Medical Cannabis in Parkinson Disease: Real-Life Patients’ Experience

• PMID: 29059132
• DOI: 10.1097/WNF.0000000000000246

Abstract

Background: The use of medical cannabis (MC) is controversial. Support for its benefits is based on small clinical series.

Objective: The aim of this study was to report the results of a standardized interview study that retrospectively assessed the effects of MC on symptoms of Parkinson disease (PD) and its adverse effects in patients treated for at least 3 months.

Methods: The survey used telephone interviews using a structured questionnaire based on subjective global impressions of change for various parkinsonian symptoms and yes/no questions on adverse effects.

Results: Forty-seven nondemented patients with PD (40 men) participated. Their mean age was 64.2 ± 10.8 years, mean disease duration was 10.8 ± 8.3 years, median Hoehn and Yahr (H&Y) was stage III. The duration of MC use was 19.1 ± 17.0 months, and the mean daily dose was 0.9 ± 0.5 g. The delivery of MC was mainly by smoking cigarettes (38 cases, 80.9%). Effect size (r) improvement for falls was 0.89, 0.73 for pain relief, 0.64 for depression, 0.64 for tremor, 0.62 for muscle stiffness, and 0.60 for sleep. The most frequently reported adverse effects from MC were cough (34.9%) in those who used MC by smoking and confusion and hallucinations (reported by 17% each) causing 5 patients (10.6%) to stop treatment.

Conclusions: Medical cannabis was found to improve symptoms of PD in the initial stages of treatment and did not cause major adverse effects in this pilot, 2-center, retrospective survey. The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from Cannabis sativa.

current treatments of Parkinson disease (PD) and parkinson-ism still provide suboptimal effects, especially regarding the
patients' quality of life. This has led to the search for alternative and often unconventional therapies. There is a wealth and steadily growing body of information in the nonmedical literature on the positive effects of cannabis products on motor symptoms (tremor, rigidity, bradykinesia) as well as on nonmotor symptoms (pain, sleep, depression, anxiety, nausea, and vomiting) and quality of life. The widely discussed adverse effects of standard PD medications encourage patients with PD and physicians to try “alternative natural treatments,”including the attractive option of medical cannabis (MC). We were able to find only a few small clinical trials of the effects of MC in PD, one of which reported improvement of motor (tremor, rigidity, and bradykinesia) and nonmotor (sleep and pain) symptoms, with no significant adverse effects in 22 patients with PD.1 In contrast, the results of 2 other studies were negative: there was no improvement of tremor after smoking cannabis among
5 patients,2 and there were no effects of oral cannabis extract on dyskinesias in a randomized, 4-week, double-blinded, crossover study on 17 patients with PD who tolerated the treatment well.3

METHODS

A retrospective observational telephone survey was conducted to collect data from patients with PD being treated at the
Movement Disorders Clinics of the Tel Aviv Sourasky Medical Center and the Rabin Medical Center. The license for MC use
was granted by the MoH for each participant.

The study was approved by the institutional review boards, and all the participating patients agreed to answer questions by telephone. The design of the structured questionnaire was based on the published MC surveys in multiple sclerosis4 and PD.5 It consists of 66 questions divided into 3 parts: (1) demographic data and comorbidities; (2) clinical characteristics of the patients, including motor and nonmotor features; and (3) details of MC use and subjective assessment of its effects on different symptoms, including adverse effects.

The effect of MC on motor and nonmotor symptoms and on the activities of daily living was evaluated according to the

modified 5-point Clinical Global Impressions Scale as follows: 1 = significant improvement, 2 = moderate improvement, 3 = mild improvement, 4 = no change, and 5 = any worsening.6 Falls before and after MC treatment were registered as yes/no. The telephone interviews were conducted (by L.B.S., J.K., and H.S.) at a prearranged date and time convenient for examinees. The interview lasted around 30 minutes, and a second call was needed to complete data collection in 9/47 cases (19.1 %).

Patients with PD who did not want to participate in the study or were not eligible according to the clinical judgment of the physicians or investigators were excluded from the study. If patients were unable to answer a question, or the question seemed inappropriate, then their response was recorded as irrelevant. All the included patients with PD answered all the questions independently. The responses were accepted as reported by the patient without any modifications, and no attempt to interpret this information was made.

Variable	Number	%
Age years
39–55	9	19.1
56–65	15	31.9
66–75	16	34.1
76–87	7	14.9
Sex
Male	40	85.1
Female	7	14.9
PD duration, y
2–5	11	23.4
5–9	15	31.9
10–15	10	21.3
16–39	11	23.4
Employed (n = 47)
Yes	17	36.2
No	30	63.8
H&Y stages (n = 40)
I	2	5
II	17	42.5
III	12	30
IV	9	22.5

Statistical Analysis

Data were analyzed using a Microsoft Excel 2007 spread-sheet. Results were expressed as means with standard deviations (SDs) or as median with interquartile range (IQR). Irrelevant answers were excluded from the statistical analysis. All the included patients with PD answered all the questions independently without any help. The data on the responses of patients with PD before and after MC were compared according to Student paired t test for dependent samples.7 The effect size for the dependent samples t test (r2) was calculated according to the method proposed by Morris,8 and interpreted according to Cohen's guidelines: ≤0.5 = small; 0.5 to 0.8 = moderate; and ≥0.8 = large.9 A higher r2 value means stronger positive effect of MC in comparison with the period before MC was used. The level of significance was 95% for all tests.

RESULTS

Between 2013 to 2015, 98 patients with PD were suitable for study enrollment: 13 patients refused to participate, 20 could not
be reached by telephone, and 4 patients had passed away. Fourteen patients were excluded from the analysis because they used MC for less than 3 months. Among them, 7 patients have not reached the necessary duration of MC treatment, and the other 7 patients interrupted treatment within 1 to 2 months because of MC inefficiency (4) or adverse effects such as loss of consciousness (1), hallucinations (1), and fatigue (1). A total of 47 patients with PD were included in the study.

Demographic Information

The mean age of the 47 subjects was 64.2 years (SD = 10.8; median = 65; IQR, [56.8–70]), of whom 40 (85.1%) were male patients. Thirty (63.8%) were retired, and the other 17 were employed. The PD duration ranged from 2 to 39 years (average, 10.8 years) (SD = 8; median = 8; IQR, [5–15]), and their H&Y stages ranged from I to IV, median = III, IQR of II to III (Table 1). Unclear answers were excluded from the statistical analysis, leading to variations in the total number of the responses.

PD Status Before MC Treatment

The major PD symptoms were reported as follows: 29/45 had rest tremor (64.4%), 24/45 had muscle stiffness (53.3%),
24/45 had freezing of gait (53.3%), 24/45 had gait disorders (53.3%), and 22/47 (46.8%) had recurrent falls (Table 2). Motor
fluctuations were reported by 36/46 patients (78.73%): 25/47 (53.2%) complained of “off ” times lasting from 0.5 to 24 hours
a day, mean of 9.3 hours (SD = 5.8; median = 8; IQR, 4.0–12). Total “on” times lasted for an average of 11.8 hours (SD = 6.9;
median = 12 hours; IQR, 6–16) in 32/47 patients (68.1%). Peak of dose dyskinesias were reported by 21/45 individuals (46.7%).

The emotional condition of the patients was self defined as depression by 43/47 patients (91.5%): it was mild in 10 patients
(21.3%), moderate in 20 (42.5%), and severe in 13 (27.7%). Memory impairment was reported by 33/44 patients (71.7%): it was mild in 8 (17.4%), moderate in 18 (39.1%), and severe in 7 (15.2%). Thirty-three of the 47 patients (70.2%) reported having problems in concentration: 8 considered them as being mild (17.0%), 17 as being moderate (36.2%), and 8 as being severe (17%). Thirty-one (67.4%) patients reported experiencing chronic pain, and 31 (66%) patients reported having sleep disorders (Table 2).

Variable	Number	%
Rest tremor	29/45	64.4
Muscle stiffness	24/45	53.3
Gait disorders	29/45	64.4
Freezing of gait	24/45	53.3
Falls	22/47	46.8
Motor fluctuations	36/46	78.3
Depression	43/47	91.5
Memory impairment	33/46	71.7
Mental concentration complaints	33/47	70.2
Chronic pain	31/47	66
Sleep disorder	31/47	66

Delivery of MC

Most (38/45, 84.4%) of the patients preferred smoking Cannabis sativa flowers and leaves (5/45, 11.1%), or oil ingestion
(4/46, 8.7%). Cigarettes or “joints” was the most common means of administration, reported by 42/46 (91.3%) of the MC users.
The other modes of administration were oil (6/46, 13 %), vaporizer (2/46, 4.3%), and bong (a bong is a filtration device generally used for smoking cannabis, tobacco, or other herbal substances) (1/46, 2.2%). Four patients (4/46, 8.7%) reported using a combination of means of delivery, and 46/47 subjects (97.9%) reported using MC for medical purposes only. Only 1 subject (2.2%) reported that, in addition to medical reasons related to PD, he used MC for recreation.

The daily dose of MC ranged from 0.2 to 2.25 g/d, mean of 0.9 g (SD = 0.5; median = 0.75; IQR, 0.5–1.0) among the 43 subjects who responded to this item in the questionnaire. The duration of MC treatment in the entire study group of 47 persons ranged from 3 to 84 months, average of 19.1 months (SD = 17.0; median = 12; IQR, 6–24). Ten patients reported a need to increase the MC dose for better effects (21.3%). Five patients (5/47, 10.6%) decided to stop MC treatment 3 to 12 months after initiating it (average, 7 months [SD = 3.9; median = 6; IQR, 4–10]). The reasons that were given for stopping the use of the MC were lack of desirable effect in 2 patients (4.3%), hallucinations in 2 (4.3%), and postural instability in 1 (2.2%).

Effects of MC on PD Symptoms General Satisfaction and Overall Effectiveness

Most of the patients (37/45, 82.2%) reported that MC improved their overall symptoms, 2 reported no difference (4.4%),
and 6 (13.3%) reported feeling worse (Table 3).

Main Effects of MC on Motor and Nonmotor Symptoms of PD

The MC treatment led to a reduction in complaints of falling (from 22/47 [46.8%] to 6/18 [33.3%]) (P <0.05, r2 = 0.89). Re- duced general stiffness of the muscles and tremor were reported by 32/44 and 30/41 individuals (72.7% and 73.2%, respectively), whereas 12 persons with stiffness and 11 those with tremor re- ported no change, and none reported worsening (P < 0.001, for both; r2 = 0.62 and 0.64, respectively). Pain reduction was re- ported by 35/43 individuals (81.4%), and 8 others reported no change (18.6%) (P < 0.001, r2 = 0.73). Three quarters of the sub- jects (35/46, 76.1%) reported an improvement in mood, 10 re- ported no change (21.7%), and 1 (2.2%) reported a worsening of mood (P < 0.001, r2 = 0.64). Most of the patients reported an im- provement in sleep quality (33/46, 71.7%), 13 reported no change (28.3%), and 1 (2.2%) reported worsening of sleep (P < 0.001, r2 = 0.60). The MC treatment had no subjective effects on memory in 23/40 patients (57.5%), it improved in 10 (25%), and worsened in 7 (17.5%). Urinary symptoms were not changed in most pa- tients (24/33, 72.7%), were improved in 6 (18.2%), and worsened in 3 (9.1%) (P > 0.05 for both, r2 = 0.03) (Table 3).

Duration of the MC treatment in the group of 47 persons ranged from 3 to 84 months, average of 19.1 months (SD = 17;
median = 12; IQR, 6–24). Ten patients reported the need to increase MC dose after starting for better effects (21.3%).

A total of 5/46 patients (10.9%) spontaneously stopped MC treatment in the interval from 3 to 12 months, on average after
7 months, (SD = 3.9; median = 6; IQR, 4–10). Reasons given for no longer using MC were lack of desirable effect in 2 subjects
(4.3%), hallucinations in 2 subjects (4.3%), and postural instability in 1 subject (2.2%).

Adverse Effects of MC

Twenty-eight patients (28/47, 59.6%) noted undesirable effects of MC, among them are mental problems (18/47, 38.3%) like confusion (8/47, 17%), anxiety (8/47, 17%), hallucinations (8/47, 17%), and short-term amnesia (3/46, 6.5%), and 1 patient (1/47, 2.1%) claimed to have developed psychosis (2.1%). Cough associated with MC smoking was reported by 15/43 patients (34.9%), 2/43 (4.7%) experienced dyspnea, 6/47 experienced dizziness (12.8%), and 7/45 experienced unsteadiness (15.6%) (Table 4).

DISCUSSION

This is a real-life survey based on reports of the patients under observation in 2 large movement disorder clinics in Israel. It
was performed in the form of a standardized telephone interview. As expected, improvement in pain, sleep, and mood were reported by a significant percentage of patients. In the context of PD, the report of significant reduction of falls is an important finding, along with significant subjective improvement in muscle stiffness and tremor. We propose that this improvement is either an indirect effect of MC for example through its positive effect on fear of falling, as well as relaxation effect on mood and attention, which may improve executive function and decrease falls. This effect may also be associated with the euphoric, analgesic, and sedating effects of MC,10 which may be different in different strains of the Cannabis sativa plant or, alternatively, be related to a placebo effect.11

The use of MC in clinical practice is controversial because of its psychotropic and antimotivational effects,12,13 as well as the
risk of addiction, reaching 9%,14 and possible posttreatment abstinence phenomena.15,16 Another concern with the use of the herbal form of MC relates to various concentrations of the main active ingredients (Δ-9-tetrahydrocannabinol and cannabidiol) in different strains of Cannabis sativa and/or indica.17

The MC treatment was accompanied by numerous adverse effects, as reported by 60.4% of our study participants, with neg-
ative psychotropic effects reported by 39.6% of them. However, no hospitalizations or severe adverse effects were reported. Treatment with MC was continued for a year or more in most cases, which may indicate a preponderance of benefits and satisfaction from this therapy. Importantly, the large percentage of subjects (10/47, 21.3%) who spontaneously increased the dose of MC might indicate a potential for addiction and abuse. In total, 12/61 patients (7/14 excluded and 5/47 included individuals, 19.7%) stopped using MC because of ineffectiveness or intolerable adverse effects.

Although a pathogenetic rationale for treating PD with MC is currently lacking, animal data support a role for cannabinoids in
motor control, because of the high density of cannabinoid receptors in the basal ganglia.18 The highest density of CB1 receptors was found in the globus pallidus and substantia nigra pars reticulata,19 where the endocannabinoid anandamide concentration is 3 times higher in comparison with other brain regions.20 There is colocalization of CB1 and D1/D2 receptors in striatal neurons,21 and locomotor activity was found to be reduced by CB1 inhibition.22 Controlled clinical studies on the therapeutic potential of MC are few and small, whereas pressure for expanding cannabis use spread by media and patients' communities and families is increasing. Currently, until further controlled studies are performed, and until the long-term results are known, the use of MC should remain limited to patients who failed the best possible established medical treatment.23

Symptom	Considered As Relevant Item (n)	Reported As Not Relevant* (n)	Improvement High	Improvement Moderate	Improvement Mild	Total**	Reported As No Change** (n)	Reported Worsening (n)	p	Effect Size (r2)
Motor symptoms
Falls (yes/no)	18	2 (10%)				12 (66.7%)	6 (33.3%)	0		0.89
Tremor	41	5 (10.9%)	10	9	11	30 (73.2%)	11 (26.8%)	0		0.64
Muscle stiffness	44	3 (6.4%)	8	10	14	32 (72.7%)	12 (27.3%)	0		0.62
OFF time	29	12 (29.3%)	2	7	9	18 (62.1%)	10 (34.5%)	1(3.4%)		0.49
ON time	32	6 (15.8%)	1	9	7	17 (53.1%)	14 (43.8%)	1(3.1%)		0.45
Dyskinesias	29	15 (34.1%)	3	4	7	14 (48.3%)	15 (51.4%)	0		0.40
Freezing of gait	28	15 (34.9%)	4	6	3	13 (46.4%)	14 (50%)	1(3.6%)		0.39
Gait disorder	40	7 (14.9%)	3	8	12	23 (57.5%)	14 (35%)	3(7.5%)		0.34
Nonmotor symptoms
Pain	43	3 (6.5%)	11	16	8	35 (81.8%)	8 (18.6%)	0		0.73
Depressed mood	46	1 (2.1%)	15	13	7	35 (76.6%)	10 (21.7%)	1 (2.2%)		0.64
Insomnia	46	1 (2.1%)	20	11	1	32 (69.6%)	13 (28.2%)	1 (2.2%)		0.60
Appetite	31	1 (3.1%)	5	3	3	11 (35.5%)	20 (64.5%)	0		0.31
Libido	36	2 (5.3%)	4	4	4	12 (33.3%)	24 (66.7%)	0		0.28
Sexual life	34	3 (8.1%)	3	1	5	9 (26.5%)	25 (73.5%)	0		0.21
Nausea	28	18 (39.1%)	1	3	2	6 (24.1%)	22 (78.6%)	0		0.18
Constipation	33	12 (26.7%)	2	2	2	6 (18.2%)	26 (78.8%)	1 (3.0%)		0.12
Attention	42	3 (6.7%)	3	5	6	14 (33.3%)	21 (50%)	7 (16.7%)		0.11
Memory	40	4 (9.1%)	2	2	6	10 (25%)	23 (57.5%)	7 (17.5%)		0.04
Urination	33	9 (21.4%)	1	2	3	7 (18.2%)	24 (72.7%)	3 (9.1%)		0.03

We acknowledge potential limitations of this study. The sample of patients was not selected through any systematic procedure
or by random recruitment. The questionnaire was administered by telephone, and the rate of agreement to participate (61/98 62.2%) suggests that this was a highly motivated population. Therefore, there is a potential for a bias to inflate the reports of
effectiveness and to minimize adverse effects. Other limitations were the retrospective self-evaluations of the examinees regarding their status over time, given the memory and concentration problems of the elderly patients with PD. We did not take into consideration the time of the interview regarding “off ” and “on,” or the impact of the euphoric effect after MC. Formal neurocognitive assessment of the interviewed patients was not performed. There could also be possible errors in the interviewer-patient patients, communications because of the difficulty to verify full comprehension of the questions during a telephone conversation. All subjects were chronically ill patients with PD with a range of related conditions, and the need for additional symptom relief may explain the reported positive MC effect.

In conclusion, the results of our study demonstrate that most of the users had found MC to improve their condition, and that
MC treatment was safe, without major adverse effects. This pilot, 2-center survey reflects in part the current state of MC treatment for PD in Israel. The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from the now intensively bred and widely cultivated Cannabis sativa.

ACKNOWLEDGMENTS

The authors acknowledge the contributions of the patients who answered to this questionnaire and thankful to Esther Eshkol
for superb editorial assistance and to all the staff of Movement Disorders Unit at the Tel Aviv Medical Center for the fruitful cooperation in this project.

REFERENCES

1. Lotan I, Treves TA, Roditi Y, et al. Cannabis (medical marijuana) treatment
   for motor and non-motor symptoms of Parkinson disease: An open-label
   observational study. Clin Neuropharmacol 2014;37:41–44.
2. Frankel JP, Hughes A, Lees AJ, et al. Marijuana for parkinsonian tremor.
   J Neurol Neurosurg Psychiatry 1990;53:436.
3. Carroll CB, Bain PG, Teare L, et al. Cannabis for dyskinesia in Parkinson
   disease: a randomized double-blind crossover study. Neurology 2004;63:
   1245–1250.
4. Consroe P, Musty R, Rein J, et al. The perceived effects of smoked cannabis
   on patients with multiple sclerosis. Eur Neurol 1997;38:44–48.
5. Venderová K, Růzicka E, Vorísek V, et al. Survey on cannabis use in
   Parkinson's disease: subjective improvement of motor symptoms.
   Mov Disord 2004;19:1102–1106.
6. Guy W. ECDEU Assessment Manual for Psychopharmacology.
   Rockville, MD: US Department of Health, Education, and Welfare
   Public Health Service Alcohol, Drug Abuse, and Mental Health
   Administration; 1976.
7. Armitage P, Berry G, Matthews JNS. Statistical methods in medical
   research. 4th ed. Oxford: Blackwell Science; 2002.
8. Morris SB. Estimating effect sizes from pretest-posttest-control group
   designs. Organizational Research Methods 2008;11:364–386.
9. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed.
   Hillsdale, NJ: Lawrence Erlbaum; 1988.
10. Grotenhermen F. Pharmacokinetics and pharmacodynamics of
    cannabinoids. Clin Pharmacokinet 2003;42:327–360.
11. Pearce DD, Mitsouras K, Irizarry KJ. Discriminating the effects of
    Cannabis sativa and Cannabis indica: A web survey of medical cannabis
    users. J Altern Complement Med 2014;20:787–791.
12. Gage SH, Munafò MR, MacLeod J, et al. Cannabis and psychosis. Lancet
    Psychiatry 2015;2:380.
13. Bloomfield MA, Morgan CJ, Kapur S, et al. The link between dopamine
    function and apathy in cannabis users: An [18F]-DOPA PET imaging study.
    Psychopharmacology (Berl) 2014;231:2251–2259.
14. Volkow ND, Baler RD, Compton WM, et al. Adverse health effects of
    marijuana use. N Engl J Med 2014;370:2219–2227.

15. Davis JP, Smith DC, Morphew JW, et al. Cannabis withdrawal,
    posttreatment abstinence, and days to first cannabis use among emerging
    adults in substance use treatment: A prospective study. J Drug Issues 2016;
    46:64–83.
16. McRae-Clark AL, Baker NL, Gray KM, et al. Buspirone treatment of
    cannabis dependence: A randomized, placebo-controlled trial. Drug
    Alcohol Depend 2015;156:29–37.
17. Burgdorf JR, Kilmer B, Pacula RL. Heterogeneity in the composition of
    marijuana seized in California. Drug Alcohol Depend 2011;117:59–61.
18. Giuffrida A, McMahon LR. In vivo pharmacology of endocannabinoids
    and their metabolic inhibitors: therapeutic implications in Parkinson's
    disease and abuse liability. Prostaglandins Other Lipid Mediat 2010;91:
    90–103.
19. Sanudo-Pena MC, Tsou KJ, Walker JM. Motor actions of cannabinoids in
    the basal ganglia output nuclei. Life Sci 1999;65:703–713.
20. Di Marzo V, Hill MP, Bisogno T, et al. Enhanced levels of endogenous
    cannabinoids in the globus pallidus are associated with a reduction in
    movement in an animal model of Parkinson's disease. FASEB J 2000;14:
    1432–1438.
21. Hermann H, Marsicano G, Lutz B. Coexpression of the cannabinoid
    receptor type 1 with dopamine and serotonin receptors in distinct neuronal
    subpopulations of the adult mouse forebrain. Neuroscience 2002;109:
    451–460.
22. Lynn AB, Herkenham M. Localization of cannabinoid receptors and
    nonsaturable high-density cannabinoid binding sites in peripheral tissues of
    the rat: implications for receptor-mediated immune modulation by
    cannabinoids. J Pharmacol Exp Ther 1994;268:1612–1623.
23. Naftali T. Medical cannabis. Harefuah 2016;155:79–82.

This originally appeared at https://pubmed.ncbi.nlm.nih.gov/29059132/