Are CBD's antioxidant properties the answer to slowing down oxidation in the human body? Find out more about CBD-as-antioxidant. To examine the effects of cannabinoids on ROS toxicity, 7- to . by reacting with ROS, the antioxidant properties of cannabidiol and other. Of the cannabinoids so far identified, cannabidiol (CBD) is among the most exciting because of its antioxidant and neuroprotective properties.
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When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects.
Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.
CBD was first isolated from marijuana in by Adams et al. Ten years later, Perez-Reyes et al. Interestingly, CBD does not induce the cannabinoid tetrad, namely hypomotility, catalepsy, hypothermia, and antinociception. Clinical and pre-clinical studies have pointed to beneficial effects of CBD on the treatment of movement disorders.
The first studies investigated CBD's actions on dystonia, with encouraging results. The mechanisms whereby CBD exerts its effects are still not completely understood, mainly because several targets have been identified. Of note, CBD displays anti-inflammatory and antioxidant actions Campos et al.
It is noteworthy that, when available, the pharmacological treatments for these movement disorders are mainly symptomatic and induce significant side effects Connolly and Lang, ; Lerner et al. Nonetheless, despite its great clinical relevance, the studies evaluating CBD's role on the pharmacotherapy of movement disorders are surprisingly few.
Here, we will review the clinical and pre-clinical evidence and draw attention to the potential of CBD in this field. CBD has several molecular targets, and new ones are currently being uncovered.
CBD antagonizes the action of CB 1 and CB 2 receptors agonists, and is suggested to act as an inverse agonist of these receptors Pertwee, In parallel, CBD inhibits the enzymatic hydrolysis and the uptake of the main endocannabinoid anandamide Bisogno et al.
The increase in anandamide levels induced by CBD seems to mediate some of its effects Leweke et al. Moreover, in some behavioral paradigms the administration of an inhibitor of anandamide metabolism promotes effects similar to CBD Pedrazzi et al.
CBD has also been shown to facilitate the neurotransmission mediated by the serotonin receptor 5-HT 1A. GPR55 has been suggested as a novel cannabinoid receptor Ryberg et al. Moreover, Hodges et al. GPR3 is suggested as a biomarker for the prognosis of multiple sclerosis Hecker et al. CBD has also been reported to act on mitochondria. In a rodent model of iron overload—that induces pathological changes that resemble neurodegenerative disorders—CBD reverses the iron-induced epigenetic modification of mitochondrial DNA and the reduction of succinate dehydrogenase's activity da Silva et al.
Of note, multiple studies associate mitochondrial dysfunctions with the pathophysiology of PD Ammal Kaidery and Thomas, In parallel, several studies show anti-inflammatory and antioxidant actions of CBD Campos et al.
In addition, it inhibits the expression of iNOS Esposito et al. CBD also displays antioxidant properties, being able to donate electrons under a variable voltage potential and to prevent the hydroperoxide-induced oxidative damage Hampson et al. In accordance, CBD decreases oxidative parameters in in vitro models of neurotoxicity Hampson et al.
Of note, the anti-inflammatory and antioxidant effects of CBD on lipopolysaccharide-stimulated murine macrophages are suppressed by a TRPV1 antagonist Rajan et al. It has also been shown that CBD can affect the expression of several genes involved in zinc homeostasis, which is suggested to be linked to its anti-inflammatory and antioxidant actions Juknat et al.
CBD's mechanisms of action. Moreover, CBD antagonizes the action of CB 1 and CB 2 receptors agonists, and is suggested to act as an inverse agonist and a negative allosteric modulator of these receptors. By acting on mitochondria, CBD increases the activity of mitochondrial complexes. The disease is characterized by motor impairment hypokinesia, tremors, muscle rigidity and non-motor symptoms e. The pathophysiology of PD is mainly associated with the loss of midbrain dopaminergic neurons in the substantia nigra pars compacta SNpc , with consequent reduced levels of dopamine in the striatum Dauer and Przedborski, The most effective and used treatment for PD is L-DOPA, a precursor of dopamine that promotes an increase in the level of dopamine in the striatum, improving the motor symptoms Connolly and Lang, Treatment with CBD for 4 weeks decreased the psychotic symptoms, evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire, without worsening the motor function or inducing adverse effects Zuardi et al.
Later, in a case series with four PD patients, it was verified that CBD is able to reduce the frequency of the events related to REM sleep behavior disorder Chagas et al. In addition, although not ameliorating PD patients' motor function or their general symptoms score, treatment with CBD for 6 weeks improves PD's patients quality of life Chagas et al. The authors suggest that this effect might be related to CBD's anxiolytic, antidepressant and antipsychotic properties Chagas et al.
When administered before the cataleptic agents haloperidol antipsychotic drug , L-nitro-N-arginine non-selective inhibitor of nitric oxide synthase or WIN ,2 agonist of cannabinoid receptors , CBD hinders the cataleptic behavior in a dose-dependent manner Gomes et al.
In accordance, Sonego et al. Moreover, CBD prevents the increased catalepsy behavior induced by repeated administration of reserpine Peres et al. In addition to preventing the loss of dopaminergic neurons—assessed by tyrosine hydroxylase immunostaining —, the administration of CBD after 6-OHDA injury attenuates the activation of microglia in substantia nigra Garcia et al.
Data from clinical and pre-clinical studies are summarized in Tables 1 , 2 , respectively. Clinical studies investigating the effects of CBD on movement disorders. Pre-clinical studies investigating the effects of CBD on movement disorders. HD is a fatal progressive neurodegenerative disease characterized by motor dysfunctions, cognitive loss and psychiatric manifestations McColgan and Tabrizi, HD is caused by the inclusion of trinucleotides CAG in the exons of the huntingtin gene, on chromosome 4 MacDonald et al.
Neurodegeneration in HD affects mainly the striatal region caudate and putamen and this neuronal loss is responsible for the motor symptoms McColgan and Tabrizi, Cortical degeneration is seen in later stages, and huntingtin inclusions are seen in few cells, but in all patients with HD Crook and Housman, The diagnosis of HD is based on motor signs accompanied by genetic evidence, which is positive genetic test for the expansion of the huntingtin gene or family history Mason and Barker, ; McColgan and Tabrizi, The pharmacotherapy of HD is still directed toward the symptomatic relief of the disease, i.
This treatment is often conducted with typical and atypical antipsychotics, but in some cases the use of dopaminergic agonists is needed Mason and Barker, ; McColgan and Tabrizi, Indeed, the role of dopamine in HD is not fully elucidated yet. Regarding the cognitive deficits, none of the investigated drugs was able to promote improvements Mason and Barker, ; McColgan and Tabrizi, Recently, there has been a growing number of studies aiming to verify the therapeutic potential of cannabinoid compounds in the treatment of HD, mainly because some cannabinoids present hypokinetic characteristics Lastres-Becker et al.
There was no significant reduction in the chorea indicators, but no toxicity was observed Consroe et al. The protective effects of CBD and other cannabinoids were also evaluated in a cell culture model of HD, with cells expressing mutated huntingtin. In this model, the induction of huntingtin promotes rapid and extensive cell death Aiken et al. These effects seem to be independent of CB 1 activation, since absence of CB 1 receptors has been reported in PC12, the cell line used Molderings et al.
The authors suggest that the cannabinoids exert this protective effect by antioxidant mechanisms Aiken et al. Regarding studies with animal models, treatment with 3-nitropropionic acid 3-NP , an inhibitor of complex II of the respiratory chain, induces striatal damage—mainly by calpain activation and oxidative injury —, being suggested as relevant to study HD Brouillet et al.
In accordance with what previously seen with CBD alone, Sativex administration attenuates all the 3-NP induced neurochemical, histological and molecular alterations Sagredo et al. Authors also observed a protective effect of Sativex in reducing the increased expression of iNOS gene induced by malonate Sagredo et al.
Malonate administration leads to striatal damage by apoptosis and inflammatory events related to glial activation, being used as an acute model for HD Sagredo et al.
In a subsequent study, it was observed that the administration of a Sativex-like combination attenuates all the malonate-induced alterations, namely: Although the beneficial effects of Sativex on cell survival are blocked by both CB 1 or CB 2 antagonists, CB 2 receptors seem to have a greater role in the protective effect observed Valdeolivas et al. Treatment with a Sativex-like combination, although not reversing animal's deterioration in rotarod performance, attenuates the elevated clasping behavior, that reflects dystonia Valdeolivas et al.
More recently, one study described the results of administering cannabinoid drugs to 7 patients 2 of them were treated with Sativex; the others received dronabinol or nabilone, agonists of the cannabinoid receptors: Tables 1 , 2 summarize data from clinical and pre-clinical studies, respectively. Dystonias are the result of abnormal muscles tone, causing involuntary muscle contraction, and resulting in repetitive movements or abnormal posture Breakefield et al.
Dystonias can be primary, for instance paroxysmal dyskinesia, or secondary to other conditions or drug use, such as tardive dyskinesia after prolonged treatment with antipsychotic drugs Breakefield et al. However, it should be noted that in two more recent studies with PD patients no worsening of motor function was seen Zuardi et al.
In accordance, Sandyk et al. The effects of CBD on dystonic movements were also evaluated in pre-clinical studies. In a hamster model of idiopathic paroxysmal dystonia, the higher dose of CBD showed a trend to delay the progression of dystonia Richter and Loscher, In addition, CBD prevents the increase in vacuous chewing movements, i. In addition, treatment with capsazepine and CBD decreases the expression of inflammatory markers, reinforcing the suggestion that the anti-inflammatory actions of CBD may be beneficial to the treatment of dyskinesia Dos-Santos-Pereira et al.
Moreover, Sativex has been used in the treatment of spasticity in multiple sclerosis. A significant portion of patients does not respond to the conventional anti-spasmodic therapies, and some strategies are invasive, posing risks of complications Flachenecker et al. Recent data point to Sativex as a valid and well-tolerated therapeutic option.
Sativex is able to treat the spasms, improving the quality of life, and displays a low incidence of adverse effects Giacoppo et al. One important concern is whether CBD is a safe therapeutic strategy. Several preclinical and clinical reports show that CBD does not alter metabolic and physiological parameters, such as glycemia, prolactin levels, blood pressure, and heart rate.
In addition, CBD does not modify hematocrit, leukocyte and erythrocyte counts, and blood levels of bilirubin and creatinine in humans. CBD also does not affect urine osmolarity, pH, albumin levels, and leukocyte and erythrocyte counts. Moreover, in vitro studies demonstrate that CBD does not alter embryonic development nor the vitality of non-tumor cell lines. The most reported side effects of CBD are tiredness, diarrhea, and changes on appetite. CBD does not seem to induce tolerance.
For a broad review of CBD's side effects, see Bergamaschi et al. In the context of movement disorders with concomitant cognitive symptoms, as the ones discussed here, it is crucial to evaluate the potential motor and cognitive side effects of CBD.
CBD does not induce catalepsy behavior in rodents—being even able to attenuate the effects of several cataleptic agents, as discussed above El-Alfy et al. In accordance, CBD does not induce extrapyramidal effects in humans Leweke et al. With respect to cognitive effects, studies report that CBD does not impair cognition, being even able to improve it in some conditions.
Pre-clinical data show that CBD restores the deficit in the novel object recognition task in mice treated with MK a protocol used to model schizophrenia Gomes et al. CBD also reverses impaired social recognition in a murine model for Alzheimer's disease Cheng et al.
In addition, studies demonstrate that CBD per se does not modify animals' performance in cognitive tasks Osborne et al. CBD also improves facial emotion recognition in cannabis users Hindocha et al. It is noteworthy that in some cases, particularly concerning multiple sclerosis and HD clinical studies, CBD per se does not seem to be beneficial. Multiple clinical studies with Sativex have not observed motor or cognitive adverse effects Aragona et al.
Nevertheless, one recent open-label study compared multiple sclerosis patients who continued the treatment with Sativex to those who quitted and reported worse balance and decrease in cognitive performance in the continuers Castelli et al.
Although the studies are scarce, CBD seems to be effective on treating dystonic movements, both primary and secondary. Data regarding HD are scarce, but the results of using Sativex in multiple sclerosis are encouraging. Reviews of the clinical use of this compound in the last decade point to effectiveness in the treatment of spasticity as well as improvement in quality of life, with low incidence of adverse effects Giacoppo et al.
In respect to PD, although the pre-clinical studies are promising, the few studies with patients failed to detect improvement of the motor symptoms after treatment with CBD. There is a significant difference between the clinical and pre-clinical PD studies. In animals, the beneficial effects are seen when CBD is administered prior to or immediately after the manipulation that induces the PD-like symptoms. In clinical practice, PD is diagnosed subsequently to the emergence of motor symptoms—that appear up to 10 years after the beginning of neurodegeneration and the onset of non-motor symptoms Schrag et al.
The fact that in clinical trials CBD is administered only after this substantial progression of the disease might explain the conflicting results. Unfortunately, the early diagnosis of PD remains a challenge, posing difficulty to the implementation of preventive strategies. The development of diagnosis criteria able to detect PD in early stages would probably expand the CBD's applications in this disease. The molecular mechanisms associated with CBD's improvement of motor disorders are likely multifaceted.
Moreover, all movement disorders are in some extent linked to oxidative stress and inflammation, and CBD has been reported to display an antioxidant and anti-inflammatory profile, in vitro and in animal models for movement abnormalities. The studies investigating the role of CBD on the treatment of movement disorders are few.
Furthermore, differences in the dose and duration of treatment as well as in the stage of the disease for instance, PD patients are treated only in an advanced stage of the disease among these studies shown in detail in Table 1 limit the generalization of the positive effect of CBD and might explain the conflicting results.
Notwithstanding, the beneficial neuroprotective profile of CBD added to the preliminary results described here are encouraging. All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.
The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. A cell-based screen for drugs to treat Huntington's disease. Current perspective of mitochondrial biology in Parkinson's disease.
Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: Various concentrations of cannabinoids and butylhydroxytoluene BHT were included to examine their ability to prevent dihydrorhodamine oxidation.
Data are reported as mean values plus and minus standard error. To examine NMDAr-mediated toxicity, rat cortical neurons were exposed to glutamate for 10 min in a magnesium-free medium, and the level of lactate dehydrogenase released was used as an index of cell injury.
Similar data also was observed when glutamate was replaced with either AMPA-specific or kainate receptor-specific ligands data not shown. Each experiment was repeated on at least four occasions with essentially the same results. Cannabinoids were present during and, in the case of NMDAr mediated toxicity, after the glutamate exposure periods. See Materials and Methods for further experimental details.
Such depolarization may activate both voltage-sensitive calcium channels 21 and facilitate NMDAr activation 22 , However, a combination of these calcium channel inhibitors did not completely block EDTA-preventable calcium-dependant cell death. Cannabinoids were present throughout the glutamate exposure period. Significant difference between EDTA and other treatments is indicated with an asterisk. Unlike cannabidiol, THC is a ligand for the brain cannabinoid receptor 24 , and this action has been proposed to explain the ability of THC to protect neurons from NMDAr toxicity in vitro 7.
This was confirmed by inclusion of a cannabinoid receptor antagonist, SRA Fig. Neither THC or cannabidiol neuroprotection was affected by cannabinoid receptor antagonist. Effect of THC, cannabidiol, and cannabinoid receptor antagonist on glutamate induced neurotoxicity. See Materials and Methods for experimental details. Studies have suggested that ROS damage may be involved in glutamate neurotoxicity 5 , 6.
To investigate whether cannabinoids could protect neurons against glutamate by reacting with ROS, the antioxidant properties of cannabidiol and other cannabinoids were assessed. Cyclic voltametry, a procedure that measures the ability of a compound to accept or donate electrons under a variable voltage potential, was used to measure the oxidation potentials of several natural and synthetic cannabinoids.
Anandamide arachidonyl-ethanolamide , which is not a cannabinoid in structure but is an endogenous ligand for the cannabinoid receptor, did not undergo oxidation in this assay Fig. Three other cannabinoids, cannabinol, nabilone, and levanantrodol, also were tested, and they, too, exhibited oxidation profiles similar to cannabidiol and THC data not shown. A A comparison of the oxidation potentials of cannabinoids and the antioxidant BHT. Anandamide, a cannabinoid receptor ligand with a noncannabinoid structure, was used as a nonresponsive control.
Experiments were repeated three times with essentially the same results. B Effect of cannabidiol and THC on dihydrorhodamine oxidation. Cannabinoids were compared with BHT for their ability to prevent tert -butyl hydroperoxide-induced oxidation of dihydrorhodamine. This experiment was repeated four times with essentially the same results. The ability of cannabinoids to be oxidized readily suggests that they may possess antioxidant properties comparable to BHT.
These properties were examined further in a Fenton reaction iron-catalyzed ROS generation. Tert -butyl hydroperoxide was used to generate ROS and oxidize dihydrorhodamine into the fluorescent compound rhodamine.
To confirm that cannabinoids act as antioxidants in the intact cell, neurons were incubated with tert -butyl hydroperoxide and varying concentrations of cannabidiol Fig.
The oxidant was chosen for its solubility in both aqueous and organic solvents, thereby facilitating oxidation in both cytosolic and membrane cell compartments.
As observed in studies with glutamate, cannabidiol protected neurons against ROS toxicity in a concentration-related manner.
A The effect of cannabidiol on oxidative toxicity in neuronal cultures. Tert -butyl hydroperoxide-induced toxicity was examined in the presence or absence of cannabidiol. B Comparison of antioxidants and cannabidiol for their ability to prevent glutamate toxicity in neurons. All drugs were present throughout the glutamate exposure period. Each experiment represents the mean of four replicates repeated on three occasions. Significant differences between cannabidiol and other antioxidants are indicated with an asterisk.
The nonpsychoactive marijuana constituent cannabidiol was found to prevent both glutamate neurotoxicity and ROS-induced cell death. The psychoactive principle of Cannabis , THC, also blocked glutamate neurotoxicity with a similar potency to cannabidiol. In both cases, neuroprotection was unaffected by cannabinoid receptor antagonist. This suggests that cannabinoids may have potentially useful therapeutic effects that are independent of psychoactivity-inducing cannabinoid receptors 12 and so are not necessarily accompanied by psychotropic side effects.
Cannabidiol blocked glutamate toxicity in cortical neurons with equal potency regardless of whether the insult was mediated by NMDAr, AMPA receptors, or kainate receptors.
This suggests that either cannabinoids antagonize all three glutamate receptors with the same affinity, or, more likely, their site of action is downstream of initial receptor activation events. Neurotoxic concentrations of glutamate induce massive calcium influx through NMDAr 4 that ultimately kills the cell. However, the mixture of calcium channel inhibitors and NMDAr antagonist did not eliminate completely glutamate toxicity or reduce cell death as efficiently as EDTA.
Cannabidiol and THC were found to be comparable with BHT antioxidant in both their ability to prevent dihydrorhodamine oxidation Fenton reaction and their cyclic voltametric profiles. Synthetic cannabinoids such as HU, nabilone, and levanantradol also exhibited similar profiles. Anandamide, which is a natural cannabinoid receptor ligand but is not structurally related to cannabinoids, did not give an antioxidant-like profile by cyclic voltametry, which indicates that cannabinoids can act as reducing agents in a chemical system.
To confirm that cannabinoids also can function as antioxidants in living cells, a lipid hydroperoxide was used to generate ROS toxicity in neuronal cultures. As observed in the Fenton reaction system, cannabidiol attenuated this ROS-induced neurotoxicity.
These observations indicate that many cannabinoids exert a considerable protective antioxidant effect in neuronal cultures. The similarity of the voltamagrams observed with cannabidiol, HU, and several other cannabinoids also suggests that the reported antioxidant effect of HU is not a feature unique to this atypical cannabinoid, as previously implied; e.
The potency of cannabidiol as an antioxidant was examined by comparing it on an equimolar basis with other commonly used antioxidants. As in the Fenton reaction system, cannabidiol protected neurons with comparable efficacy to the potent antioxidant BHT. The similar antioxidant abilities of cannabidiol and BHT in this chemical system and their comparable protection in neuronal cultures implies that cannabidiol neuroprotection is caused by an antioxidant effect.
The antioxidative properties of cannabinoids suggest a therapeutic use as neuroprotective agents, and the particular properties of cannabidiol make it a good candidate for such development. Although cannabidiol was similar in neuroprotective capacity to BHT, cannabidiol has no known tumor-promoting effects [unlike BHT 25 , 26 ].
The lack of psychoactivity associated with cannabidiol allows it to be administered in higher doses than would be possible with psychotropic cannabinoids such as THC. Furthermore, the ability of cannabidiol to protect against neuronal injury without inhibiting NMDAr may reduce the occurrence of toxicity or side effects associated with NMDAr antagonists
CBD as an Antioxidant: These Studies Show HOW it Works
While not entirely known by the public, the US government has been aware of CBD's antioxidant properties since , as revealed by a patent. Much like cannabinoids produce an entourage effect, antioxidants have a “ network effect,” too. In his book The Antioxidant Miracle: Your. However, although research into the therapeutic effects of CBD is rapidly Furthermore, CBD is known to be a reasonably potent antioxidant.