dis. 73C, 356–365.
Evans, R.M., Wease, K.N., MacDonald, C.J., Khairy, H.A., Ross, R.A., and Scott, R.H. (2008). Modulation of sensory neuron potassium conductances by Anandamide indicates roles for metabolites. Br. J. Pharmacol. 154, 480–492.
García-Morales, V., Montero, F., and Moreno-López, B. (2015). cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo. Neuropharmacology.
Goonawardena, A.V., Riedel, G., and Hampson, R.E. (2011). cannabinoids alter spontaneous firing, bursting, and cell synchrony of hippocampal principal cells. Hippocampus 21, 520–531.
Hill, A.J., Jones, N.A., Smith, I., Hill, C.L., Williams, C.M., Stephens, G.J., and Whalley, B.J. (2014). Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci. Lett. 566, 269–274.
Hill, T.D.M., Cascio, M.-G., Romano, B., Duncan, M., Pertwee, R.G., Williams, C.M., Whalley, B.J., and Hill, A.J. (2013). Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br. J. Pharmacol. 170, 679–692.
Naderi, N., Shafieirad, E., Lakpoor, D., Rahimi, A., and Mousavi, Z. (2015). Interaction between cannabinoid Compounds and Capsazepine in Protection against Acute Pentylenetetrazole-induced Seizure in Mice. Iran. J. Pharm. Res. IJPR 14, 115–120.
Patel, R.R., Barbosa, C., Brustovetsky, T., Brustovetsky, N., and Cummins, T.R. (2016). Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain J. Neurol.
Rosenberg, E. C., Patra, P. H., & Whalley, B. J. (2017). Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. epilepsy & Behavior: E&B. https://doi.org/10.1016/j.yebeh.2016.11.006
Ross, H.R., Napier, I., and Connor, M. (2008). Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J. Biol. Chem. 283, 16124–16134.
Rzepa, E., Tudge, L., and McCabe, C. (2015). The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP.
Sales-Carbonell, C., Rueda-Orozco, P.E., Soria-Gómez, E., Buzsáki, G., Marsicano, G., and Robbe, D. (2013). Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony. Proc. Natl. Acad. Sci. U. S. A. 110, 719–724.
The occurrence of seizures was reduced by less than 50% in a further 37.5% with no effect observed in the remaining 12.5% (Cunha et al., 1980; Pickering et al., 2011). Another clinical trial investigating the therapeutic properties of CBD in epilepsy is currently underway. In 1949, the anti-convulsant activity of THC was tested on 5 children with severe grand mal epilepsy. In 3 children, THC was equally effective as previously tried therapies, in one child seizures were almost completely prevented and in the last one all seizures were stopped (Davis and Ramsey, 1949). In one very public case, a girl with Dravet syndrome (loss of function mutation in the sodium channel SCN1A), went from having more than 50 convulsive seizures per day to less than 3 nocturnal seizures per month by using extract from a Cannabis variety Charlotte’s Web, which has a THC content of 0.5% and a CBD content of 17% (Maa and Figi, 2014).
Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C., Gagliardi, R., Sanvito, W.L., Lander, N., and Mechoulam, R. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21, 175–185.
Davis, J.P., and Ramsey, H.H. (1949). Anti-epileptic action of marijuana-active substances. Federation Proceedings, vol. 8, p284.
Maa, E., and Figi, P. (2014). The case for medical marijuana in epilepsy. Epilepsia 55, 783–786.
Pickering, E.E., Semple, S.J., Nazir, M.S., Murphy, K., Snow, T.M., Cummin, A.R., Moosavi, S.H., Guz, A., and Holdcroft, A. (2011). cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety. Chron. Respir. Dis. 8, 109–118.