Cannabis in Parkinson’s Disease — The Patient’s Perspective Versus Clinical Trials: A Systematic Literature Review Part 2

Non-motor symptoms of PD Sleep

Cannabis-based products have been frequently investigated regarding sleep problems in different disorders. Most PD patients (c.80% at late stages) complain of sleep disorders. Their treatment is challenging as they are multifactorial and, in the majority, no defined causes are identified. 

Sleep disorders are a common health problem that many people face in their lives. Good sleep has an extremely important impact on physical health and brain function, especially on memory. Sleep quality will integrate, consolidate and review memories in the brain, thereby strengthening memory. Therefore, sleep disorders may directly affect brain function and memory.

Sleep is one of the important activities of the brain. It helps to remove waste from the brain, thus promoting the enhancement of memory. At the same time, during sleep, the brain will put the learning and experiences of the day into the correct memory area. Without adequate sleep, this process will be disrupted, leading to memory loss. So if you often feel like your memory is lacking, it may be due to a lack of sleep.

Sleep disorders directly affect the brain's memory mechanism. It causes an imbalance of chemicals in the brain, which affects brain function. Lack of sleep may also increase the risk of some neurodegenerative diseases, such as Alzheimer's disease. Therefore, through good sleep quality, you can help protect brain health and memory.

Maintaining healthy sleep habits can improve your brain's memory. First, set a sleep time that you can stick to every day and stick to it. Secondly, create a quiet, comfortable and clean sleeping environment to get enough sleep. Finally, avoid excessive use of electronic devices, especially before bed, as this can affect sleep quality.

In summary, there is a strong link between sleep disorders and memory. High-quality sleep is not only good for physical health but can also effectively improve people's memory. Therefore, everyone should realize the importance of sleep and actively take measures to improve sleep quality and protect brain health and memory. We need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material with many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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A case series by Chagas et al. [36] reported positive initial observation of four patients with REM sleep behaviour disorder (RBD) treated with CBD. On the other hand, a randomised study on 33 patients (conducted in the same centre) showed no advantage of CBD over placebo regarding the reduction of RBD. The authors reported better sleep satisfaction at the 4th and 8th weeks in the CBD versus a placebo group with p = 0.049 and p = 0.038 respectively. 

This effect was, however, transient [16]. Leehey et al. [22] also reported improvements in sleep, reflected by SCOPA-sleep change, but no effect of treatment with CBD on RBD. A study by Lotan et al. [26] reported, among others, improvement in the quality of sleep, but no specific questionnaire or test was applied to measure it.

Pain

Pain is a common problem in PD of heterogeneous origin and with only a partial response to dopaminergic treatment. The reduction of pain, reflected by improvements in the Visual Analogue Scale (VAS), was reported in the study by Lotan et al. [26]. 

The paper by Shohet et al. [25] examined pain sensation in a very elaborate manner, with similar conclusions. The authors reported a decrease in the cold and hot pain thresholds in patients smoking cannabis using the Quantitative Sensory Testing method. In both papers, assessments were performed before, and 30 minutes after, smoking cannabis, and the patients were not blinded regarding the received treatment.

Neuropsychiatric symptoms

Neuropsychiatric symptoms of PD are among the most researched in terms of cannabis treatment. De Faria et al. [18] performed a double-blind, placebo-controlled study on the efficacy of CBD 300 mg on PD-related anxiety. 

The authors proved that anxiety and anxiety-induced tremors in PD, measured during a Simulated Public Speaking Test, were significantly reduced. Interestingly, while psychosis was an exclusion criterion in the majority of trials on cannabis and CBD, a paper by Zuardi et al. [24] reported improvements in psychosis in six PD patients treated with CBD 150–300 mg, and no additional antipsychotic treatment, reflected by score reductions in the Parkinson Psychosis Questionnaire and on the Brief Psychiatric Rating Scale. 

On the other hand, in a study by Sieradzan et al. [20], focused on the intensity of LID, 5/7 patients experienced sedation, hallucinations of varying intensities, dizziness or disorientation. A paper by Peball et al. [37] assessed the safety and efficacy of nabilone, a synthetic analogue of tetrahydrocannabinol, in the treatment of non-motor symptoms of PD. 

In phase I of the study, nabilone was titrated, while in phase II subjects were randomly assigned to a previously established dose of nabilone or a placebo. The authors reported a significant reduction in UPDRS-MDS I, in particular the 'anxious mood' and 'nighttime sleeping problems' items of the scale. 

Interestingly, although pain-related endpoints (King's Parkinson Pain Scale and VAS of pain) improved significantly during the open-label trial phase, this was not confirmed in the randomised phase.

Patient's perspective

In contrast to the modest effect found in randomised, double-blinded clinical trials, patients' subjective perception of cannabis treatment is good. 

Table 2 summarises papers detailing surveys among patients. Such surveys have taken various forms (i.e. performed by a physician in person, over the phone, by email, or by the patient accessing a website), and some papers have also included patients with other diseases (multiple sclerosis [31], atypical parkinsonism [28]), or have focused only on one symptom (e.g. pain). 

While different approaches and presentations of the results make direct comparisons difficult, improvements in such non-motor symptoms as pain or anxiety have been reported most frequently. Patients have also reported improvements in motor signs of PD, with tremors and rigidity mentioned in the majority of studies. This is in line with the findings of non-blinded clinical trials. 

The results of the surveys are also difficult to interpret because we might have expected patients to give different answers to anonymous internet-based questionnaires rather than those collected by physicians.

Discussion

In our paper, we have aimed to summarise the current knowledge regarding different cannabis-based products in PD treatment. Strikingly, there is a high total number of papers on the treatment of PD with cannabis, compared to a low number of actual original clinical trials. 

This reflects the great interest in these types of medication expressed by both patients and clinicians. While advanced therapies such as vector-based treatment of PD are appearing on the horizon [38], many patients turn instinctively to the methods they consider 'traditional' or 'natural'. The upshot is that studies in randomised controlled trials have included motor signs assessed mainly in UPDRS scale part III, such as resting tremor, rigidity and bradykinesia. 

Some non-motor symptoms, such as RBD and anxiety, have also been assessed in randomised trials. Other authors have used an open-label approach to assess motor symptoms, dyskinesia, pain etc. The chief limitations of the currently available studies on cannabis-based products in PD are small sample sizes and differing schedules of administration of the products. 

There are many differences in the method of intake of cannabis and/ or the dosage of CBD. Smoking marijuana cigarettes seems to make an objective measurement of the dose difficult. This leads to difficulties in comparing the studies. There are also some cultural differences between the investigated groups. Some authors have suggested that cannabis and cannabis products may require very individual dosing and that large randomised studies may fail to show their efficacy for that reason. Progress in genetic testing and identification of subtypes of PD may also lead to the development of more individualised approaches [39, 40]. Open-label studies with positive results carry an additional bias because cannabis intake according to popular understanding leads to a high expectation of a positive effect. Treatment with marijuana and its compounds can lead to complications. 

Fear of addiction and psychotic side effects can be among the most important issues discouraging patients from cannabis treatment. Some symptoms of cannabinoid treatment may be unpleasant for patients. These include somnolence, dizziness, nausea, vomiting, tachycardia, hypotension, dry mouth, diarrhoea, loss of balance and fatigue, as well as psychiatric symptoms such as disorientation, confusion, hallucinations, and altered mood [14]. 

These are usually most pronounced at the beginning of treatment. All of these symptoms are undesirable in the older PD population, and can also exacerbate preexisting symptoms frequent among PD patients, such as hypotension or visual disturbances [41, 42]. Importantly, CBD, in contrast to THC, is considered not to cause psychotic symptoms [34]. It has been proven that psychotic symptoms are a result of CB-1 receptor activation, which is not achieved when CBD is administered in physiological concentrations [43]. A study by Zuardi et al. [24] may encourage the belief that CBD relieves psychotic symptoms. On the other hand, nabilone seems to cause such complications fairly frequently (5/7 patients) [20]. 

Treatment is mostly associated with long-term use and may lead to withdrawal symptoms. Cognitive dysfunction can also appear as a long-term effect of cannabis consumption [44]. Dependency and a lack of official licences in many countries may also be contributory factors. One potentially positive aspect of marijuana treatment may be an increase in weight [31]. Although generally seen as a drawback, this may benefit advanced PD patients with malnutrition, something which is observed in 50% of PD patients [45]. 

We conclude that currently there is insufficient evidence to routinely recommend the addition of cannabis or CBD-based products to PD treatment regimes. While subjective reports claim positive results of cannabinoids on a range of symptoms, randomised placebo-controlled trials in the literature currently do not demonstrate improvements in motor signs, and show inconsistent impacts on LID, anxiety, and psychosis. 

Legal limitations, lack of social acceptance, and troubling side effects may be obstacles in the administration of cannabis. Large, randomised, double-blind, long-term studies with a representative number of patients and dose standardisation are needed to assess the real efficacy of these treatments. In particular, placebo control is needed to provide an adequate assessment of the efficacy of cannabinoids in PD therapy. 

This should include placebo substitutes of both CBD and cannabis administered by inhalation, with careful monitoring of the doses administered to patients. Based on our literature review, we conclude that non-motor symptoms of PD such as pain, anxiety and sleep seem to respond better to cannabis treatment than do motor signs. 

Therefore future studies should perhaps focus on non-motor symptoms, especially as these frequently place a higher burden on PD patients' quality of life than do motor symptoms.

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