Cannabinoids as neuroprotectants


The discovery of the endogenous cannabinoid system set up the basis of an intense research into the therapeutic potentials of cannabinoids, in a variety of neurological-related disorders, such as gliomas, cerebral ischemia, multiple sclerosis, and so on.[1] In fact, this is exactly the main focus of this article, trying to examine possible involvements of the endocannabinoid system into neuroprotection processes.

The endocannabinoid system consists of two main receptors, CB1 and CB2, as well as three of the most important types of endocannabinoid ligands. CB1 mainly populates the central and peripheral neurons, and in lower concentrations are also present in the numerous peripheral tissues, whereas CB2 is mostly present in organs of the immune system, included in the brain (glial cells).

Anandamide was the first endocannabinoid to be identified, followed by 2-arachidonoyl glycerol (2-AG)[2]. Recently, a third endocannabinoid was reported, and was named 2-arachidonyl glyceryl ether (or noladin ether). Differently to the classical neurotransmitters, such as dopamine, serotonin and others, the endocannabinoid Anandamide emerges in very low concentrations in the brain.

Cannabinoids in neurons protection

Endocannabinoids have been tested in models of excitotoxicity, which is a concept of neuronal cell death, caused by over-activation of excitatory amino acid receptors. Thus, cannabinoids have been shown to protect neurons from toxic attacks, such as excitotoxicity, traumatic injury and ischaemia. This neuroprotective action may rely on different mechanisms like:

  • Inhibition of glutamatergic neurotransmission;
  • Modulation of glial cell function;
  • Antioxidant capacity;
  • Control of the microvasculature, and is supported by the observation that the brain overproduces endocannabinoids upon damage.

Another study, conducted by Jin, K.L et al., observed CB1 cannabinoid receptor induction after an experimental stroke, starting from 2 hours and continuing for more than 72hrs. These results are consistent with a neuroprotective effect from endogenous cannabinoids[3]. Several groups have noted that although anandamide and its precursor are present in very low or almost undetectable levels in the brain, their concentrations increase post-mortem or during the injury.

Hansen et alt. in their study found that high levels of the anandamide phospholipid precursor are produced in response to injury, and that 24h after a head trauma, anandamide levels increased by almost three fold, with no associated increase in 2-AG formation[4]. On the contrary, Dr Mechoulam at al conducted another study that showed that both anandamide and 2-AG are produced during brain damages, however, the production of these specific endocannabinoids might depend on the species, age, severity of the trauma and type of injury. Moreover, anandamide and 2-AG seem to be endogenous neuroprotective agents, produced by the brain, and probably by other neuronal systems.[5]

The cannabis plant psychoactive constituent, 9-THC, which is a cannabinoid receptor agonist, is also neuroprotective. Cannabidiol, also reduces glutamate toxicity. Though, the processes of neuroprotection by the various plant, synthetic and endogenous cannabinoids are not clear. In some cases it has been shown that cannabinoid receptors are involved, however the neuroprotective effects of compounds that do not bind to these cannabinoid receptors are also implicated.

Moreover, another study, conducted by Hampson et al., examined another potential therapeutic role for cannabinoids as neuroprotectants, also describing their mechanism of action on the neuronal level.

The study showed that during ischemic episode, big quantities of the excitatory neurotransmitter, glutamate, are released. This event causes neuronal death by over-stimulating NMDAr receptors, AMPA and kainate-type receptors, and results in accumulation of toxic levels of intracellular calcium and metabolic stress. Antioxidants or antagonists to NMDAr and AMPA/kainate receptors have demonstrated (In vitro and in vivo studies) to reduce such neurotoxicity.

Cannabinoids as Antioxidants in neuro-degenerative processes

Cells use glutathione, ascorbate, and a-tocopherol as antioxidants (easily oxidizable compounds) that protect vital cellular structures (e.g., membranes, DNA, proteins,) from toxic reactive oxygen species (ROS).

According to different studies, ROS damage may be involved in glutamate neurotoxicity. The antioxidant properties of cannabidiol and other cannabinoids have been demonstrated by cyclic voltammetry. A procedure that measures the ability of a compound to donate or accept electrons under a variable voltage potential. In general, cannabinoids could protect neurons against glutamate by reacting with ROS.

Cannabidiol is significantly more protective than dietary antioxidants (a-tocopherol or ascorbate). In addition, Cannabidiol blocks glutamate toxicity in cortical neurons with equal potency regardless of whether the attack was mediated by NMDAr, AMPA receptors, or kainate receptors. The neuroprotection observed by THC and CBD seems to be cannabinoid receptor independent. This suggests that cannabinoids may have a therapeutic effects that are independent of psychoactivity-inducing cannabinoid receptors[6] and so are not necessarily accompanied by psychotropic side effects

Although cannabidiol is similar in neuroprotective capacity to the antioxidant butylated hydroxytoluene (BHT), cannabidiol has no known tumour-promoting effects (unlike BHT[7]). The lack of psychoactivity associated with cannabidiol allows it to be administered in higher doses than it would be possible with psychotropic cannabinoids such as THC. Previous studies have indicated that cannabidiol is not toxic, even when chronically administered to humans or given in large acute doses[8].

Did you like the post? Give us some feedback! This post has been done based on existent research to the date of publication of the article. Due to the increase in studies based on medical cannabis, the information provided can vary over time and we’ll keep informing in further writings.

[1] Nagayama T, et alt.  Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. 1999. J Neurosci. 19:2987–2995.

[2] Sugiura, T. et alt. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. 1995. Biochem. Biophys. Res. Commun. 215, 89–97

[3] Hansen, H.H. et alt. Anandamide, but not 2-arachidonylglycerol, accumulates during in vivo neurodegenration. J. Neurochem. 2001. 78, 1415–1427

[4] Mechoulam, R et alt. Cannabinoids and brain injury: therapeutic implications. 2002. Trends in Molecular Medicine, 8(2), 58–61.doi:10.1016/s1471-4914(02)02276-1

[5] Jin, K. L., et alt. CB1 cannabinoid receptor induction in experimental stroke. 2000. Annals of Neurology, 48(2), 257–261.doi:10.1002/1531-8249(200008)48:2<257::aid-ana18>;2-p

[6] Hampson, A. J et alt. Cannabidiol and (-) 9-tetrahydrocannabinol are neuroprotective antioxidants. 1998. Proceedings of the National Academy of Sciences, 95(14), 8268–8273.doi:10.1073/pnas.95.14.8268

[7] Thompson, J.A., Bolton, J.L. and Malkinson. A.M. 1991. Relationship between the metabolism of butylated hydroxytoluene (BHT) and lung tumor promotion in mice. Exp. Lung Res. 17, 439-453. doi:10.1016/0300-483X(94)02943-O

[8] Consroe, P. et alt. Controlled clinical trial of cannabidiol in Huntington’s disease. 1991. Pharmacology Biochemistry and Behavior, 40(3), 701–708.doi:10.1016/0091-3057(91)90386-g

About Mario

Graduado en Lenguas y Culturas Modernas, Después de varios años de investigación personal y de participar en conferencias sobre el mundo del cáñamo industrial, me he unido a la redacción de Kalapa Clinic, donde he recibido formación directa de los médicos especializados de la clínica; esto me ha brindado la oportunidad de convertirme en un experto en las aplicaciones terapéuticas de los cannabinoides.

Es de esta manera donde mi pasión por el debate intercultural, las ganas de eliminar los perjuicios y conociendo el potencial terapéutico de la planta, se conjugan bajo un único objetivo: explicar a la mayor cantidad personas, los beneficios de los cannabinoides y como la planta de cannabis puede mejorar la vida de muchas personas.

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