Cannabidiol and Seizures: Research References

mouseHere is a 40-year list of relevant articles from 2013 back to 1973. For some thoughts on the possible application to children and adults with MECP2 Duplication Syndrome, see Cannabidiol: Can it help?

Z. Shirazi-zand, L. Ahmad-Molaei, F. Motamedi and N. Naderi. (2013). The role of potassium BK channels in anticonvulsant effect of cannabidiol in pentylenetetrazole and maximal electroshock models of seizure in mice. Epilepsy Behav, 28(1), 1-7

Cannabidiol is a nonpsychoactive member of phytocannabinoids that produces various pharmacological effects that are not mediated through putative CB1/CB2 cannabinoid receptors and their related effectors. In this study, we examined the effect of the i.c.v. administration of potassium BK channel blocker paxilline alone and in combination with cannabidiol in protection against pentylenetetrazol (PTZ)- and maximal electroshock (MES)-induced seizure in mice. In the PTZ-induced seizure model, i.c.v. administration of cannabidiol caused a significant increase in seizure threshold compared with the control group. Moreover, while i.c.v. administration of various doses of paxilline did not produce significant change in the PTZ-induced seizure threshold in mice, coadministration of cannabidiol and paxilline attenuated the antiseizure effect of cannabidiol in PTZ-induced tonic seizures. In the MES model of seizure, both cannabidiol and paxilline per se produced significant increase in percent protection against electroshock-induced seizure. However, coadministration of cannabidiol and paxilline did not produce significant interaction in their antiseizure effect in the MES test. The results of the present study showed a protective effect of cannabidiol in both PTZ and MES models of seizure. These results suggested a BK channel-mediated antiseizure action of cannabidiol in PTZ model of seizure. However, such an interaction might not exist in MES-induced convulsion.
T. D. Hill, M. G. Cascio, B. Romano, M. Duncan, R. G. Pertwee, C. M. Williams, B. J. Whalley and A. J. Hill. (2013). Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB receptor-independent mechanism. Br J Pharmacol

BACKGROUND AND PURPOSE: Epilepsy is the most prevalent neurological disease and is characterised by recurrent seizures. Here we investigate: (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDS) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors. EXPERIMENTAL APPROACH: The anticonvulsant profiles of two CBDV BDSs (50-422 mg kg-1 ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip-strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays. KEY RESULTS: CBDV BDSs exerted significant anticonvulsant effects in the PTZ (>/=100 mg kg-1 ) and audiogenic seizure models (>/=87 mg kg-1 ), and suppressed pilocarpine-induced convulsions (>/=100 mg kg-1 ). The isobolographic study revealed the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip-strength were found. The Delta9 -THC and Delta9 -THCV content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CONCLUSIONS AND IMPLICATIONS: CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor, and were of comparable efficacy to purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for treatment of epilepsy.
N. A. Jones, S. E. Glyn, S. Akiyama, T. D. Hill, A. J. Hill, S. E. Weston, M. D. Burnett, Y. Yamasaki, G. J. Stephens, B. J. Whalley and C. M. Williams. (2012). Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure, 21(5), 344-52

Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (>/= 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.

T. Barichello, R. A. Ceretta, J. S. Generoso, A. P. Moreira, L. R. Simoes, C. M. Comim, J. Quevedo, M. C. Vilela, A. W. Zuardi, J. A. Crippa and A. L. Teixeira. (2012). Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur J Pharmacol, 697(1-3), 158-64

Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10mul of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with cannabidiol (2.5, 5, or 10mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of cannabidiol at different doses reduced the TNF-alpha level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.
N. A. Jones, A. J. Hill, I. Smith, S. A. Bevan, C. M. Williams, B. J. Whalley and G. J. Stephens. (2009). Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther, 332(2), 569-77

Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
F. J. Alvarez, H. Lafuente, M. C. Rey-Santano, V. E. Mielgo, E. Gastiasoro, M. Rueda, R. G. Pertwee, A. I. Castillo, J. Romero and J. Martinez-Orgado. (2008). Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res, 64(6), 653-8

To test the neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol (CBD), piglets received i.v. CBD or vehicle after hypoxia-ischemia (HI: temporary occlusion of both carotid arteries plus hypoxia). Nonhypoxic-ischemic sham-operated piglets remained as controls. Brain damage was studied by near-infrared spectroscopy (NIRS) and amplitude-integrated electroencephalography (aEEG) and by histologic assessment (Nissl and FluoroJadeB staining). In HI+vehicle, HI led to severe cerebral hemodynamic and metabolic impairment, as reflected in NIRS by an increase in total Hb index (THI) and a decrease in the fractional tissue oxygenation extraction (FTOE); in HI+CBD the increase of THI was blunted and FTOE remained similar to SHAM. HI profoundly decreased EEG amplitude, which was not recovered in HI+vehicle, indicating cerebral hypofunction; seizures were observed in all HI+vehicle. In HI+CBD, however, EEG amplitude recovered to 46.4 7.8% baseline and seizures appeared only in 4/8 piglets (both p < 0.05). The number of viable neurons decreased and that of degenerating neurons increased in HI+vehicle; CBD reduced both effects by more than 50%. CBD administration was free from side effects; moreover, CBD administration was associated with cardiac, hemodynamic, and ventilatory beneficial effects. In conclusion, administration of CBD after HI reduced short-term brain damage and was associated with extracerebral benefits.
J. D. Wilkinson, B. J. Whalley, D. Baker, G. Pryce, A. Constanti, S. Gibbons and E. M. Williamson. (2003). Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects? J Pharm Pharmacol, 55(12), 1687-94

Cannabis is under clinical investigation to assess its potential for medicinal use, but the question arises as to whether there is any advantage in using cannabis extracts compared with isolated Delta9-trans-tetrahydrocannabinol (Delta9THC), the major psychoactive component. We have compared the effect of a standardized cannabis extract (SCE) with pure Delta9THC, at matched concentrations of Delta9THC, and also with a Delta9THC-free extract (Delta9THC-free SCE), using two cannabinoid-sensitive models, a mouse model of multiple sclerosis (MS), and an in-vitro rat brain slice model of epilepsy. Whilst SCE inhibited spasticity in the mouse model of MS to a comparable level, it caused a more rapid onset of muscle relaxation, and a reduction in the time to maximum effect compared with Delta9THC alone. The Delta9THC-free extract or cannabidiol (CBD) caused no inhibition of spasticity. However, in the in-vitro epilepsy model, in which sustained epileptiform seizures were induced by the muscarinic receptor agonist oxotremorine-M in immature rat piriform cortical brain slices, SCE was a more potent and again more rapidly-acting anticonvulsant than isolated Delta9THC, but in this model, the Delta9THC-free extract also exhibited anticonvulsant activity. Cannabidiol did not inhibit seizures, nor did it modulate the activity of Delta9THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. antispasticity), Delta9THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) Delta9THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb might be due to the Delta9THC content.
E. Gordon and O. Devinsky. (2001). Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia, 42(10), 1266-72

We review the safety of alcohol or marijuana use by patients with epilepsy. Alcohol intake in small amounts (one to two drinks per day) usually does not increase seizure frequency or significantly affect serum levels of antiepileptic drugs (AEDs). Adult patients with epilepsy should therefore be allowed to consume alcohol in limited amounts. However, exceptions may include patients with a history of alcohol or substance abuse, or those with a history of alcohol-related seizures. The most serious risk of seizures in connection with alcohol use is withdrawal. Alcohol withdrawal lowers the seizure threshold, an effect that may be related to alcohol dose, rapidity of withdrawal, and chronicity of exposure. Individuals who chronically abuse alcohol are at significantly increased risk of developing seizures, which can occur during withdrawal or intoxication. Alcohol abuse predisposes to medical and metabolic disorders that can lower the seizure threshold or cause symptoms that mimic seizures. Therefore, in evaluating a seizure in a patient who is inebriated or has abused alcohol, one must carefully investigate to determine the cause. Animal and human research on the effects of marijuana on seizure activity are inconclusive. There are currently insufficient data to determine whether occasional or chronic marijuana use influences seizure frequency. Some evidence suggests that marijuana and its active cannabinoids have antiepileptic effects, but these may be specific to partial or tonic-clonic seizures. In some animal models, marijuana or its constituents can lower the seizure threshold. Preliminary, uncontrolled clinical studies suggest that cannabidiol may have antiepileptic effects in humans. Marijuana use can transiently impair short-term memory, and like alcohol use, may increase noncompliance with AEDs. Marijuana use or withdrawal could potentially trigger seizures in susceptible patients.
A. R. Martin, P. Consroe, V. V. Kane, V. Shah, V. Singh, N. Lander, R. Mechoulam and M. Srebnik. (1987). Structure-anticonvulsant activity relationships of cannabidiol analogs. NIDA Res Monogr, 79, 48-58

Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1″,1″-dialkylhexyl and 1″,1″-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.
F. R. Ames and S. Cridland. (1986). Anticonvulsant effect of cannabidiol. S Afr Med J, 69(1), 14
R. Karler, L. D. Calder and S. A. Turkanis. (1984). Changes in CNS sensitivity to cannabinoids with repeated treatment: tolerance and auxoesthesia. NIDA Res Monogr, 54, 312-22
P. Consroe, M. A. Benedito, J. R. Leite, E. A. Carlini and R. Mechoulam. (1982). Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol, 83(3-4), 293-8

In mice, running, clonic and tonic convulsions and lethality were assessed following transcorneal (electroshock) current or convulsant drugs, each administered alone and after cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gamma-aminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin (PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC). Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC = current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to prevent the occurrence of the other behavioral endpoints of the above treatments. CBD also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.
B. K. Colasanti, C. Lindamood, 3rd and C. R. Craig. (1982). Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats. Pharmacol Biochem Behav, 16(4), 573-8

Rats rendered chronically epileptic by bilateral implantation of cobalt into frontal cortices were simultaneously prepared with permanent electrodes for longitudinal recording of the electroencephalogram (EEG) and electromyogram (EMG). Delta-8-tetrahydrocannabinol (delta-8-THC; 10 mg/kg), delta-9-tetrahydrocannabinol (delta-9-THC; 10 mg/kg), cannabidiol (CBD; 60 mg/kg), or polyvinylpyrrolidone (PVP) vehicle (2 ml/kg) was administered IP twice daily from day 7 through 10 after cobalt implantation, at which time generalized seizure activity in non-treated cobalt-epileptic rats was maximal. Relative to PVP-treated controls, CBD did not alter the frequency of appearance of seizures during the course of repeated administration. In contrast, both delta-8-THC and delta-9-THC markedly reduced the incidence of seizures on the first and second days of administration. Interictal spiking during this period, on the other hand, was actually enhanced. On the third and fourth days, tolerance to the effect on seizures was evident, with a return of seizure frequency of THC-treated rats to values not significantly different from those of controls. Unlike the effect on seizures, no tolerance developed to the marked suppression of rapid eye movement (REM) sleep induces by delta-8-THC and delta-9-THC. REM sleep remained reduced in the treated animals during the first 2 days after termination of THC administration. In contrast, REM sleep time was unaffected by repeated administration of CBD. These results suggest that delta-8-THC and delta-9-THC exert their initial anticonvulsant effect by limiting the spread of epileptogenic activity originating from the cobalt focus.
S. A. Turkanis and R. Karler. (1981). Excitatory and depressant effects of delta 9-tetrahydrocannabinol and cannabidiol on cortical evoked responses in the conscious rat. Psychopharmacology (Berl), 75(3), 294-8

The influences of delta 9-tetrahydrocannabinol (THC) and cannabidiol on electrically evoked cortical potentials of conscious rats with chronically implanted electrodes were investigated. Specifically, the cannabinoids’ effects on a transcallosal evoked response were compared with those of ethosuximide, phenytoin, and pentylenetetrazol. THC produced dose-related opposite effects: Low doses increased the amplitude of the response, whereas higher doses reduced the response. Other drugs that can cause or exacerbate seizures, i. e., phenytoin and pentylenetetrazol, also increased the amplitude of the cortical response. In contrast, cannabidiol, over a wide dosage range, caused only depression. Ethosuximide, like cannabidiol, elicited a depressant effect. The data indicate that under the conditions of the present investigation, cannabidiol shares electrophysiological properties with ethosuximide but not with phenytoin, and that cannabidiol is a relatively selective, centrally acting drug. In addition, our findings support the suggestion that augmentation of neurotransmission in central pathways may contribute to the convulsant actions of THC, and the cannabinoids’ depressant effects may, at least partially, account for their anticonvulsant actions.
R. Karler and S. A. Turkanis. (1981). The cannabinoids as potential antiepileptics. J Clin Pharmacol, 21(8-9 Suppl), 437S-448S

Comparative studies of the anticonvulsant properties of the cannabinoids and prototype antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an anticonvulsant, cannabidiol (CBD), in contrast to delta 9-tetrahydrocannabinol (THC), is relatively selective in terms of both central nervous system (CNS), depressant and excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and phenobarbital, varies greatly with the species; (3) the large potency difference between the cannabinoids and the antiepileptics in the mouse appears to be due to dispositional differences, because brain concentrations of all the drugs are very similar; (4) tolerance to the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure models, tolerance developed in one, but “reverse tolerance” developed in the other two; and (5) the results of a study of the electrophysiologic mechanisms of action indicate that cannabidiol produces some unique effects and that its spectrum of antiepileptic activity may be different from that of the prototype drugs. The anticonvulsant nature of cannabidiol suggests that it has a therapeutic potential in at least three of the four major types of epilepsy: grand mal, cortical focal, and complex partial seizures.

P. Consroe, A. Martin and V. Singh. (1981). Antiepileptic potential of cannabidiol analogs. J Clin Pharmacol, 21(8-9 Suppl), 428S-436S

In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous) dose-response effects of (–)-cannabidiol (CBD) for preventing AGS and for causing rototod neurotoxicity (ROT) were determined. Also, the anti-AGS and ROT effects of 10 CBD analogs, given in intravenous doses equivalent to the AGS-ED50 (15 mg/kg) and ROT-ID50 (31 mg/kg) of CBD, were ascertained. Compared to CBD, (–)-CBD diacetate and (–)-4-(2′-olivetyl)-alpha-pinene were equally effective whereas (–)-CBD monomethyl ether, (–)-CBD dimethyl ether, (–)-3′-acetyl-CBD monoacetate, (+)-4-(2′-olivetyl)-alpha-pinene, (–)-and (+)-4-(6′-olivetyl)-alpha-pinene, (+/-)-AF-11, and olivetol were less effective anticonvulsants. Except for (–)- and (+)-4-(2′-olivetyl)-alpha-pinene and olivetol, all analogs showed less ROT than CBD. Also, CBD and all analogs were not active in tetrahydrocannabinol seizure-susceptible rabbits, the latter a putative model of cannabinoid psychoactivity in humans. These data suggest anticonvulsant requirements of 2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the resorcinol system and correct stereochemistry. Moreover, findings of separation of anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate, suggest that additional structural modifications of CBD may yield novel antiepileptic drugs.
P. Consroe and B. S. Fish. (1981). Rabbit behavioral model of marijuana psychoactivity in humans. Med Hypotheses, 7(8), 1079-90In a genetically unique colony of tetrahydrocannabinol-seizure susceptible (THC-SS) rabbits, nonfatal convulsions are elicited by delta 9THC, the major psychoactive ingredient of marijuana. The major characteristics of cannabinoid-produced psychoactivity (the “high”) in humans, e.g., dose-effect relationships, specificity of response to only psychoactive cannabinoids, tolerance development, EEG correlates, and delta 9THC-cannabidiol interactive effects, are also characteristics of cannabinoid-induced behavioral convulsions in the rabbits. Because of these and other theoretical and practical considerations, it is hypothesized that the THC-SS rabbit represents a novel laboratory animal model of marijuana-induced psychoactivity in humans.
C. Lindamood, 3rd and B. K. Colasanti. (1980). Effects of delta 9-tetrahydrocannabinol and cannabidiol on sodium-dependent high affinity choline uptake in the rat hippocampus. J Pharmacol Exp Ther, 213(2), 216-21

Doses of delta 9-tetrahydrocannabinol (delta 9-THC) and cannabidiol (CBD) affording the same degree of protection against seizures induced by maximal electroshock were compared for their effects on sodium-dependent high affinity choline uptake into six rat brain regions: cortex, striatum, medulla-pons, hypothalamus, midbrain and hippocampus. One hour after administration of CBD, 60 mg/kg i.p. in vitro choline uptake was not altered in any brain region. In contrast, 1 hr after administration of delta 9-THC, 10 mg/kg i.p., in vitro choline uptake in hippocampus and hypothalamus was significantly reduced. Moreover, in vivo administration of delta 9-THC was followed by a dose-related reduction in in vitro hippocampus choline uptake. Kinetic analysis of hippocampal choline uptake after administration of delta 9-THC, 10 mg/kg i.p., indicated that there was a reduction in Vmax with no change in the Km of the transport system. After direct addition to the hippocampal homogenates (in vitro) both delta 9-THC and CBD inhibited choline uptake, with IC50 values of 4.6 and 15.9 microM, respectively. Kinetic analysis revealed that the in vitro choline uptake inhibition induced by delta 9-THC was noncompetitive in nature. These results suggest that the septal-hippocampal cholinergic tract is a major site of action of delta 9-THC and may provide a neurochemical basis for the differential pharmacological properties of delta 9-THC and CBD.
R. Karler and S. A. Turkanis. (1980). Subacute cannabinoid treatment: anticonvulsant activity and withdrawal excitability in mice. Br J Pharmacol, 68(3), 479-841 The effects of subacute treatment with cannabidiol, delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin and phenobarbitone on anticonvulsant activity and on withdrawal excitability in mice were compared in three electrically induced seizure-threshold tests. 2 In the maximal electroshock-threshold test, subacute treatment did not alter the anticonvulsant activity of cannabidiol, phenytoin or phenobarbitone, but tolerance developed to delta 9-THC. 3 In the 60 Hz electroshock-threshold test, the activity of delta 9-THC and cannabidiol did not change, but tolerance developed to phenobarbitone, and there was an increase in sensitivity to phenytoin. 4 In the 6 Hz electroshock-threshold test, there was an increase in sensitivity to both delta 9-THC and cannabidiol, there was tolerance to phenobarbitone, while the activity of phenytoin did not change. 5 Although tolerance developed in some of the seizure-threshold tests to delta 9-THC and phenobarbitone, tolerance to cannabidiol and phenytoin did not develop in any of the tests. 6 Hyperexcitability followed withdrawal from only delta 9-THC (6 Hz and 60 Hz electroshock-threshold tests) and phenobarbitone (maximal electroshock-threshold and 60 Hz electroshock-threshold tests). 7 The delta 9-THC withdrawal hyperexcitability suggests that the use of marihuana may jeopardize the control of seizures in epileptics.
S. A. Turkanis, K. A. Smiley, H. K. Borys, D. M. Olsen and R. Karler. (1979). An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia, 20(4), 351-63

The effects of cannabidiol (CBD) on electrically evoked kindled seizures were studied in conscious, unrestrained rats with chronically implanted cortical and limbic electrodes, and the results were compared with those of delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin (PHT), and ethosuximide (ESM). All drugs were anticonvulsant, but there were marked differences in their effects on afterdischarge (AD) threshold, duration, and amplitude. CBD, like PHT and delta 9-THC, elevated the AD threshold; in contrast, ESM decreased the threshold but suppressed AD spread. CBD, however, also resembled ESM inasmuch as both drugs decreased AD duration and amplitude. Electrophysiologically, the antiseizure effects of CBD were a combination of those of PHT and ESM. The combination of effects may account for the observation that CBD was the most efficacious of the drugs tested against limbic ADs and convulsions. Other properties of CBD were also noted: For example, compared with delta 9-THC, it is a much more selective anticonvulsant vis-a-vis motor toxicity. CBD also lacks the CNS excitatory effects produced by delta 9-THC, PHT, and ESM. These characteristics, combined with its apparently unique set of electrophysiological properties, support the suggestion that CBD has therapeutic potential as an antiepileptic.
P. Chiu, D. M. Olsen, H. K. Borys, R. Karler and S. A. Turkanis. (1979). The influence of cannabidiol and delta 9-tetrahydrocannabinol on cobalt epilepsy in rats. Epilepsia, 20(4), 365-75

The mechanisms of the anticonvulsant activity of cannabidiol (CBD) and the central excitation of delta 9-tetrahydrocannabinol (delta 9-THC) were investigated electrophysiologically with conscious, unrestrained cobalt epileptic rats. The well-known antiepileptics, trimethadione (TMO), ethosuximide (ESM), and phenytoin (PHT), were included as reference drugs. Direct measurements were made of spontaneously firing, epileptic potentials from a primary focus on the parietal cortex and convulsions were monitored visually. ESM and TMO decreased the frequency of focal potentials, but PHT and CBD exerted no such effect. Although CBD did not suppress the focal abnormality, it did abolish jaw and limb clonus; in contrast, delta 9-THC markedly increased the frequency of focal potentials, evoked generalized bursts of polyspikes, and produced frank convlusions. 11-OH-delta 9-THC, the major metabolite of delta 9-THC, displayed only one of the excitatory properties of the parent compound: production of bursts of polyspikes. In contrast to delta 9-THC and its 11-OH metabolite, CBD, even in very high doses, did not induce any excitatory effects or convulsions. The present study provides the first evidence that CBD exerts anticonvulsant activity against the motor manifestations of a focal epilepsy, and that the mechanism of the effect may involve a depression of seizure generation or spread in the CNS.
S. A. Turkanis, P. Chiu, H. K. Borys and R. Karler. (1977). Influence of delta9-tetrahydrocannabinol and cannabidiol on photically evoked after-discharge potentials. Psychopharmacology (Berl), 52(2), 207-12

Two cannabinoids, delta9-tetrahydrocannabinol and cannabidiol, and several reference drugs were compared relative to their effects in a recently developed anticonvulsant test system, the after-discharge potentials of the visually evoked response; the potentials were recorded electrophysiologically from electrodes permanently mounted over the visual cortices of conscious rats. In anticonvulsant doses, trimethadione and ethosuximide produced an extensive depression of after-discharge activity, whereas diphenylhydantoin and cannabidiol exerted no such effect. In contrast, anticonvulsant doses of delta9-tetrahydrocannabinol and subconvulsant doses of pentylenetetrazol markedly increased after-discharge activity, which may represent a manifestation of their central nervous system excitatory properties. The data from the present study support our previously published ovservations from several other anticonvulsant tests that indicate the anticonvulsant characteristics of cannabidiol resemble those of diphenylhydantoin rather than those of trimethadione and that the central excitatory properties of delta9-tetrahydrocannabinol distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.
P. Consroe and A. Wolkin. (1977). Cannabidiol–antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther, 201(1), 26-32

A comparison of the anticonvulsant and neurotoxic effects of cannabidiol (CBD), delta 9tetrahydrocannabinol, cannabinol and antiepileptic drugs (phenytoin, phenobarbital, carbamazepine, chlordiazepoxide, clonazepam, ethosuximide and trimethadione) was made in rats. Median effective potencies (ED 50 values) for maximal electroshock, audiogenic seizures and TD50 values for a rotor rod neurotoxicity test were calculated. Additionally, the interactive effects of CBD and the antiepileptic drugs against maximal electroshock and audiogenic seizures were studied. Each drug was given orally at peak effect time. CBD was an effective and relatively potent anticonvulsant in both maximal electroshock and audiogenic seizure tests. The anticonvulsant potency of phenytoin was significantly increased when combined with phenobarbital, CBD and phenobarbital plus CBD. Additionally, CBD reliably reduced the anticonvulsant potencies of chlordiazepoxide, clonazepam, trimethadione and ethosuximide. These data indicate that CBD is an effective anticonvulsant with a specificity more comparable to drugs clinically effective in major than minor seizures. Furthermore, it appears that CBD enhances the anticonvulsant effects of the former and reduces the effects of the latter types of antiepileptic drugs.

P. Consroe, P. Martin and D. Eisenstein. (1977). Anticonvulsant drug antagonism of delta9tetrahydrocannabinol-induced seizures in rabbits. Res Commun Chem Pathol Pharmacol, 16(1), 1-13

A population of New Zealand White rabbits exhibit behavioral convulsions when given low doses of psychoactive cannabinoids of marijuana. Carbamazepine, diazepam and phenytoin were most effective in blocking these convulsions caused by delta9tetrahydrocannabinol (delta9THC). Phenobarbital and ethosuximide also blocked convulsions but only at toxic doses. Cannabidiol was effective in blocking convulsions when given concurrently with, but not prior to delta9THC.

E. A. Carlini, R. Mechoulam and N. Lander. (1975). Anticonvulsant activity of four oxygenated cannabidiol derivatives. Res Commun Chem Pathol Pharmacol, 12(1), 1-15.

A pharmacological comparison between cannabidiol (CBD) and four CBD derivatives, namely CBD-aldehyde-diacetate (I), 6-oxo-CBD-diacetate (II), 6-hydroxy-CBD-tri-acetate (III), and 9-hydroxy-CBD-triacetate (IV) was carried out in mice. Protection against maximal electroshock convulsions, potentiation of pentobarbital sleeping-time and reduction of spontaneous motor activity were the effects measured. All 5 compounds were equally potent in potentiating barbiturate sleeping time at doses ranging from 6.25 to 100 mg/kg. At 12.5 and 25 mg/kg only CBD and IV were able to decrease significantly the spontaneous motor activity. CBD, II, III and IV were also active in protecting mice against electroconvulsive shock at doses of 100-200 mg/kg, although at the larger dose CBD and compound II were the most efficient. Compound I was toxic, killing about half of the animals within 24 h after injection.

I. Izquierdo and M. Tannhauser. (1973). Letter: The effect of cannabidiol on maximal electroshock seizures in rats. J Pharm Pharmacol, 25(11), 916-7

I. Izquierdo, O. A. Orsingher and A. C. Berardi. (1973). Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Psychopharmacologia, 28(1), 95-102

E. A. Carlini, J. R. Leite, M. Tannhauser and A. C. Berardi. (1973). Letter: Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol, 25(8), 664-5

 

2 responses to “Cannabidiol and Seizures: Research References

  1. Pingback: Cannabidiol: Can it help? | MECP2 Duplication Syndrome Blog

  2. Pingback: Canada’s Reworked Medical Marijuana Program | MECP2 Duplication Syndrome Blog

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