By Moisés García Arencibia
Doctor of Biochemistry and Molecular Biology, he has worked mainly on the neuroprotective potential of cannabinoids. He is currently a Professor of Cell Biology at the University of La Laguna.
Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. There is currently no cure for the condition. Could cannabis be of use in protecting the brains of Parkinson's patients or alleviating their symptoms?
Parkinson's disease is a chronic degenerative disease of the central nervous system which mainly affects the areas of the brain that are responsible for controlling movement. It generally appears in people aged over 60 (although in the case of Young-Onset Parkinson's disease, it affects under-40s) and it is more common among men than in women.
Parkinson's disease is characterised by the death of the neurons in an area of the brain known as substantia nigra. These neurons are responsible for producing dopamine, one of the neurotransmitter molecules that are required for signals to travel properly through the brain. Depletion of dopamine alters signalling from the basal ganglia, the area in charge of controlling movement. As a result, the primary symptoms of the disease are motor symptoms. As well as the characteristic shaking commonly associated with the disease, other symptoms include stiffness, postural instability and bradykinesia (slowness in executing movements). In subsequent stages of the disease, sensory, sleep and emotional problems (depression or anxiety) can also appear, coupled with dementia in the latter phases.
In approximately 5% of cases, the disease is the result of the mutation of certain genes. However, in the great majority of patients, the cause is unknown, and is probably a combination of genetic predisposition and environmental factors.
At this time, there is no cure for the disease and medical intervention is limited to treating the symptoms. One of the main forms of treatment, levodopa (or L-DOPA), used to compensate for dopamine depletion, ceases to be effective after a few years and causes uncontrolled movements (dyskinesia) in patients. New compounds therefore need to be researched to protect against neuron death and/or relieve the symptoms of the disease.
Could cannabis be useful in treating Parkinson's disease? As early as the end of the nineteenth century, the use of cannabis for treating Parkinson's was first described in Europe in William Richard Gowers's "Manual of Diseases of the Nervous System" (Philadelphia, PA, USA: P. Blakiston's Son & Co; 1888). One hundred and thirty years on, let us now examine the scientific evidence.
The compounds of cannabis known as cannabinoids (of which over 100 have been described) act on our brain by binding with structures called the CB1 receptor (mainly found in neurons and responsible for the psychoactive effect of some of these cannabinoids) and the CB2 receptor (mainly found in glial cells and responsible inter alia for the inflammatory response). These receptors, together with the endogenous molecules that activate them (endocannabinoids) form part of the endocannabinoid system, an intercellular communication system found in our bodies.
Many cannabinoids have great neuroprotective potential. By binding with the CB1 receptor in neurons, they can protect them from a range of harmful stimuli. They also have an anti-inflammatory capacity, mediated by the glial CB2 receptor. Finally –though no less importantly– cannabinoids are important antioxidant compounds, protecting neurons from the damage of oxidative stress (a very important factor in Parkinson's disease) independently of the receptor, due to their molecular structure, or mediated by other non-cannabinoid receptors, such as the nuclear PPAR receptors which act as antioxidants. This has been demonstrated in numerous preclinical studies (in vitro and in laboratory animal models) for different diseases, including Alzheimer's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis (motor neurone disease).
The area of the basal ganglia, which is affected in Parkinson's disease, has a high density of CB1 cannabinoid receptors. This makes sense, given that one of the functions of the endocannabinoid system is to control movement, generally by inhibiting it. Given the importance of the endocannabinoid system in this structure, there has been speculation on the potential that manipulating the system might have for Parkinson's disease. The endocannabinoid system has been found to be altered in Parkinson's disease, both in experimental animal models and in patients with the condition. Studies have described an increase in CB1 receptor in neurons from the basal ganglia, an increase in CB2 receptor in the glial cells responsible for inflammation and an increase in the level of endocannabinoids. This has been interpreted as the body's response to the damage caused by the disease. Some consider the endocannabinoid system to be the brain's innate defence mechanism.
Pharmacological studies on animal models have shown the neuroprotective potential of compounds with an antioxidant capacity, such as Δ9-tetrahydrocannabinol (Δ9-THC, the main psychoactive composite of cannabis), cannabidiol (CBD, the other most important cannabinoid, which has no psychoactive activity) and Δ9-tetrahydrocannabivarin (Δ9-THCV) and those with an anti-inflammatory capacity through the CB2 receptor (such as Δ9-THCV). Although activation of the CB1 receptor is a neuroprotective strategy used in other conditions, it is contraindicated in the case of Parkinson's disease, since it would exacerbate the motor symptoms by aggravating patients' immobility. There are data to show that blocking these CB1 receptors with the Δ9-THCV increases movement in animal models of Parkinson's disease.
Despite the large quantity of preclinical evidence that has been accumulated, none of the clinical research performed to date has shown positive results.
Observational studies seem to suggest that cannabis could improve motor symptoms. In some studies, patients who consumed cannabis reported experiencing improvements in some of the symptoms of the disease: tremor, bradykinesia, uncontrolled movements caused by treatment, problems with sleep and pain. In other studies, however, patients experienced no improvement in shaking after smoking a single dose of cannabis. In another study in which CBD was administered, patients reported improvements in some psychotic symptoms and in their sleep problems. Observational studies of this kind present numerous problems: the researchers cannot control the variables of the experiment; there is no control group with which to compare the effect; and measurements are indirect and based on the patient's own reports. Such studies therefore produce many variables which can confuse the result. Principal amongst these is the placebo effect. Aware that they are consuming cannabis, patients may report that they feel better precisely because they believe that cannabis consumption will make them feel better. Although this effect is not unimportant, it would be more desirable to see a "real" effect. This can be achieved by performing randomised double-blind clinical trials in which neither the patient nor the researcher knows whether the patient is taking the treatment or a control substance.
Unfortunately, few randomised double-blind clinical trials have been carried out with cannabis on people with Parkinson's. And in those trials that have been conducted, few patients have been recruited. The results from this small number of clinical trials have not been promising. In recent studies using both isolated Δ9-THC and a cannabis extract with Δ9-THC and CBD, no beneficial effects were observed in the motor symptoms, now were any benefits described in quality of life or sleep problems. In another study in which CBD was administered for six weeks, no effect was observed either on the motor symptoms or in neuroprotection, albeit there was an improvement in the patients' quality of life. Although they were performed on only a small numbers of patients, these studies seem to indicate that cannabis is not beneficial for treating the motor symptoms of the disease, though it might be helpful for treating secondary symptoms. Studies need to be carried out with a larger number of patients and with other types of compound whose effectiveness has been demonstrated in preclinical studies, such as Δ9-THCV. In many countries, this would require a change in the law, amending the current classification of cannabis as a drug of abuse to make it easier to use in research.
In light of these results, cannabis consumption does not appear to be the best strategy for treating Parkinson's disease, given its capacity to activate the CB1 receptor through compounds such as Δ9-THC and others. However, treatment with compounds that have a better pharmacological profile, such as Δ9-THCV combined with CBD, either in pure state or as a botanical extract from plants enriched with those compounds, might prove useful.
