We will emphasize the neuroprotective, antiinflammatory, and . Unlike the psychoactive properties associated with Δ9-THC, CBD has been. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived. Of the cannabinoids so far identified, cannabidiol (CBD) is among the most exciting because of its antioxidant and neuroprotective properties.
of The CBD Properties Neuroprotective
Various concentrations of cannabinoids and BHT were included to examine their ability to prevent dihydrorhodiamine oxidation. To confirm that cannabinoids act as antioxidants in the intact cell, neurons were also incubated with the oxidant t-butyl hydroperoxide and varying concentrations of cannabidiol FIG.
The t-butyl hydroperoxide oxidant was chosen for its solubility in both aqueous and organic solvents, which facilitates oxidation in both cytosolic and membrane cell compartments. Cell toxicity was assessed hours after insult by measuring lactate dehydrogenase LDH release into the culture media.
All experiments were conducted with triple or quadruple values at each point and all plates contained positive glutamate alone and baseline controls. The assay was validated by comparison with an XTT based metabolic activity assay. As shown in FIG. The middle cerebral artery of chloral hydrate anesthetized rats was occluded by insertion of suture thread into it. The animals were allowed to recover from the anesthetic and move freely for a period of two hours.
After this time the suture was removed under mild anesthetic and the animals allowed to recover for 48 hours. Then the animals were tested for neurological deficits, sacrificed, and the infarct volume calculated. To examine the infarct volume, animals were anesthetized, ex-sanguinated, and a metabolically active dye 3-phenyl tetrazolium chloride was pumped throughout the body.
All living tissues were stained pink by the dye, while morbid regions of infarcted tissue remained white. Brains were then fixed for 24 hours in formaldehyde, sliced and the infarct volumes measured. Control animals received injections of vehicle without drug. IV doses would be expected to be times less because of reduction of first pass metabolism. This data shows that infarct size was approximately halved in the animals treated with cannabidiol, which was also accompanied by a substantial improvement in the neurological status of the animal.
These studies with the nonpsychotropic marijuana constituent, cannabidiol, demonstrate that protection can be achieved against both glutamate neurotoxicity and free radical induced cell death. THC, the psychoactive principle of cannabis, also blocked glutamate neurotoxicity with a potency similar to cannabidiol. In both cases, neuroprotection is unaffected by the presence of a cannabinoid receptor antagonist. These results therefore surprisingly demonstrate that cannabinoids can have useful therapeutic effects that are not mediated by cannabinoid receptors, and therefore are not necessarily accompanied by psychoactive side effects.
Cannabidiol also acts as an anti-epileptic and anxiolytic, which makes it particularly useful in the treatment of neurological diseases in which neuroanatomic defects can predispose to seizures e. A particular advantage of the cannabinoid compounds of the present invention is that they are highly lipophilic, and have good penetration into the central nervous system.
The volume of distribution of some of these compounds is at least L in a 70 kg person 1. The lipophilicity of particular compounds is also about as great as that of THC, cannabidiol or other compounds that have excellent penetration into the brain and other portions of the CNS. Cannabinoids that lack psychoactivity or psychotoxicity are particularly useful embodiments of the present invention, because the absence of such side effects allows very high doses of the drug to be used without encountering unpleasant side effects such as dysphoria or dangerous complications such as obtundation in a patient who may already have an altered mental status.
Cannabidiol and THC have been shown to be comparable to the antioxidant BHT, both in their ability to prevent dihydrorhodamine oxidation and in their cyclic voltametric profiles. Several synthetic cannabinoids also exhibited profiles similar to the BHT, although anandamide, which is not structurally related to cannabinoids, did not. These findings indicate that cannabinoids act as antioxidants in a non-biological situation, which was confirmed in living cells by showing that cannabidiol attenuates hydroperoxide induced neurotoxicity.
The potency of cannabidiol as an antioxidant was examined by comparing it on an equimolar basis with three other commonly used compounds. This unexpected superior antioxidant activity in the absence of BHT tumor promoting activity shows for the first time that cannabidiol, and other cannabinoids, can be used as antioxidant drugs in the treatment including prophylaxis of oxidation associated diseases, and is particularly useful as a neuroprotectant.
The therapeutic potential of nonpsychoactive cannabinoids is particularly promising, because of the absence of psychotoxicity, and the ability to administer higher doses than with psychotropic cannabinoids, such as THC. This example describes in vitro and in vivo assays to examine the effect of cannabidiol CBD on three lipoxygenase LO enzymes: Enzyme studies were performed using a u. The reaction was initiated by addition of 0.
Recordings examined the absorption at nm minus the value at a reference wavelength of nm. Human platelets and leukocytes were purified from buffy coat preparations NIH Blood Bank using a standard Ficoll based centrifugation method used in blood banks. Prior to use, cells were washed three times to eliminate contaminating cell types.
Cultured rat basophillic leukemia cells RBL-2H3 were used as a source of 5-lipoxygenase. Cells were incubated with arachidonic acid and stimulated with the calcium ionophore A Lipids were extracted and separated by reverse phase HPLC. Product formation was assessed as the area of a peak that co-eluted with an authentic standard, had a greater absorbance at nm than at either or nm, and the formation of which was inhibited by a lipoxygenase inhibitor.
Lipids were extracted with 1 volume of ethyl ether, which was dried under a stream of nitrogen. The ability of HETE s -hydroxy-eicosatetraenoic acid, the product of the action of lipoxygenase on arachidonic eicosatetraenoic acid to protect cortical neurons from NMDAr toxicity was measured as described in Example 3.
As shown in FIGS. The leukocyte LO is similar, while the platelet LO is structurally and functionally different, from the porcine LO used in the in vitro enzyme study. Importantly, this is the first demonstration FIG. Although the mechanism of this protection is unknown at the present time, HETE is known to be an important neuromodulator, due to its ability to influence potassium channel activity.
The present invention includes a treatment that inhibits oxidation associated diseases in a subject such as an animal, for example a rat or human. The method includes administering the antioxidant drugs of the present invention, or a combination of the antioxidant drug and one or more other pharmaceutical agents, to the subject in a pharmaceutically compatible carrier and in an effective amount to inhibit the development or progression of oxidation associated diseases.
Although the treatment can be used prophylactically in any patient in a demographic group at significant risk for such diseases, subjects can also be selected using more specific criteria, such as a definitive diagnosis of the condition. The administration of any exogenous antioxidant cannabinoid would inhibit the progression of the oxidation associated disease as compared to a subject to whom the cannabinoid was not administered. The antioxidant effect, however, increases with the dose of the cannabinoid.
The vehicle in which the drug is delivered can include pharmaceutically acceptable compositions of the drugs of the present invention using methods well known to those with skill in the art. Any of the common carriers, such as sterile saline or glucose solution, can be utilized with the drugs provided by the invention.
Routes of administration include but are not limited to oral, intracranial ventricular icv , intrathecal it , intravenous iv , parenteral, rectal, topical ophthalmic, subconjunctival, nasal, aural, sub-lingual under the tongue and transdermal. The antioxidant drugs of the invention may be administered intravenously in any conventional medium for intravenous injection such as an aqueous saline medium, or in blood plasma medium.
Such medium may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, lipid carriers such as cyclodextrins, proteins such as serum albumin, hydrophilic agents such as methyl cellulose, detergents, buffers, preservatives and the like.
Given the low solubility of many cannabinoids, they may be suspended in sesame oil. Given the excellent absorption of the compounds of the present invention via an inhaled route, the compounds may also be administered as inhalants, for example in pharmaceutical aerosols utilizing solutions, suspensions, emulsions, powders and semisolid preparations of the type more fully described in Remington: The Science and Practice of Pharmacy 19 th Edition, in chapter Embodiments of the invention comprising pharmaceutical compositions can be prepared with conventional pharmaceutically acceptable carriers, adjuvants and counterions as would be known to those of skill in the art.
The compositions are preferably in the form of a unit dose in solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, injectable and infusible solutions, for example a unit dose vial, or a metered dose inhaler. If the antioxidant drugs are to be used in the prevention of cataracts, they may be administered in the form of eye drops formulated in a pharmaceutically inert, biologically acceptable carrier, such as isotonic saline or an ointment.
Conventional preservatives, such as benzalkonium chloride, can also be added to the formulation. In ophthalmic ointments, the active ingredient is admixed with a suitable base, such as white petrolatum and mineral oil, along with antimicrobial preservatives. Specific methods of compounding these dosage forms, as well as appropriate pharmaceutical carriers, are known in the art. The Science and Practice of Pharmacy, 19th Ed. The compounds of the present invention are ideally administered as soon as a diagnosis is made of an ischemic event, or other oxidative insult.
For example, once a myocardial infarction has been confirmed by electrocardiograph, or an elevation in enzymes characteristic of cardiac injury e. CKMB , a therapeutically effective amount of the cannabinoid drug is administered. A dose can also be given following symptoms characteristic of a stroke motor or sensory abnormalities , or radiographic confirmation of a cerebral infarct in a distribution characteristic of a neurovascular thromboembolic event.
The dose can be given by frequent bolus administration, or as a continuous IV dose. The following table lists examples of some dibenzopyran cannabinoids that may be useful as antioxidants in the method of the present invention.
R-group substituents are H if not indicated otherwise. Chemical structures of some of the dibenzopyran cannabinoids are shown below. The following table lists examples of some cannabinoids which are structural analogs of cannabidiol and that may be useful as antioxidants in the method of the present invention. A particularly useful example is compound CBD, cannabidiol. The invention being thus described, variation in the materials and methods for practicing the invention will be apparent to one of ordinary skill in the art.
Such variations are to be considered within the scope of the invention, which is set forth in the claims below. Year of fee payment: Cannabinoids have been found to have antioxidant properties, unrelated to NMDA receptor antagonism.
This new found property makes cannabinoids useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases.
The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV dementia. Nonpsychoactive cannabinoids, such as cannabidoil, are particularly advantageous to use because they avoid toxicity that is encountered with psychoactive cannabinoids at high doses useful in the method of the present invention.
A particular disclosed class of cannabinoids useful as neuroprotective antioxidants is formula I wherein the R group is independently selected from the group consisting of H, CH 3 , and COCH 3. A method of treating diseases caused by oxidative stress, comprising administering a therapeutically effective amount of a cannabinoid that has substantially no binding to the NMDA receptor to a subject who has a disease caused by oxidative stress.
The method of claim 1 , wherein the cannabinoid is nonpsychoactive. The method of claim 1 , wherein the cannabinoid is not an antagonist at the NMDA receptor. The method of claim 1 , wherein the cannabinoid is: Thus, except in preclinical models of neonatal ischaemia see below and [ 20 ] , CBD has been found not to display any signs of CB 1 or CB 2 receptor activation, and yet is no less active than cannabinoid receptor agonists against the brain damage produced by different types of cytotoxic insults [ 71 — 75 ], reviewed in [ 76 ].
What then are the cannabinoid receptor-independent mechanisms by which CBD acts as a neuroprotective agent? Finding the correct answer to this question is not easy, although data obtained in numerous investigations into different pathological conditions associated with brain damage indicate that CBD does normalize glutamate homeostasis [ 71 , 72 ], reduce oxidative stress [ 73 , 77 ] and attenuate glial activation and the occurrence of local inflammatory events [ 74 , 78 ].
Furthermore, a recent study by Juknat et al. These authors found a greater influence of CBD on genes controlled by nuclear factors known to be involved in the regulation of stress responses including oxidative stress and inflammation [ 79 ]. This agrees with the idea that there may be two key processes underlying the neuroprotective effects of CBD.
The first and the most classic mechanism is the capability of CBD to restore the normal balance between oxidative events and anti-oxidant endogenous mechanisms [ 69 ] that is frequently disrupted in neurodegenerative disorders, thereby enhancing neuronal survival. As has been mentioned above [ 73 , 77 ], this capability seems to be inherent to CBD and structurally-similar compounds, i.
Alternatively, or in addition, the anti-oxidant effect of CBD may involve intracellular mechanisms that enhance the ability of endogenous anti-oxidant enzymes to control oxidative stress, in particular the signaling triggered by the transcription factor nuclear factor-erythroid 2-related Factor 2 nrf-2 , as has been found in the case of other classic anti-oxidants.
According to this idea, CBD may bind to an intracellular target capable of regulating this transcription factor which plays a major role in the control of anti-oxidant-response elements located in genes encoding for different anti-oxidant enzymes of the so-called phase II-anti-oxidant response see proposed mechanism in Figure 1.
This possibility is presently under investigation reviewed in [ 69 ]. Mechanisms proposed for the neuroprotective effects exerted by CBD in neurodegenerative disorders. The second key mechanism for CBD as a neuroprotective compound involves its anti-inflammatory activity that is exerted by mechanisms other than the activation of CB 2 receptors, the canonic pathway for the anti-inflammatory effects of most of cannabinoid agonists [ 70 ].
Anti-inflammatory effects of CBD have been related to the control of microglial cell migration [ 80 ] and the toxicity exerted by these cells, i. Therefore, it could well be that CBD may produce its anti-inflammatory effects by the activation of these nuclear receptors and the regulation of their downstream signals although various aspects of this mechanism are pending further research and confirmation see proposed mechanism in Figure 1.
Other mechanisms proposed for the neuroprotective effects of CBD include: Although the neuroprotective properties of CBD have been already examined in numerous acute or chronic neurodegenerative disorders, we will address here only three disorders, i.
CBD has demonstrated significant effects in preclinical models of these three disorders, but, in some cases, its combination with other phytocannabinoids i. Brain damage by hypoxia-ischaemia HI affects 0. Energy failure during ischaemia provokes the dysfunction of ionic pumps in neurons, leading to accumulation of ions and excitotoxic substances such as glutamate. The consequent increase in intracellular calcium content aggravates the neuron dysfunction and activates different enzymes, starting different processes of immediate and programmed cell death.
During post ischaemic reperfusion, inflammation and oxidative stress aggravate and amplify such responses, increasing and spreading neuron and glial cell damage. Excitotoxicity, inflammation and oxidative stress play, therefore, a particularly relevant role in HI-induced brain cell death in newborns [ 83 ]. Unfortunately, the therapeutic outcome in NHIBD is still very limited and there is a strong need for novel strategies.
Using forebrain slices from newborn mice subjected to glucose-oxygen deprivation, a well-known in vitro model of NHIBD, we have already reported that CBD is able to reduce necrotic and apoptotic damage [ 20 ]. This neuroprotective effect is related to the modulation of excitotoxicity, oxidative stress and inflammation, as CBD normalizes the release of glutamate and cytokines as well as the induction of iNOS and COX-2 [ 20 ].
Surprisingly, we found that co-incubation of CBD with the CB 2 receptor antagonist AM abolished all these protective effects, suggesting that CB 2 receptors are somehow involved in neuroprotective effects of CBD in immature brain [ 20 ]. In this model, the administration of CBD after the HI insult also reduces immediate brain damage by modulating cerebral haemodynamic impairment and brain metabolic derangement, and preventing the appearance of brain oedema and seizures.
These neuroprotective effects are not only free from side effects but also associated with some beneficial cardiac, haemodynamic and ventilatory effects [ 84 ]. These protective effects restore neurobehavioural performance in the following 72 h post HI [ 85 ]. HD is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the protein huntingtin.
The mutation consists of a CAG triplet repeat expansion translated into an abnormal polyglutamine tract in the amino-terminal portion of huntingtin, which due to a gain of function becomes toxic for specific striatal and cortical neuronal subpopulations, although a loss of function in mutant huntingtin has been also related to HD pathogenesis see [ 86 ] for review.
Major symptoms include hyperkinesia chorea and cognitive deficits see [ 87 ] for review. Thus, even though a few compounds have produced encouraging effects in preclinical studies i. CBD has also been studied in rats lesioned with malonate, a model of striatal atrophy that involves mainly glial activation, inflammatory events and activation of apoptotic machinery.
We are presently studying the efficacy of this phytocannabinoid combination in a transgenic murine model of HD, i. Previous clinical studies had already used CBD, but they concentrated on symptom relief i. PD is also a progressive neurodegenerative disorder whose aetiology has been, however, associated with environmental insults, genetic susceptibility or interactions between both causes [ 95 ].
The major clinical symptoms in PD are tremor, bradykinesia, postural instability and rigidity, symptoms that result from the severe dopaminergic denervation of the striatum caused by the progressive death of dopaminergic neurons of the substantia nigra pars compacta [ 96 ]. CBD has also been found to be highly effective as a neuroprotective compound in experimental models of parkinsonism, i.
This observation is particularly important in the case of PD due to the relevance of oxidative injury to this disease, and because the hypokinetic profile of cannabinoids that activate CB 1 receptors represents a disadvantage for this disease because such compounds can acutely enhance rather than reduce motor disability, as a few clinical data have already revealed reviewed in [ 98 ].
Therefore, major efforts are being directed at finding cannabinoid molecules that may provide neuroprotection through their anti-oxidant properties and that may also activate CB 2 receptors, but not CB 1 receptors, or that may even block CB 1 receptors, actions which may provide additional benefits, for example by relieving symptoms such as bradykinesia. The experimental evidence presented in this review supports the idea that, from a pharmaceutical point of view, CBD is an unusually interesting molecule.
As presented above, its actions are channeled through several biochemical mechanisms and yet it causes essentially no undesirable side effects and its toxicity is negligible [ 2 ]. It has shown valuable activities in numerous pharmaceutically important areas: However, commercial issues apart, CBD has tremendous potential as a new medicine. Thus, because the mechanisms that underlie its anti-inflammatory effects are different from those of prescribed drugs, it could well prove to be of considerable benefit to a large number of patients, who for various reasons are not sufficiently helped by existing drugs.
In type 1-diabetes, we have shown that in mice CBD very significantly lowers the number of insulin-producing cells that are affected even after the disease has advanced [ ].
Its neuroprotective effects are extremely valuable as no drugs exist that have similar properties. Aren't we missing a valuable new pathway to a family of very promising new therapeutic agents?
RP's research is supported in part by funding from GW Pharmaceuticals. RM is a consultant of GW Pharma. National Center for Biotechnology Information , U. Br J Clin Pharmacol. Published online May Author information Article notes Copyright and License information Disclaimer. Received Mar 8; Accepted May This article has been cited by other articles in PMC. Abstract Cannabidiol CBD is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified.
Table 1 A selection of receptors, ion channels, enzymes and cellular uptake processes that CBD has been reported to activate, antagonize or inhibit in vitro. Open in a separate window. CBD in specific neurodegenerative disorders: CBD and Huntington's disease HD is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the protein huntingtin.
CBD and Parkinson's disease PD is also a progressive neurodegenerative disorder whose aetiology has been, however, associated with environmental insults, genetic susceptibility or interactions between both causes [ 95 ]. However, it may help to reduce cognitive damage caused by neuroinflammation and work to combat all kinds of neurodegenerative disease.
Pockets of research have indicated that pre-treatment with marijuana can protect the brain from concussion and head trauma, which should be of note to athletes in the National Football League NFL , jockeys and others. Anybody working in industries or partaking in activities where the chance of concussion is increased may benefit from regularly medicating with cannabis.
But the occasional CBD dietary supplement, whether vaped, as part of an edible or mixed in with your meals may be incredibly helpful for brain health. In , a study found that patients with traumatic brain injuries had a reduce chance of dying from brain trauma if they had distinguishable amounts of THC in their body.
Sometimes, post-concussion syndrome PCS occurs after a concussion. This is a complication that can affect a person for several months following the original trauma.
The Mayo Clinic picks out fatigue, headaches, anxiety, dizziness, insomnia, memory loss, concentration difficulties, increased sensitivity to noise and light and general irritability as common symptoms of PCS. Several psychiatric issues which happen following a concussion are attributed to PCS. Researchers have found that patients who experience head trauma are at greater risk of depression and suicide, with a new study worryingly suggesting that a single concussion can increase long-term suicide risk by percent.
However, the devastating symptoms of PCS may be manageable with cannabis treatment. Memory loss and a reduction in cognitive function following a head trauma may be reversible, if the results of a study into rodents are repeated in humans. Moreover, rodent research has uncovered that CBD is a potent antidepressant which creates positive changes much more quickly than conventional antidepressants such as SSRIs. These can take several weeks to make improvements, whereas CBD starts combatting depression after the first dose and remains an effective treatment with consistent use.
Cannabis and concussions: harnessing CBD’s neuroprotective properties
Science keeps proving cannabinoids have antioxidant and neuroprotective properties. Lab research has shown promising results for CBD as a. Australia has one of the highest marijuana prevalence rates in the world and socio-political discussions rage about the legalisation of marijuana for medical and. While the legalization of marijuana is spreading across North America, the interest in cannabidiol or CBD oil is also rapidly growing. The extract.