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Parkinson's disease and cannabis

Picture of Viola Brugnatelli

Parkinson's disease and cannabis - Cannabiscientia

 

Millions of people around the world suffer from Parkinson's disease. The lack of effective treatments over time and the onset of often serious side effects push more and more patients to seek alternative treatments. Among these there is certainly Therapeutic Cannabis.

But is cannabis really effective in Parkinson's disease?

 

INDEX

 

1. HISTORY OF PARKINSON

Well before Hippocrates and Galen defined the canons of Western medicine, in 600 BC the Indian doctor Charaka wrote the Charaka Samhita (the collection of Charaka), a compendium of medical practices, already in use in India for centuries, which still constitute the foundations of Ayurvedic medicine. In his book, he spoke of Kampa Vata (Sanskrit terms indicating, respectively, "tremor" and "energizing force of the body and mind") describing what is now known as Parkinson's disease. Charaka anticipated the English doctor James Parkinson by more than two thousand years, author of a short essay from 1817 entitled "Shaking Palsy" where he described a syndrome characterized by tremor, rigidity and reduction of movement which was subsequently named after him .

But Charaka's insights and discoveries did not stop there. The Ayurvedic doctor recommended treating his patients with Mucuna pruriens (Kapikachhu in Sanskrit), a kind of purple pea whose toasted seeds produce a drink similar to coffee, with aphrodisiac properties. The secret of this plant in alleviating the symptoms of Parkinson's, certainly unknown to Charaka, is that it contains a certain amount of levodopa, the first anti-Parkinson's active ingredient used successfully in the 1960s. Even today, even in the West, Mucuna pruriens is used by patients suffering from this disease.

The origin and cause of Parkinson's disease are currently unknown. Although mutations of specific genes have been found in 5% of affected patients, it is believed that this is due to a combination of genetic predisposition and risk factors that are not yet well understood.

Parkinson's is a slowly evolving neurodegenerative disease, which mainly affects around 60 years of age, with a higher prevalence among men. It is characterized by the progressive accumulation of a protein called α-synuclein, in inclusions called Lewy bodies, present at the level of the substantia nigra, a particular area of ​​the brain (midbrain) that controls movements. This causes a decrease in the synthesis and release of dopamine, an important neurotransmitter involved in neuromodulation, i.e. the modulation of brain activities.

Parkinson's is characterized by so-called motor symptoms and non-motor symptoms, which can manifest themselves in the various stages of the disease.

The motor symptoms are mainly:

  • Tremor;
  • Muscle stiffness;
  • Bradykinesia, i.e. slowness of movements;
  • Postural instability.

Non-motor symptoms include:

  • Anxiety and depression;
  • Ache;
  • Cognitive and language disorders;
  • Difficult sleeping.

The treatment of choice involves the use of levodopa (L-dopa) or analogues, which increase the bioavailability of dopamine and counteract the onset of symptoms. These drugs are very effective at the beginning of therapy but undergo a rapid tolerance phenomenon, whereby they significantly lose effectiveness over time. The use of these drugs has been associated with the development of adverse motor symptoms, particularly dyskinesia (involuntary movements).

Dopamine agonists and monoamine oxidase (MAO) inhibitors have also shown efficacy, but side effects are often unbearable. Surgery, including Deep Brain Stimulation (DBS) or lesion intervention, is used to reduce motor symptoms in more severe cases.

Proper nutrition and rehabilitation interventions are very useful in treating symptoms. Both Charaka and James Parkinson agreed on this: even though they were so distant in time and space, the two doctors strongly believed in the idea that prevention was the most effective remedy for any pathology.

However, an effective cure for Parkinson's disease that remains effective over time has not yet been found.

 

2. CANNABIS, CANNABINOIDS AND NEUROPROTECTION


Neurodegenerative diseases - Parkinson's and Alzheimer's disease are the most widespread - are characterized by a progressive loss of neuronal function. For these diseases, inflammation, the immune response in general and oxidative stress are among the main factors that cause damage and dysfunction of neurons.

Cannabis and cannabinoids – THC, CBD and THCV mainly – have anti-inflammatory and anti-oxidant properties that have been established by decades of research and this contributes to their neuroprotective effect. [1]

Cannabis-induced neuroprotection also occurs through other mechanisms:

  • Inhibition of glutamatergic transmission in the brain and consequent reduction of excitotoxicity (a phenomenon of neuronal toxicity resulting from exposure to relatively high concentrations of glutamic acid, a neurotransmitter);
  • Improved function of the blood-brain barrier, which protects the brain from external substances;
  • Regulation of cerebral blood flow;
  • Reduction of damage following traumatic brain injury;
  • Regulation of programmed cell death.

In addition to being neuroprotective, cannabis is a well-tolerated substance, with modest side effects. For this reason, scientific research has been investigating for some time whether the potential of therapeutic cannabis and its constituents could also be exploited to treat the symptoms of Parkinson's.

 

3. CANNABIS AND CANNABINOIDS IN MOVEMENT CONTROL

In addition to inducing neuroprotective effects, the Endocannabinoid System is also expressed in many areas of the brain that control movement.

CB1 receptors are found in large quantities in the substantia nigra and basal ganglia of the Central Nervous System (CNS). Here we also find high concentrations of endocannabinoids, especially anandamide.

CB2 receptors are not highly expressed in the CNS, although they have been found in many non-neuronal cells, such as astrocytes and microglia, with an immune protective function.

Researchers at the University of Colorado recently demonstrated that activating CB1 receptors on spinal cord astrocytes reduced tremor in animal models of essential tremor. [2]

THCV, a phytocannabinoid present in smaller quantities in the Cannabis plant, with anti-inflammatory and anti-oxidant properties, improves Parkinson's symptoms in animal models, probably through the interaction with CB2. [3]

Other receptors of the Endocannabinoid System, such as GPRs and TRPs, are also implicated in neuroprotection and the control of body movements.

A 2014 study in an animal model of Parkinson's demonstrated that depletion of the GPR6 receptor, a receptor similar to cannabinoid receptors GPRs, present in the basal ganglia, induces an increase in dopamine in the brain and an improvement in motor activity, especially of levodopa-induced dyskinesia. [4]

A few years later it was demonstrated that CBD acts as an inverse agonist of GPR6 and therefore could be used as a potential treatment for Parkinson's. [5]

 

4. PARKINSON AND CANNABIS: FROM PRECLINICAL STUDIES TO HUMAN EXPERIMENTS

Despite a large amount of pre-clinical experimental data on the neuroprotective and tremor-reducing effects induced by cannabis and cannabinoids, studies carried out on humans have not given definitive results that would justify their use in therapy.

A 2001 British pilot study showed that nabilone, a synthetic analogue of THC, was able to reduce levodopa-induced dyskinesia. [6] However, the study was carried out on a small number of patients [7] and did not include a comparison with placebo.

Another British study from 2004, randomized and with placebo, with 17 participants, showed that cannabis, although well tolerated, did not induce improvements in dyskinesia and parkinsonism. [8]

CBD has not shown significant effects in reducing the motor symptoms of Parkinson's either, although in a 2014 Brazilian study, 21 treated patients reported an overall improvement in quality of life. [9]

Also in Brazil, researchers administered CBD or a placebo to around twenty Parkinson's patients, before subjecting them to a test where they were asked to speak in public. In this simulation of an anxiety-provoking situation, patients who received a dose of 300 mg of CBD showed a decrease in anxiety and tremor. [10]

Nabilone also seems to improve the quality of life of Parkinson's patients. In 2020, researchers from the Parkinson's Disease Working Group at the University of Innsbruck (Austria) showed that 4 weeks of nabilone treatment improved anxiety and sleep disturbances in Parkinson's patients. [11]

 

5. THE PATIENTS' POINT OF VIEW

If the clinical data do not seem to support the use of therapeutic cannabis and cannabinoids in Parkinson's, the patients' point of view is instead different. A simple Google search is enough to find direct testimonies of how the use of cannabis has improved the lives of many people suffering from Parkinson's.

People who, in general, were no longer able to get relief from the use of traditional drugs. Non-motor symptoms such as anxiety and sleep disorders seem to benefit most from the use of cannabis, but there is no shortage of testimonies from patients reporting improvements in tremor and postural rigidity.

To remain within the academic sphere, these testimonies are supported by various surveys, surveys carried out with very specific scientific criteria.

For example, one of these studies was published in 2021 in the Journal of Parkinson Disease, by researchers from the University of Hamburg, Germany.

To evaluate the point of view of the German Parkinson's community, 1,348 questionnaires were analyzed. Cannabis use was reported by 8.4% of patients. Of these, most are:

  • younger than non-users,
  • they live in big cities,
  • they know the legal and clinical aspects of therapeutic cannabis better.

Reduction in pain and muscle cramps has been reported by more than 40% of cannabis users. More than 20% reported improvements in stiffness/akinesia, immobility, tremor, depression, anxiety, and restless legs syndrome. Symptom improvement was reported by 54% of users who took CBD orally and 68% who inhaled THC-containing cannabis.

Compared to taking CBD, inhaling THC has been reported more frequently to reduce akinesia and stiffness. No particular side effects have been reported. 65% of non-users declared themselves interested in using therapeutic cannabis. [12]

 

6. PARKINSON AND CANNABIS: FEW STUDIES ON HUMAN AND DIFFICULTIES IN CARRYING THEM OUT

Why are there these discrepancies between clinical trial data and patients' views?

One explanation could be that of the placebo effect. Knowing that they use cannabis, patients are led to feel better precisely because they expect cannabis to make them feel better. The placebo effect is still important, but to support the use of medical cannabis in Parkinson's and avoid false hopes in patients, it is advisable to have conclusive scientific data, supported by randomized, placebo and double-blind clinical studies.

This type of study, especially on a large sample of patients, is not easily feasible. The main reason is the high costs. Normally these costs are borne by the pharmaceutical companies that own the patent of the drug to be tested, who by "sponsoring" the study benefit financially if it is successful.

For cannabis the matter is more complicated because, being a plant, it is not easily patentable. Even when there is the possibility of patenting formulations, as in the case of Sativex® - a drug based on THC and CBD extracts - one comes up against another big problem: cannabis and THC (in some cases also CBD ) are still included in the narcotics lists, almost all over the world. This makes it very complicated to have the necessary authorizations even to carry out research on these compounds and, once again, this causes costs to rise.

To simplify things and not deprive thousands of people of certain data on a treatment that offers great potential, against a disease for which there are not many effective drugs available, it would be appropriate to overcome prohibitionist laws that are no longer in step with the times. It is more necessary than ever that cannabis and its constituents are no longer classified as substances of abuse, to make their use in research and therapy easier.

 

7. PARKINSON AND CANNABIS: CONCLUSIONS

Pre-clinical experiments on cells and animals indicate that cannabis, THC, CBD and THCV have great potential as a treatment for the motor and non-motor symptoms of Parkinson's.

The few randomized and double-blind clinical studies, carried out on a small number of patients, report minimal benefits in the use of cannabis and cannabinoids for the motor symptoms of Parkinson's. On the other hand, a systematic review of the scientific literature carried out in 2023 (in which data from all clinical studies carried out so far were brought together) shows that cannabis and derivatives are useful for improving the non-motor symptoms of Parkinson's , especially: [13]

  • ache,
  • anxiety,
  • insomnia,
  • life quality.

Furthermore, the so-called Real World Data (RWD) shows that a good percentage of patients who used these substances as anti-parkinsonian therapy reported benefits, especially an improvement in quality of life.

To reach a definitive conclusion, well-designed clinical studies are needed, where the right dosages, the most suitable cannabis varieties, the best route of administration and a large number of patients are taken into consideration.

These studies are more desirable than ever, considering the thousands of people affected by Parkinson's every year, but they can only be carried out through greater research funding and when cannabis is removed from the drug tables.

 

References

  1. Joseph Maroon, Jeff Bost.
    Review of the neurological benefits of phytocannabinoids.
    Surg Neurol Int. 2018 Apr 26;9:91.[↑]
  2. Eva Maria Meier Carlsen, Sarah Falk, Urszula Skupio, Laurie Robin, Antonio C Pagano Zottola, Giovanni Marsicano, Jean-François Perrier.
    Spinal astroglial cannabinoid receptors control pathological tremor.
    Nat Neurosci. 2021 Mar 18.[↑]
  3. C García, C Palomo-Garo, M García-Arencibia, Ja Ramos, Rg Pertwee, J Fernández-Ruiz.
    Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ⁹-THCV in animal models of Parkinson’s disease.
    Br J Pharmacol. 2011 Aug;163(7):1495-506.[↑]
  4. Oeckl, P., Hengerer, B., & Ferger, B. (2014).
    G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson’s disease.
    Experimental neurology, 257, 1–9.[↑]
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    GPR3 and GPR6, novel molecular targets for cannabidiol.
    Biochem Biophys Res Commun. 2017 Aug 12;490(1):17-21.[↑]
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    Neurology. 2001 Dec 11;57(11):2108-11.[↑]
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  8. C B Carroll, P G Bain, L Teare, X Liu, C Joint, C Wroath, S G Parkin, P Fox, D Wright, J Hobart, J P Zajicek.
    Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study.
    Neurology. 2004 Oct 12;63(7):1245-50.[↑]
  9. Marcos Hortes N Chagas, Antonio W Zuardi, Vitor Tumas, et al.
    Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J
    Psychopharmacol. 2014 Nov;28(11):1088-98.[↑]
  10. Stephanie Martins de Faria, Daiene de Morais Fabrício, Vitor Tumas, et al.
    Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease.
    J Psychopharmacol. 2020 Feb;34(2):189-196.[↑]
  11. Marina Peball, Mario Werkmann, Philipp Ellmerer, et al.
    Nabilone for non-motor symptoms of Parkinson’s disease: a randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal study (The NMS-Nab Study).
    J Neural Transm (Vienna). 2019 Aug;126(8):1061-1072.[↑]
  12. Ferhat Yenilmez, Odette Fründt, Ute Hidding, Carsten Buhmann.
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    J Parkinsons Dis. 2021;11(1):309-321[↑]
  13. Karan Varshney, Akash Patel, Siraaj Ansari, et al.
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    Cannabis Cannabinoid Res. 2023 Oct;8(5):716-730.[↑]