Cannabis in Parkinson’s Disease — The Patient’s Perspective Versus Clinical Trials: A Systematic Literature Review Part 1

ABSTRACT

Cannabis and cannabinoids are often considered in the treatment of Parkinson's Disease (PD). The purpose of this paper was to perform a systematic review of the available data on cannabis treatment. 

Parkinson's disease is a chronic disease that affects the nervous system, often causing symptoms such as movement disorders and tremors. However, in addition to its motor effects, Parkinson's disease may also have an impact on our memory. However, while this effect is real, we can't be too pessimistic because there are many ways to improve our memory and quality of life.

First, let's take a look at the specific effects of Parkinson's disease on memory. However, in most cases, Parkinson's disease primarily affects motor ability. However, other neurological symptoms such as cognitive impairment, difficulty concentrating, and memory loss sometimes occur. These symptoms may affect people's daily lives and ability to work, especially older adults. However, they do not necessarily affect every patient, nor are they evident at every moment.

So, how to deal with the impact of Parkinson's disease on memory? Here are some simple ways:

First, stay positive. While your memory may be affected, worry and depression will only exacerbate the effects. Maintaining an optimistic attitude can help you better deal with difficulties and challenges in life.

Secondly, keep yourself healthy. Good health can delay the progression of the disease, such as maintaining good eating habits, proper exercise, and regular living habits.

Third, keep up your mental training. This method can activate our brain nerve cells and help us strengthen memory and cognitive abilities. Such as playing puzzle games, constantly learning new things, maintaining social activities, etc.

Finally, focus on the treatment of the disease. Prompt detection and treatment of Parkinson's disease can relieve symptoms and reduce the impact on memory.

In conclusion, Parkinson's disease indeed affects memory, but this does not mean that we should be bound by this condition. Staying positive, staying healthy, engaging in mental training, and focusing on treatment are all ways we can minimize this impact and improve our quality of life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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We aimed to assess randomized trials as well as surveys among patients. We identified 569 papers on PD and cannabinoid treatment. Of these, there were only seven papers featuring randomised trials on the effects of different cannabinoids on PD. 

The results of these trials did not support the efficacy of cannabinoids in the treatment of motor signs of PD. Based on the available data, we conclude that there is currently insufficient data to support the administration of cannabinoids to PD patients. Larger, randomized studies of cannabis use in PD should be conducted.

Keywords: Parkinson's Disease, cannabis, CBD, marijuana, non-motor symptoms.

Introduction

Parkinson's Disease (PD) is the second most common neurodegenerative disease, after Alzheimer's Disease. With a lack of causative treatment, most interventions are directed at reducing motor and non-motor symptoms of the disease. Cannabis (marijuana) is obtained from the Cannabis plant. 

Tetrahydrocannabinol (THC) is the main psychoactive component of cannabis, while cannabidiol (CBD) is the most widely described component in the context of neurological treatment. The first papers on the effect of cannabis on movement disorders came from observational studies. Consroe et al. [1] reported in 1986 that CBD exacerbated Parkinsonian symptoms in patients with dystonia of various types (Meige's syndrome, torticollis). 

The study included a total of five patients, one with PD and dystonia induced by levodopa. Interestingly, doses of CBD applied in the study were quite high, reaching 600 mg/d. A paper by Frankel et al. [2] described five patients treated with marijuana cigarettes, along with diazepam, levodopa, and apomorphine, each given on consecutive days. 

The authors reported no benefit of marijuana on PD tremor. The current concept of the efficacy of cannabis in the treatment of PD is derived from the discovery of the endocannabinoid system (ECS). Endocannabinoid signaling is altered in most neurological disorders. Phytocannabinoids act via the cannabinoid receptors 1 (CB-1R) and 2 (CB-2R). 

Both types of receptors are expressed in the central nervous system, with a predominance of CB-1R. CB-1R is expressed in the basal ganglia, with especially high concentrations in the medial part of the internal pallidum [3]. CB-2R receptor expression is elevated in microglial cells within the substantia nigra (SN) of PD patients, and both the striatum and SN of lipopolysaccharide (LPS)-lesioned mice. 

The main endogenous ligands of CB-1R and CB-2R are anandamide and 2-arachidonoylglycerol [4, 5]. Slowing the progression of PD is the key target in its treatment. Evidence from in vitro studies on cell lines indicates that CBD may protect cells from MPP+-induced toxicity [6] or reduce amyloid-mediated neural toxicity [7]. The neuroprotective effects of CBD have been assessed in some studies using animal models of PD. Lastres-Becker et al. [8] showed both in vivo and in vitro that the administration of CBD counteracted neurodegeneration caused by the injection of 6-hydroxydopamine in the medial prosencephalic bundle. 

The authors hypothesized that this effect could be related to the anti-inflammatory and/or antioxidative effects of cannabinoids. Garcia-Arencibia et al. [9] tested many cannabinoid compounds following the lesion of dopaminergic neurons in the SN. 

They concluded that the acute administration of CBD seemed to have a neuroprotective action; however, the administration of CBD one week after the lesion had no significant effect. Some authors have also reported a reduction in the pro-inflammatory markers nuclear factor-κB, cyclooxygenase-2 activity, and phospho-ERK levels after CBD treatment [10]. 

Interestingly, it has been reported by some authors that the neuroprotective effect of CBD may be unrelated to a cannabinoid receptor, as CBD does not have a direct effect on CB-2R in physiological concentrations [11, 12]. 

Others have indicated that CB-2R should be the key target for studies on the neuroprotective effects of cannabinoids because it is expressed in both reactive microglia and astrocytes, and thus may promote neuroinflammation [13]. 

The ability to modulate impaired basal ganglia activity by phytocannabinoids has been extensively investigated recently. This is postulated to be achieved by the ability of exogenous cannabinoids to: a) affect synaptic neurotransmission; b) influence corticostriatal plasticity; and c) have neuroprotective and anti-inflammatory properties [11, 14]. The purpose of this systematic review was to evaluate available studies for the clinical efficacy of the treatment of motor (tremor, bradykinesia, falls, dyskinesia) and non-motor (anxiety, pain, sleep disorders) symptoms with medical marijuana and cannabinoids in patients with PD.

Materials and method

Searches were performed according to the PRISMA guidelines 2020 [15]. The PubMed and Scopus databases were searched. The terms "Parkinson" plus "Marijuana", "Cannabis", "Nabilone", "Dronabinol" and "Nabiximols" were used. 

Reviews of the literature and case reports were excluded. We also included one paper assessing, among other drugs, the effect of rimonaband, a CB1 antagonist, on PD patients. Only full-text articles published in English from 2000 until 27 September 2021 were included in the final analysis.

Results

Searching with the terms "Parkinson" AND "marijuana" OR "Cannabis"; "nabilone"; "dronabinol"; "nabiximols" revealed 514 results in the Scopus database and 207 results in the PubMed database. After automatic (EndNote) and manual (M.F.) removal of duplicates, a total of 569 papers were identified that met the search criteria. In the next step, available abstracts were read to identify the original research papers on the effect of treatment on patients with PD. 

We excluded original papers regarding the knowledge of medical personnel or their attitudes to treatment with cannabis. A PRISMA flow diagram of the search procedure is available as supplementary material 1. We identified a total of 18 original papers or case series on the effect of cannabis-based products on the symptoms of PD. Among those, there were seven double-blinded randomized trial results available. 

Three of the seven assessed the effect of pure CBD on PD symptoms [16–18], one study involved treatment with THC and CBD in combination [19], and two papers summarised the results of randomized clinical trials with nabilone [20, 21]. 

Table 1 summarises the findings from the randomized studies. There were five open-label studies/ case series on the effect of treatment with CBD [22–24] or smoking/vaporization of cannabis [25, 26] in PD. Finally, seven of the papers summarised findings from online or telephone surveys of patients with PD on the effects of marijuana (sometimes in addition to other treatments) on PD symptoms [27–33].

Motor signs of PD

There have been very few studies focusing on the effect of cannabis on motor signs of PD. For a summary of randomized papers on cannabis treatment in PD, please refer to Table 1. 

Different treatment regimens have been applied. Lotan et al. [26] reported in an unblinded trial a positive effect of smoking cannabis on such PD motor signs as tremor, rigidity, and bradykinesia, reflected in a significant decrease in UPDRS part III scores (33.1 ± 13.8 at baseline to 23.2 ± 10.5; p < 0.001) after treatment. This is consistent with the findings of Shohet et al., where the authors focused on the sensation of pain, but also reported lower total UPDRS III scores during treatment (from 38.1 ± 18 to 30.4 ± 15.6; p < 0.0001) [25]. 

Both papers assessed direct effects 30 minutes after smoking a marijuana cigarette. The positive effects of marijuana consumption reported in open studies have not been confirmed in randomized double-blind trials. Chagas et al. [34] assessed patients in "ON" status on the UPDRS III scale before and after six weeks of treatment with CBD. They reported no improvement regarding motor signs of PD in groups receiving CBD 75 mg and 300 mg versus placebo. 

However, they reported significant improvements in total PDQ-39 scores in the group receiving 300 mg CBD vs a placebo group, as well as in a subset of questions regarding activities of daily living. 

Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa treatment. We have identified three clinical trials measuring the effects of cannabinoids on LID intensity. The study by Carroll et al. [19] was a randomized study with a crossover phase. It included 19 patients with PD and LID. Patients received a combination of THC 2.5 mg and CBD 1.25 mg tablets. 

The total dosage of THC was limited to 0.25 mg/kg/day, and the majority of patients did not reach that limit. The results showed a good safety profile, but no benefit. Although the authors did not provide detailed calculations of the total CBD dosage received by each patient, it was much lower than the dose administered in other studies on CBD (up to 25 mg/kg/day). 

A small (n = 7) double-blind crossover trial by Sieradzan et al. [20] demonstrated the efficacy of nabilone in LID reduction. A paper by Mesnage et al. [35] assessed the efficacy of three substances - neuropeptides neurokinin B, neurotensin, and anandamide. Of these, anandamide acted as a CB receptor antagonist. Patients were randomly assigned to one of the three substances or a placebo. 

The authors reported a lack of improvement in the delay of the "ON" period, duration of the "ON" period, the percentage of Parkinsonian motor improvement (UPDRS III), or the severity of the LID.

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