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Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures.
- 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.
Source, British Epilepsy Association. Published by Elsevier Ltd. All rights reserved
Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo
- 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 μM) effects were assessed in vitro using the Mg2+-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg2+-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 μM 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 CB1 receptors and displayed no agonist activity in [35S]guanosine 5′-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB1 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.
- A growing number of phytocannabinoids have been shown to possess biological activity (Pertwee, 2008) and, in particular, to affect neuronal excitability in the CNS. Phytocannabinoid actions are reported to be mediated by G protein-coupled cannabinoid CB1 and CB2 receptors and potentially by other non-CB receptor targets (Howlett et al., 2004; Pertwee, 2008). CB1 receptors are highly expressed in the hippocampus (Herkenham et al., 1990; Tsou et al., 1998) and are well known to modulate epileptiform and seizure activity (Shen and Thayer, 1999; Wallace et al., 2001). Moreover, the endocannabinoid (eCB) system has been shown to be a key determinant of hippocampal epileptiform activity (Wallace et al., 2002; Monory et al., 2006; Ludányi et al., 2008). The major psychoactive compound Δ9-THC was the first phytocannabinoid reported to affect epileptiform activity; Δ9-THC, a partial agonist at CB1 receptors, was shown to inhibit excitatory glutamatergic neurotransmission in hippocampal neurons under low Mg2+ conditions (Shen and Thayer, 1999; but see Straiker and Mackie, 2005).
- CBD is the major nonpsychoactive component of Cannabis sativa whose structure was first described by Mechoulam and Shvo (1963); CBD has recently attracted renewed interest for its therapeutic potential in a number of disease states (Pertwee, 2008). CBD has been proposed to possess anticonvulsive, neuroprotective, and anti-inflammatory properties in humans. Thus, within the CNS, CBD has been proposed to be protective against epilepsy, anxiety, and psychosis and to ameliorate diseases of the basal ganglia, such as parkinsonism and Huntington's disease (Iuvone et al., 2009; Scuderi et al., 2009). CBD neuroprotective effects may be augmented by reported antioxidant properties (Hampson et al., 1998; Sagredo et al., 2007). Early studies suggested that CBD had anticonvulsant potential in one small-scale phase I clinical trial (Cunha et al., 1980). In this regard, there is a significant unmet clinical need for epilepsy, with ∼30% of epileptic patients experiencing intractable seizures regardless of conventional AED treatment (Kwan and Brodie, 2007). CBD is extremely well tolerated in humans; for example, CBD at doses of 600 mg does not precipitate any of the psychotic symptoms associated with Δ9-THC (Bhattacharyya et al., 2009). At present, CBD is used therapeutically in Sativex (1:1 Δ9-THC/CBD; GW Pharmaceuticals, Porton Down, UK) to alleviate pain symptoms in multiple sclerosis and cancer pain. CBD has anticonvulsant effects in animal models of maximal electroshock (Karler et al., 1974; Consroe and Wolkin, 1977; Consroe et al., 1982); however, CBD remains untested in other animal seizure models (Gordon and Devinsky, 2001) and so has yet to fulfill its potential indications as a clinical anticonvulsant.
- In the present study, we demonstrate the potential of CBD as an AED. We show that CBD caused concentration-related and region-dependent attenuation of chemically induced epileptiform activity in hippocampal brain slices using in vitro MEA electrophysiological recordings. Furthermore, CBD reduced seizure severity and mortality in an in vivo model of generalized seizures. We also investigated the specific role of CB1 receptors in CBD action and found only a low-affinity interaction and lack of clear agonist effects. Overall, these data are consistent with CBD acting to mediate antiepileptiform and antiseizure effects in vitro and in vivo, respectively, potentially by CB1 receptor-independent mechanisms.
Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors.
- Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.
Can CBD Help Our Canine Companions?
With the exception of insects, the presence and regulatory role of endocannabinoid system in all animals has been confirmed by the scientific studies. Like humans, animals produce endocannabinoids, that act on specific receptors that are found throughout the body, and regulate various physiological roles. In diseased states, the activation of these receptors with phytocannabinoids could be helpful to treat the underlying problem. Cannabinoids, particularly cannabidiol (CBD), has the potential to treat various medical problems, in a non-toxic way.You may wonder if you should consider giving CBD to your beloved dog, or family pet? Does it work? Is it really safe?
Yes, it works safely for various medical conditions!
THC may be harmful for pets, and it may also cause psychoactive effects. No study has ever reported CBD is harmful to pets, but rather it is beneficial in many ways. Not all, but most, of the edible canine cannabis treats are virtually THC-free, completely non-psychoactive and non-toxic to pets. These edible treats are derived from hemp, instead of marijuana, due to legal issues. These companies don’t make any therapeutic claims as veterinary cannabinoid use has not been legalized yet. Still, there are few issues to selling CBD-infused edible cannabis treats for pets. These edibles can safely treat inflammation, pain, cancer-related health problems, and can also be used for palliative care or end-of-life ailments.
Most pet owners don’t want to see their four-legged friends suffering with inoperable or late stage cancer, or with severe arthritis. These painful conditions can prevent pets from eating, and they tend to suffer muscle wasting. For years, canine diseases have typically been treated with synthetic veterinary drugs. As with humans’ pain medications, veterinary pain medications, like Rimadyl, may cause moderate to serious side effects. Certain drugs can cause liver and kidney damage; nonetheless, these drugs are still being prescribed by veterinarians as there is no way to legally prescribe CBD.
Maybe veterinarians are not ready to use CBD as medicine, but many pet owners are not willing to wait anymore. They’re purchasing CBD-laced edible treats to relieve their pet’s problems.
The feedback from pet owners has vouched for the use of CBD treats to soothe anxious dogs, particularly in cases of separation anxiety, thunderstorm fears, traveling in cars, anxiety during veterinary visits, and social anxiety in canines.
Pharmacokinetics of CBD in dogs
Due to legal restrictions, veterinary research studies to optimize safe and effective doses of CBD for various medical conditions are quite difficult to conduct. Additionally, these studies are expensive. The available pharmacological data on animals is scarce. Unlike humans, dogs metabolize cannabinoids in a different way.
In dogs, 2-AG and anandamide are the primary messenger cannabinoids. These chemicals activate CB1 and CB2 receptors in the brain and other regions, respectively. Being an agonist to these receptors, CBD weakly binds to these receptors for a longer duration, and evokes long-lasting therapeutic response without causing toxic effects.
After intravenous infusion, CBD distribution was reported to be rapid, followed by prolonged elimination with a terminal half-life of 9 hours. The total body clearance may take up to about 17 hours after administration. The oral bioavailability appears to be low (13-19%), which may be due to the first pass effect in the liver. With low bioavailability, the risk of developing systemic toxicity may be low in dogs.
Once the effects wane, the dog’s liver metabolizes the cannabidiol and eliminate it via the urine or bile in a sustained and safe manner. This might be the possible reason for achieving immediate but prolonged therapeutic response in CBD-treated animals.
Claims that Support CBD Use in Pets
Like human use, veterinary marijuana use has caught the scientific community’s interest, and the interest of the general public lately; but unfortunately, cannabis still remains a Schedule I drug. This is why clinicians, medical and veterinary researchers have been fearful to conduct collaborative research studies.
Fortunately, encouraging research evidence is now surfacing that is helpful to gain public acceptance, and several independent organizations are demanding medical marijuana legalization across the globe. Marijuana advocates have petitioned the Drug Enforcement Administration to consider rescheduling marijuana, which has been unsuccessful thus far.
At this time, the number of human research studies that are underway to explore the potential medical benefits of cannabis are not appreciable. It may take at least half a decade to see promising veterinary cannabinoid research results. Until then, we need to rely on anecdotal evidence and testimonials of pet owners. It has been proven that animals share 70% biological homology with humans. So we have some grounds to believe that cannabis could be useful for treating canines.
To our surprise, we see favorable testimonials that support veterinary cannabinoid use, even on the AVMA website. The AVMA website has published testimonials of pet owners who endorsed cannabis use and who claim its use has dramatically improved the quality of life and mobility in animals that were previously unable to ambulate. More over, cannabis has improved appetite and reduced the reliance on conventional medications, particularly in animals that are intolerant to those drugs.
One study has found that the endocannabinoid system and cannabinoids could prevent immune-mediated and inflammatory allergic disorders, including skin problems, in dogs. Another study has concluded that CBD has anticonvulsant and anti-epileptic properties with ‘high protective index’, compared to Phenytoin and Phenobarbital, the conventional anticonvulsant drugs.
A survey study conducted by AHVMA has reported that 61.8% to 95% of pet owners have endorsed the health benefits of CBD-laced treats, ranging from ‘moderate to excellent’. Some of the medical conditions that were relieved by these edible treats include pain, nervous system problems, inflammation, anxiety, nausea and/or vomiting, digestive system problems, tumors, seizures/convulsions, skin problems and phobias, including fireworks or thunderstorm phobias.
We are well aware that cannabinoids can alleviate rheumatoid pain in humans. However, dogs don’t suffer rheumatoid arthritis, but mostly suffer osteoarthritis (OA), a bone and joint disease that occurs as a result of joint(s) wear-and-tear. OA can cause neuropathic pain, for which cannabinoids can be helpful.
Both the research evidence and the testimonials of the pet owners appear to be encouraging.
- Julianna hated to see her beloved dachshunds suffer with painful disc problems and side effects, even after unsuccessful treatments with Tramadol and Rimadyl. She chose to treat her dogs with CBD-infused oil. After few weeks, the mood and mobility of the dogs improved without any notable side effects.
- One pet owner acknowledged the anti-convulsive benefit of CBD and his dog’s epileptic episodes have reduced to one per month after cannabis treatment.
- One California-based pet owner has said that CBD has significantly improved the health of his dog after an injury.
- David Bourgouin’s dog suffered traumatic injury between the chest and the leg. The injury caused a large cyst that limited the dog’s mobility and surgery was recommended by the veterinarian. Due to the high cost of surgery, David opted to treat his dog with CBD and the results were amazing. After a few weeks, the dog has been able to run without any signs of persistent pain.
The bottom line is this: the American Medical Association (AMA) has been urging the Federal Government to reschedule marijuana. Legalization would be helpful to conduct veterinary research studies, and to develop cannabinoid-based formulations. Like the AMA, the AVMA has called veterinarians for scientific debate on this issue, which is noteworthy.
CBD is a nature’s gift, not just for humans, but also our pets too. With CBD, pet owners can treat their four-legged companion’s medical conditions without toxicity. Although CBD is not a cure-all medication, it can ease the pet’s discomfort, relieve debilitating pain and extend their lives. By opting for CBD, pet owners need not turn to euthanizing their pets to end their pets’ suffering.
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Not intended to diagnose, treat, cure or prevent any disease.
Consult your vet before using in your pet.
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