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Marihuana and epilepsy: Paradoxical anticonvulsant and convulsant effects
Abstract
The effects of marihuana and cannabinoids on natural and experimental models of epilepsy are reviewed. The psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol, paradoxically exerts both a convulsant and anti-convulsant action. For example, it provokes myoclonus, psychomotor and grand mal seizures in epileptic beagles; however, at comparable doses it blocks maximal electroshock seizures in rats. In contrast, cannabidiol only exerts the anticonvulsant effects and lacks convulsant and psychotropic action. The anticonvulsant action of cannabinoids may result from decreased neural excitability and suppression of post-tetanic potentiation. The convulsant action of Δ9-tetrahydrocannabinol may result from a production of hypersynchronous neural discharge. Given these findings, epileptics should be discouraged from using marihuana since there is some risk of provoking seizures. However, because of anticonvulsant potency and lack of convulsant or psychotropic action, cannabidiol should receive clinical trials with epileptic humans as a test of its anticonvulsant effectiveness.
... Consistent with this latter observation levo-, but not dextro-mantradol enhanced potency and efficacy of diazepam blockade of pentylenetetrazol induced seizures [417]. Chronic injections of THC increase GABA content of rat brain [420] and THC itself has been reported to have unique anticonvulsant properties [421]. Cannabinoids, albeit variably, inhibit neurotransmission [422] and have been reported to augment GABA effects [423]. ...
... Mechanism(s) underlying these various effects are unclear [417]. However, on the other hand, THC has been reported to have both convulsant as well as anticonvulsant properties [421]. It can diminish effects of GABA [422,427], enhance focal epileptic potentials and seizure activity [428] and can inhibit uptake of GABA in hippocampus [196]. ...
Olfactory hallucinations without subsequent myoclonic activity have not been well characterized or understood. Herein we describe, in a retrospective study, two major forms of olfactory hallucinations labeled phantosmias: one, unirhinal, the other, birhinal. To describe these disorders we performed several procedures to elucidate similarities and differences between these processes. From 1272, patients evaluated for taste and smell dysfunction at The Taste and Smell Clinic, Washington, DC with clinical history, neurological and otolaryngological examinations, evaluations of taste and smell function, EEG and neuroradiological studies 40 exhibited cyclic unirhinal phantosmia (CUP) usually without hyposmia whereas 88 exhibited non-cyclic birhinal phantosmia with associated symptomology (BPAS) with hyposmia. Patients with CUP developed phantosmia spontaneously or after laughing, coughing or shouting initially with spontaneous inhibition and subsequently with Valsalva maneuvers, sleep or nasal water inhalation; they had frequent EEG changes usually ipsilateral sharp waves. Patients with BPAS developed phantosmia secondary to several clinical events usually after hyposmia onset with few EEG changes; their phantosmia could not be initiated or inhibited by any physiological maneuver. CUP is uncommonly encountered and represents a newly defined clinical syndrome. BPAS is commonly encountered, has been observed previously but has not been clearly defined. Mechanisms responsible for phantosmia in each group were related to decreased gamma-aminobutyric acid (GABA) activity in specific brain regions. Treatment which activated brain GABA inhibited phantosmia in both groups.
... Currently, there has been an increase in clinical trials that examine the beneficial effects of highly diluted CBD medication [226][227][228]. Although new therapeutics have been developed over the last two decades, the proportion of patients with intractable epilepsy has not been reduced [229]. In recent years, tremendous interest has been elicited by several online fora and the press regarding the positive effects of CS and its various preparations in the treatment of refractory epilepsy [230]. ...
Background
Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect it elicits whether in humans or rodents may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions.
Methodology
Articles from reliable databases such as Science Direct, PubMed, Google scholar, Scopus and Ovid were searched. Specific search methods were employed using multiple keywords: ‘‘Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases’’. For the inclusion/exclusion criteria, only relevant articles related to medicinal cannabis and its various compounds were considered.
Result and conclusion
The current review highlights the role, effects and involvement of cannabis; cannabinoids and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Also, cannabis utilization in many disease conditions such as Alzheimer’s and Parkinson’s disease among others. In conclusion, the usage of cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe especially when recommended dosage is adhered to. Furthermore, an in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.
... 10 This may explain why the patients with CUD in our study had 1.56 times higher odds of hospitalization for epilepsy compared to the patients without CUD. Cannabis use may initiate different types of seizure thresholds by increasing synchronicity 37 that could affect the course of drug therapy. 38 The studies that evaluated the effect of THC, CBD and other cannabinoid derivatives varied in rebound effect (reducing seizure threshold) and were also studied in different models and species. ...
Background and Objectives
Recent evidence has suggested that cannabis use precipitates cerebrovascular events. We investigated the relationship between cannabis use disorder (CUD) and hospitalization for epilepsy.
Methods
Nationwide inpatient sample (NIS) was analyzed from 2010 to 2014 for patients (age 15‐54) with a primary diagnosis of epilepsy (N = 657 072) and comparison was made between patients with ICD‐9 classification of CUD and without CUD. We utilized logistic regression to study the association (odds ratio [OR]) between CUD and epilepsy.
Results
The incidence of CUD in epilepsy patients was 5.77%, and patients with CUD had a threefold higher likelihood of emergency admissions. Patients with CUD were younger (25‐34 years), male and African American. In regression analysis, adjusted for confounders, cannabis (OR, 1.56), tobacco (OR, 1.20), and alcohol (OR, 1.63) use disorders were found to be associated with higher odds of epilepsy hospitalization, but lower odds with cocaine (OR, 0.953), amphetamine (OR, 0.893), and opioid (OR, 0.828) use disorders.
Conclusions and Scientific Significance
With the increasing prevalence of medical marijuana legalization, there is increased use of medicinal marijuana. Studies of cannabidiol and marijuana for epilepsy have been highly publicized, leading to its off‐label use for treatment. There is limited evidence to suggest that the cannabinoids may also induce a seizure. This study found that CUD is independently associated with a 56% increased likelihood of epilepsy hospitalization and this association persists even after adjusting for other substance use disorders and confounders. (Am J Addict 2019;1–9)
... A proconvulsant effect is also seen in models mimicking genetic based generalized epilepsies and absence seizures. Δ 9 -THC and its metabolites seem to induce hypersynchrony with slowly propagating epileptic discharges [32]. While Δ 9 -THC showed some potential as an anticonvulsant agent the potential to increase seizure activity along with its neurotoxic and psychotropic side effect profile limited its potential benefit in patients with epilepsy. ...
Epilepsy is a chronic disease of the central nervous system characterized by recurrent unprovoked seizures. Up to 30% of patients continue to have seizures despite treatment with appropriate anticonvulsant medications. The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis. The endocannabi-noid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in Cannabis a potential therapeutic option for patients with treatment resistant epilepsy. Many in vitro and in vivo studies have demonstrated the anticonvulsant effects of several phytocannabinoids including Δ 9-tetrahydrocannabinol (Δ 9-THC) and Cannabidiol (CBD). Several small observational studies demonstrated a favorable response to cannabis herbal extracts (CHE) containing high concentrations of CBD in children with treatment resistant epilepsy. Two large double blinded clinical trials assessing the efficacy of pharmaceutical grade CBD have also been performed in children with treatment resistant seizures in Dravet syndrome and Lennox-Gastaut syndrome. Both studies demonstrated an improvement in seizure reduction in children taking CBD as compared to the placebo groups. To date there is very limited data regarding the use of cannabis based products to treat adult patients with treatment resistant epilepsy with only one randomized double blinded placebo controlled clinical trial underway.
... Marijuana's anticonvulsant properties were noted in the fifteenth century (29), yet few studies have been conducted in humans (2,(30)(31)(32)(33)(34)(35)(36)(37). In a single case report marijuana smoking was reported to be necessary for seizure control (2). ...
... Cannabinoids influence levels of major catecholaminergic transmitters such as dopamine and norepinephrine (51). Cannabinoids also influence thalamocortical projections, which could alter seizure threshold by increasing synchronicity (52). Further, there is a dose-dependent effect of cannabinoids on CNS excitability, with low doses producing activation and high doses reducing electrical activity (51). ...
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.
... Some data support the possible use of cannabis or cannabinoids in the treatment of epilepsy, but they can exert both convulsant and anticonvulsant effects [133,134]. The hippocampus is an area of the CNS particularly prone to the generation of seizures and is the subject of much study in this area. ...
Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids) affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS) regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.
... 18 THC can also have proconvulsant properties in other models (eg, mongrel dogs administered intravenous penicillin G) 19 or when administered in high doses or to certain animal species (including rats and normal and epileptic beagles). [20][21][22][23] Cannabidiol and its derivative analogs have anticonvulsant properties, without stimulatory or convulsant properties. In animal models, cannabinoids have been shown to reduce electrical kindling, inhibit seizure activity induced by maximal electroshock or ␥-aminobutyric acid (GABA)-inhibiting drugs, and prevent simple partial seizures induced by the convulsant metals applied to the cortex. ...
Although more data are needed, animal studies and clinical experience suggest that marijuana or its active constituents may have a place in the treatment of partial epilepsy. Here we present the case of a 45-year-old man with cerebral palsy and epilepsy who showed marked improvement with the use of marijuana. This case supports other anecdotal data suggesting that marijuana use may be a beneficial adjunctive treatment in some patients with epilepsy. Although challenging because of current federal regulations, further studies are needed to examine the role of marijuana in the treatment of this disorder.
There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use.
This article is part of a Special Issue titled Cannabinoids and Epilepsy.
THC is one of the 60 natural cannabinoids contained in the marihuana plant, which is psychoactive. It is a long-acting agent with multiple pharmacological effects. THC produces bronchodilation, but can also cause airway irritation. Marihuana smoke possesses toxic components, including carbon monoxide, tar, and carcinogens, which cause significant adverse pulmonary effects. THC causes a dose-dependent tachycardia, which is exacerbated by chronotropes and antagonized by (β-blockers, diazepam, and clonidine. Increases of blood pressure can occur, but orthostatic hypotension is also observed. Marihuana exacerbates angina pectoris in patients with exercise-inducible myocardial ischemia. Some patients report relief of neuropathic pain and discomfort after smoking marihuana or ingesting THC. However, in a controlled study on healthy volunteers who were studied by using the sensory decision theory to account for the psychoactive drug effects, marihuana smoking caused hyperalgesia. As an antiemetic, THC is much less effective than metoclopramide or 5-HT3 receptor antagonists, and it often causes unwanted psychoactive effects. THC is not effective as a premedication for anesthesia, and preoperative marihuana smoking exacerbates perioperative tachycardia. THC interacts with other drugs: it increases the depressant effects of sedatives and mitigates the effects of stimulants. In addition, severe adverse psychoactive side-effects have been observed when this agent is combined with barbiturates. In combination with opiates or ethanol, THC increases sedation and respiratory depression. The existing data indicate that marihuana or THC is not an acceptable adjunct to anesthesia.
In the late 19th century, British neurologists found that cannabis had a limited role in epilepsy therapy. Cannabinoid receptors are found in the brainstem, limbic and neocortical areas that modulate seizure activity. The recent studies of the effects of THC, CBD, and related cannabinoids in animal models of epilepsy reveal that (1) the effects vary significantly in different models, in different species, and for the different derivatives; (2) the mechanisms by which the cannabinoids exert their anti-or proconvulsant effects is not well-defined; and (3) the effects of acute administration (e.g., increasing seizure threshold) may be followed, in certain models, by a rebound effect (e.g., decreasing seizure threshold).
No well-controlled studies have evaluated cannabinoids in the treatment of epilepsy patients. However, clinical anecdotes and single case reports suggest that marijuana may reduce seizure frequency or, conversely may provoke seizure activity in select cases, while in most instances it has no significant effect on seizure activity. Several clinical studies have examined the efficacy of CBD on seizure frequency. These studies found either some reduction in seizure frequency or no statistically significant reduction compared to placebo. The few epidemiological studies that have been conducted suggest that marijuana use may protect against seizures induced by illicit drugs such as heroin and cocaine. The limited evidence therefore suggest that marijuana and the cannabinoids may have antiepileptic effects in man, but these effects may be specific to partial or tonic-clonic seizures.
In the latest years, the interest into the biological properties of cannabinoids has met a new lease of life, in the trail of recent acknowledgements about the endogenous cannabinoid systems. Nevertheless, research effort has been mostly addressed either at psychotoxic effects of cannabis (amotivational sindrome) or at the role of cannabis abuse in the genesis of some psychiatric disorders (e.g. chronic psychoses). However, clinical investigations on the possible therapeutic use of cannabis and its active components has led to new perspectives for research. Scientific evidence for a possibile therapeutical use of cannabinoids, agonists and antagonists, shows how the political controversy upon the issue of cannabis legalization, beyond specific sides, ended up to hamper scientific efforts: thus, research into the toxic effects of smoked cannabis has proceeded with no parallel increase in the knowledge about possible therapeutical profiles of cannabinoids compounds. We recommend that clinical and neurobiological research on both the negative and positive effects of cannabinoids meet a reprise, with no prohibitionist implication, so as to allow scientific knowledge to improve. This article deals with the evidence of cannabinoids' effects and their therapeutic potential in a variety of medical conditions, of general (emesis, loss of appetite, glaucoma, asthma, neoplastic growth) and neuropsychiatric (spasms, pain, epilepsy, neuronal overstimulation, craving for heroin).
For millennia there has been interest in the potential therapeutic effects of marijuana (cannabis), including its potential
antiepileptic effects. A flurry of research on cannabis and seizures occurred in the 1970s, when purified tetrahydrocannabinol
(THC) became available for research. The results demonstrated that a variety of seizures, including kindled seizures can be
suppressed by THC, but typically at toxic doses.1–3 It was also reported that prophylactic administration of THC can delay limbic kindling in rats2 and cats.3 In contrast, other studies that received less attention described proepileptic or proconvulsant effects of a variety of cannabinoids,
including THC.4–6 Because of a lack of knowledge about the mechanisms of cannabis’s effects oh the brain, research on cannabis and epilepsy
declined to a very low level in the 1980s.
Mice were kindled to produce minimal convulsions by repeated application of either electrical or chemical stimuli. Electrical kindling involved the use of corneal electrodes; chemical kindling involved the use of pentylenetetrazol or picrotoxin. Delta-9-tetrahydrocannabinol (delta-9-THC) appeared to be capable of enhancing kindling to all three stimuli. In the studies with electroshock and pentylenetetrazol, in contrast to those with picrotoxin, a single exposure to delta-9-THC sufficed to facilitate the subsequent kindling, and the enhancement of kindling persisted after withdrawal of the cannabinoid. In the case of electrical kindling, the cannabinoid may promote the phenomenon by decreasing the convulsion threshold. Because the threshold was not lowered to all kindling stimuli, however, other mechanisms must be involved. In general, the data indicate that even a single dose of delta-9-THC can promote the development of long-lasting elevations of CNS excitability.
A study of the effects of Δ-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on the spinal monosynaptic pathway in unanesthetized spinal cats was undertaken in order to elucidate potential mechanisms of the convulsant and anticonvulsant actions of these cannabinoids. To this end, the effects of the drugs on pre- and posttetanic monosynaptic responses were compared with those of phenytoin (PHT). The data indicated that small doses of Δ9-THC enhanced both pre- and posttetanic potentials, a result which suggests that excitatory effects on synaptic transmission may contribute to the convulsant action of the drug. Relatively large doses of Δ9-THC, on the other hand, and all doses of CBD depressed the reflex, as did PHT; such depression may account, at least partially, for the anticonvulsant effects of the cannabinoids. The present study provides direct evidence that the cannabinoids produce both excitatory and depressant effects on central synaptic transmission; such results are consistent with the well-documented effects of the cannabinoids on CNS excitability.
The effects of delta 9-tetrahydrocannabinol (delta 9-THC), two of its metabolites, 8 beta-hydroxy-delta 9-THC and 11-hydroxy-delta 9-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. delta 9-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-delta 9-THC did not precipitate convulsions, but it did elicit all the other effects of delta 9-THC; the 8 beta-hydroxy derivative, on the other hand, exerted only two delta 9-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of delta 9-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to delta 9-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the delta 9-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of delta 9-THC are not a universal characteristic of this class of drugs.
Somatosensory and visual evoked potentials in the classical afferent primary pathways in cats anesthetized with alpha-chloralose were studied in order to characterize the effects of delta 9-tetrahydrocannabinol (THC) and the synthetic analog, dimethylheptylpyran (DMHP) on central sensory processing. THC and DMHP slowed primary cortical responses to radial nerve or ventralis posterolateralis (VPL) stimulation in a dose dependent manner. THC did not alter VPL activity evoked by radial nerve stimulation. Amplitude of the primary somatic response was depressed at the 4 mg/kg dose. Responses of visual cortex and lateral geniculate nucleus, evoked by stimulation of optic chiasm, were unchanged at the doses studied. However, the nonmodality-specific response of the anterior marginal association cortex to stimulation of either modality was depressed by THC. Data suggest the association cortex which exhibits sensory convergence was most sensitive to the effects of THC. Findings were consistent with a thalamocortical site of action for THC. DMHP produced similar effects and was more potent.
1. Neither cannabichromene (CBC) nor delta 9-tetrahydrocannabinol (THC) protected mice from electroshock-induced seizures, although THC inhibited postictal mortality. Minor effects were produced on seizure latency and duration. 2. CBC had a weak analgetic action in mice; THC had a moderate and lengthy effect, which was potentiated at 2 hr by concurrent CBC. 3. Both CBC (10-75 mg/kg, i.p.) and THC (20 mg/kg) reduced motility of mice, the THC equalling the highest dose of CBC. 4. Performance of a conditioned avoidance response was strongly impaired by THC, but not by CBC, nor did CBC combined with THC have influence on the effects of THC.
The influence of delta 9-tetrahydrocannabinol (delta 9-THC) on cat spinal motoneurons was investigated with intracellular recording techniques in order to identify possible mechanisms of action of the drug's central excitatory and depressant properties. delta 9-THC increased the amplitude of the excitatory postsynaptic potentials (EPSPs) and decreased the amplitude of the inhibitory postsynaptic potentials (IPSPs); these excitatory effects do not appear to be the result of changes in the afferent input. However, an observed increase in membrane resistance may account for, or contribute to, the enhanced EPSPs. The cannabinoid also concomitantly caused depression, as evidenced by a rise in the firing threshold for the motoneuron action potential. The responses of the motoneuron to the drug suggest synaptic sites and mechanisms of action.
Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.
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.
This study tested the hypothesis that cannabinoid agonists, applied locally into the pars reticulata of substantia nigra (SNpr), could modulate striatonigral transmission, without affecting the response of SNpr neurons to iontophoretically-applied GABA. Multibarreled glass capillary electrode assemblies were used for extracellular recording of the spontaneous electrical activity of single SNpr cells in anesthetized rats. Local pressure ejection of the cannabinoid agonists Win 55212-2 (WIN2) and CP 55940 increased SNpr spontaneous firing rate by 13-46%, similar to the effects of systemic injections. Neither WIN2 nor CP 55940 had an effect on the slowing of SNpr neuron activity in response to iontophoretic GABA. Local pressure application of Win 55212-3 (the much less active enantiomer of WIN2) produced an insignificant decrease in SNpr firing rate. Similarly, locally applied vehicle (45% 2-hydroxypropyl-beta-cyclodextrin) produced insignificant decreases in SNpr firing. A second application of cannabinoid agonist produced a much smaller effect, suggesting desensitization. Increasing the interval between CP 55940 applications to 45 min showed recovery of sensitivity to the agonist. Local application of the cannabinoid antagonist, SR 141716A, significantly decreased spontaneous cell firing by 34%. CP 55940, when given immediately following or concurrently with the antagonist application failed to produce the expected increase in discharge rate over baseline. A second application of CP 55940 45 min later produced a 26% increase in firing rate. Bicuculline methiodide (BMI) was applied locally causing a significant increase in SNpr cell firing. CP 55940, when locally administered concurrently with bicuculline methiodide, had no further effect on the firing rate of the cell. Based on the reported presynaptic localization of cannabinoid receptors in SNpr, these findings suggest that cannabinoids act within the SNpr to modulate striatonigral neurotransmission presynaptically. The effect of SR 141716A suggests that an endogenous cannabinoid may mediate striato-nigral transmission.
Considerable controversy exists regarding the role of marijuana as a therapeutic agent; however, many practitioners are taught very little about existing marijuana data. The authors therefore undertook a comprehensive literature review of the topic. References were identified using textbooks, review and opinion articles, and a primary literature review in MEDLINE. Sources were included in this review based primarily on the quality of the data. Some data exists that lends credence to many of the claims about marijuana's properties. In general, however, the body of literature about marijuana is extremely poor in quality. Marijuana and/or its components may help alleviate suffering in patients with a variety of serious illnesses. Health care providers can best minimize short term adverse consequences and drug interactions for terminally ill patients by having a thorough understanding of the pharmacology of marijuana, potential adverse reactions, infection risks, and drug interactions (along with on-going monitoring of the patient). For chronic conditions, the significance and risk of short and long term adverse effects must be weighed against the desired benefit. Patients who are best suited to medicinal marijuana will be those who will gain substantial benefit to offset these risks, and who have failed a well-documented, compliant and comprehensive approach to standard therapies.
The pharmacological interaction between cannabidiol (CBD) and (−)δ
9-trans-tetrahydrocannabinol (δ
9-THC) has been studied in rabbits, mice and rats by administering mixtures containing varying amounts of both substances. CBD blocked the following effects of δ
9-THC: catatonia in mice, corneal areflexia in rabbits, the increased defecation and decreased ambulation after chronic treatment and exposures of rats in an open field arena, and the aggressiveness of rats previously stressed by REM sleep deprivation. On the other hand, CBD potentiated the δ
9-THC-induced analgesia in mice and the δ
9-THC-impairing effect on climbing rope performance of rats.
These interactions are tentatively explained by postulating that CBD directly antagonizes the excitatory effects and/or indirectly potentiates the depressant effects of δ
9-THC.
Two cannabinoids, 9 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 9 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 observations 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 9 distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.
Le cannabidiol administr dose de 100 mg par os et de 30 mg par injection i.v. fut inactif dans les sujets d'tude. Le cannabinol, dose orale de 400 mg, le fut aussi. Ces constituants du cannabis ne contribuent donc pas l'effet pharmacologique.
The anti-convulsant properties of
9-trans-tetrahydrocannabinol (
9-THC) were examined in rats subjected to daily convulsions induced by direct electrical stimulation of either the anterior limbic cortex or the amygdala. During the development of the convulsions (kindling) and during the repeated daily injections of
9-THC, electroencephalographic records were taken. THC was administered daily until the animals were behaviorally tolerant. The drug had, initially, a very pronounced effect on the sub-cortical seizures and a slightly lesser effect on the cortical seizures—either stopping them entirely or reducing their duration. However, as the animals became tolerant to THC (defined behaviorally and electrically), the anti-convulsant properties of the drug diminished.
The natural Cannabis sativa compounds, cannabidiol, cannabinol,
9- and
8-tetrahydrocannabinol, in that order of potency, decreased the susceptibility of rat dorsal hippocampus to seizure discharges caused by afferent stimulation. The drugs were effective following both intraperitoneal injection and topical application. They were more active, on a dose basis, than the well-known antiepileptic agents mysoline and diphenylhidantoin. Within the dose range effective in depressing hippocampal seizures, they had no effect on hippocampal evoked responses. This suggested that they might act by interfering with K+ release from hippocampal cells, which is known to be the causative factor in hippocampal seizures. This point was investigated using cannabidiol, which was found to effectively block the release of K+ from the hippocampus caused by afferent stimulation.
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.
During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
The antiepileptic and prophylactic effects of delta9-tetrahydrocannabinol (delta9-THC) and delta8-THC were examined in rats that developed generalized seizures in response to intermittent electrical stimulation of the amygdala (kindling). Both isomers of the THC were able to acutely suppress kindled seizures, but consistent antiepileptic effects were obtained only with high, toxic dosages. Tolerance to the antiepileptic effects of THC developed very rapidly when the drugs were give repeatedly, and there was evidence that the repeated administration of a high dosage of delta9-THC resulted in a state of acute physical dependence. Administration of the isomers of THC during seizure development resulted in a suppression of kindling, suggestive of a prophylactic effect. The rate of rekindling after withdrawal of the drugs was not significantly different from that of vehicle-treated control rats, however, indicating that a genuine prophylactic effect was not obtained.
Neither the acute nor the chronic i.p. administration of delta-6-tetrahydrocannabinol affected the passage of lithium from blood to brain in normal rats.
Intraperitoneal injections of delta 8-tetrahydrocannabinol (THC) and delta 9-THC failed to affect myoclonic response to photic stimulation in Senegalese baboons (Papio papio). However, both isomers of THC exerted dose-related antiepileptic effects upon established kindled convulsions provoked by electrical stimulation of amygdala in the same species. Delta 9-THC was more potent than delta 8-THC, in terms of both antiepileptic effects and general toxicity. The antiepileptic effects of the THC isomers appear to be due mainly to the suppression of propagation of the induced afterdischarge to distant cerebral structures, although high doses also seem to suppress afterdischarge at the site of stimulation.
Acute administration of delta8-tetrahydrocannabinol (delta8-THC) or delta9-THC failed to affect partially developed or fully developed kindled amygdaloid seizures in cats. However, delta9-THC was quite effective in suppressing focal AD in the stimulated amygdala when administered very early in kindling, before the development of any clinical manifestations. This finding suggested that chronic administration of delta9-THC during kindling might block the process of seizure development, which was supported by the observation that three of four cats failed to kindle when treated with the drug. The cat that failed to be protected by delta9-THC was also insensitive to the general electroclinical effects of moderately high doses of delta9-THC. The prophylactic activity of delta9-THC is in contrast to the ineffectiveness of diphenylhydantoin, a drug whose anticonvulsant activity is often compared with that of THC.
Cannabidiol appears to be a potent diphenylhydantoin like anticonvulsant agent; it also seems to lack hallucinogenic and other neurotoxic properties typical of other marihuana compounds either in man or in laboratory animals.
The effects of the intravenous injection of Δ⁹ -tetrahydrocannabinol (0.01 to 5 mg/kg body weight) on the EEG, behavior, and photically induced epilepsy, have been studied in 11 adolescent baboons (Papio papio) with marked photosensitive epilepsy. Tameness, anorexia, and akinesia were evident for 4 hr or more after 0.5 to 5 mg/kg. The EEG showed prolonged bursts of symmetrical, rhythmic spikes and waves at about 3/sec associated with no motor signs other than fixation of gaze. There was no consistent enhancement or diminution in the EEG or myoclonic response to intermittent photic stimulation after drug administration.
Cannabidiol (3.5 mg/kg, i.p.) depressed hippocampal facilitation and posttetanic potentiation of evoked responses in rats, such, as had been reported before for diphenylhydantoin. Both diphenylhydantoin (80 mg/kg, i.p.) and cannabidiol blocked the increase of hippocampal RNA concentration caused by afferent stimulation, and depressed the acquisition of a conditioned avoidance response in rats. Neither drug affected the retention of such response when given by posttrial injection, nor the spontaneous locomotor activity of mice. The effects of both agents may be explained by the interference they have been previously shown to produce with the release of K+ from the hippocampus during stimulation. In fact, hippocampal facilitation and posttetanic potentiation and the RNA response to stimulation have been shown to be phenomena which depend on this K+ release, and have been attributed a role in learning.
The pharmacological effects of marihuana in man and animals have been attributed to Δ1 and Δ6 tetrahydrocannabinol (THC). Recently, one of the metabolites of THC, 7-OH-THC, has been reported to have intoxicating properties. A comparative study was carried out on the EEG and behavioral effects of cannabinol, cannabidiol, Δ6-THC, 7-OH-Δ6-THC and 7-Acetoxy Δ6-THC acetate in six chronically implanted rabbits bearing cortical and subcortical leads. Drugs were dissolved in polyethyleneglycol and administered i.v. once every 7 days in a crossover experimental design. 7-OH-Δ6-THC and 7-Acetoxy-Δ6THC acetate proved to be at least twice as active as Δ6-THC in inducing EEG changes (disruption of theta waves, appearance of spikes and waves, blockade of the "arousal" reaction) and behavioral alterations (excitation, exophthalmus, mydriasis, corneal arreflexia, ataxia and swaying). Pretreatment with 1 or 2 mg/kg of reserpine, s.c., did not substantially alter the subjects response to THC. Amphetamine 2 mg/kg, i.v., in animals pretreated with 2 or 4 mg/kg Δ6-THC, reverses in part the depression induced by THC.
The anticonvulsant activity of orally administered δ
9-tetrahydrocannabinol (δ
9-THC), δ
8-THC, cannabidiol (CBD) and cannabinol (CBN) was tested in mice utilizing electroshock and chemoshock methods. In doses tested δ
9-THC afforded no protection to mice from chemoshock seizures and was effective against electroshock only in high doses (160–200 mg/kg). CBD and CBN (150–200 mg/kg) were without effect in both tests.
An interaction between cannbinoids was apparent when all three were administered simultaneously (each at 50 mg/kg) because this combination produced a significant reduction in the duration of the hind-limb extensor phase of the electroshock seizures.
The administration of δ
9-THC significantly potentiated the anticonvulsant effectiveness of phenytoin against electroshock seizures and this effect was further potentiated by the concurrent administration of CBD. Whilst the potentiation of phenytoin by δ
9-THC (50 mg/kg) was of the order of 1.5 times, the combination of δ-9THC and CBD (each 50 mg/kg) produced a four-fold potentiation.
Neither within-cannabinoid interaction nor cannabinoid potentiation of phenobarbitone effectiveness could be demonstrated in chemoshock tests.
The mechanism of the cannabinoid facilitation of phenytoin is unknown but it possibly involves activity at central nervous system level rather than being a metabolic interaction. This drug interaction may have potential clinical significance.