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Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study This is an open access article distributed under the Creative Commons Attribution License, which permits Dr. Genevieve Newton describes the state of the research on cannabis in the treatment of tic disorders and what her young son's experience with cannabis has been like.

Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Associated Data

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abstract

Objectives

Assessing the effectiveness and tolerability of medical cannabis (MC) treatment on Gilles de la Tourette syndrome (GTS) patients.

Methods

We report on an open-label, prospective study on the effect of MC on adult GTS patients. MC mode of use was decided by the treating neurologist and the patient. Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) content within MC product and monthly dose were titrated during the study. Following treatment initiation, patients were assessed after 4 and 12 weeks for efficacy, tolerability, and side effects.

Results

Eighteen patients entered the study. Baseline Yale Global Tic Severity Scale- (YGTSS) Total (range 0-100) was 60.3 ± 17.1. Three patients did not reach the end of follow-up period. The most common mode of administration was smoking (80%). Following twelve weeks of treatment, a significant 38% average reduction (p = 0.002) of YGTSS-Total and a 20% reduction (p = 0.043) of Premonitory Urge for Tic Scale (PUTS) were observed. Common side effects were dry mouth (66.7%), fatigue (53.3%), and dizziness (46.7%). Three patients suffered from psychiatric side effects including worsening of obsessive compulsive disorder (stopped treatment), panic attack, and anxiety (resolved with treatment modification). Six patients (40%) reported cognitive side effects regarding time perception, visuospatial disorientation, confusion, slow processing speed, and attention.

Conclusions

MC treatment demonstrates good efficacy and tolerability in adult GTS patients. Predilection for smoking rather than using oil drops requires further comparative studies to evaluate the efficacy of each. Cognitive and psychiatric side effects have to be monitored and addressed.

1. Introduction

Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and one or more phonic tics that continue for at least one year [1]. GTS is a relatively common condition with a prevalence of 0.3-0.8% in school-age children [2, 3]. Tics have a pattern of waxing and waning course with a wide range of frequencies and intensities. Environmental factors such as stress, anxiety, and fatigue may transiently exacerbate tics [4]. GTS is strongly associated with many psychiatric comorbidities, including attention deficit/hyperactivity disorder (ADHD), obsessive compulsive behavior/disorder (OCB/OCD), depression, anxiety, sleep disorders, and rage attacks [1]. Current research suggests alterations to the cortico-striato-thalamo-cortical pathways, specifically the dysfunction of the dopaminergic pathway, in the pathophysiology of GTS [5, 6]. Dopaminergic activity is found to be increased in GTS. Animal trials have demonstrated that specific disinhibition of the striatum, thus altering the release of dopamine, generated motor and vocal tics demonstrative of those in GTS [7]. Due to the significant role of dopamine in the development of tics, the current Food and Drug Administration (FDA) approved pharmacotherapy for GTS has been centered around dopaminergic receptors in the synaptic cleft [8]. Therapy for GTS is tailored to the frequency and severity of symptoms. The most recent therapy guidelines have been published by the American Academy of Neurology (AAN) in 2019 [9] and the European Society for the Study of Tourette Syndrome (ESSTS) in 2021 [10–12]. Behavioral therapy, such as comprehensive behavioral intervention for tics (CBIT), is safe and effective and should be considered as an initial treatment choice. Medications for tics include antipsychotics, D2 antagonists, which are the most widely used drugs for the treatment of tics caused by GTS; however, these medications might cause severe side effects (SEs), such as parkinsonism, metabolic syndrome, and hyperprolactinemia, especially with chronic use, that create issues with compliance and are not sufficiently effective. Alpha-2-adrenergic agonists, vesicular monoamine transporter 2 inhibitors, benzodiazepines, antiepileptics, and botulinum toxin are also acceptable treatment approaches with varied treatment efficacy, and for refractory, “malignant” syndrome, deep brain stimulation may be advised [13, 14]. The endocannabinoid neuronal system regulates the activity of the striatal dopaminergic pathway through activation of cannabinoid receptor type 1 (CB1) located in the central nervous system, mainly in the basal ganglia [15]. Activation of CB1 receptors modulates body movement and transmission of glutamate, gamma-aminobutyric acid (GABA), norepinephrine, serotonin, and acetylcholine neurotransmitters in the brain [15, 16]. Cannabis was suggested as a possible treatment for GTS since the late 1980s in an anecdotal report by Sandyk and Awerbuch [17]. Two consecutive randomized controlled trials (RCTs), published during 2002-2003 by Mueller-Vahl et al., using tetrahydrocannabinol (THC, dronabinol), have demonstrated safety and efficacy in the treatment of tics in patients with GTS [18, 19]. After showing promising results in phase 1 [20], a recent multicenter phase 2 RCT [21] with Lu AG06466 (formerly known as ABX-1431), a modulator of endocannabinoid neurotransmission, has failed to prove effective in the suppression of tics compared to placebo. A phase 2, uncontrolled trial of THX-110, a therapeutic combination of delta 9-tetrahydracannabinol and palmitoylethanolamide, has shown improvement of tic symptoms of more than 20%, with manageable side effects [22]. An ongoing RCT called CANNA-TICS is assessing whether treatment with cannabis extract nabiximols (Sativex®) is superior to placebo in patients with chronic tic disorders [23]. In addition to these RCTs, retrospective data analysis and case series [24–27] along with multiple case reports [28–37] have been published and summarized in a recent review of the literature by Szejko et al. [38], suggesting that cannabis-based medicine (CBM) could be effective and relatively safe in suppressing tics and in the treatment of associated psychiatric comorbidities in patients with GTS. In the recent AAN guideline recommendation summary [9], cannabis-based therapies were suggested to have limited evidence to reduce tic severity, although, where regional legislation allows, physicians may consider treatment with CBM in otherwise treatment-resistant adults with clinically relevant tics (level C). Recent ESSTS guidelines state that in resistant cases, treatment with agents with limited evidence base could be considered, such as CBM [12]. This is also illustrated in the ESSTS algorithm for the treatment of tics suggesting considering alternative medication, such as CBM, in patients who do not respond appropriately to behavioral therapy and to various pharmacotherapies [11]. In Israel, although consumption of cannabis is outlawed, there is an option to allow patients to consume the drug under supervision, and at least 50,000 patients use medical cannabis (MC) regularly, particularly for pain and posttraumatic stress disorder. MC has been an approved treatment by the Ministry of Health (MOH) for resistant GTS since 2013. MC can be taken as an oil extract, through inhalation, or by smoking of dried female buds. The THC to cannabidiol (CBD) percentage within a specific cannabis product is fixed in one of the following ratios: 1 : 20, 3 : 15, 5 : 5, 5 : 10, 10 : 10, 10 : 2, 15 : 3, and 20 : 4. Varying ratios of THC : CBD percentage exert different influences. The licensed treating physician decides which ratio to recommend; however, there is insufficient data to guide which ratio to prescribe for the different severity of symptoms. In a group of 42 patients treated with MC at our GTS clinic (not part of this study cohort), we observed in a retrospective manner a significant reduction in the number and intensity of tics, as well as a decrease in premonitory urges in 83% of the patients [24]. The treatment resulted in subjective improvements in both symptom severity and quality of life, with no serious adverse events. Our preliminary results combined with publications from other centers justify the need for additional controlled studies to further evaluate and characterize the effects of MC on GTS symptoms. By using an open-label, prospective design, this study is aimed at determining the preferred method of use, efficacy, and tolerability of 12 weeks of treatment with MC in adult patients with GTS.

2. Materials and Methods

2.1. Study Design

Eighteen patients with GTS who satisfied the selection criteria, as outlined below, were chosen to participate in our open-label clinical trial based at Tel-Aviv Sourasky Movement Disorders Unit (MDU). Each subject signed a written informed consent before inclusion in the trial. In addition, since driving under the influence of cannabis is forbidden by the Israeli law, patients were instructed and gave their oral commitment to avoid driving. The study was approved by the research ethics (Helsinki) committee at our center. MC was consumed as oil extract, vaporized, or smoked dried buds. The treating neurologist (S.A.) and the patient together decided on the method of consumption during the visit before initiating treatment. The percentage of THC and CBD was preset to 10% and 2%, respectively. All patients received the same general instructions for treatment titration, which was to start with 1 drop or puff a day and increase by 1 drop or puff as needed. There was no fixed schedule for the incremental increases; thus, each patient freely raised the dose as well as the number of daily consumptions until clinical benefit was achieved or SE emerged over a follow-up period of 12 weeks. Patients were assessed 4 and 12-weeks following treatment initiation to gather data regarding treatment efficacy, tolerability, and SEs.

2.2. Selection Criteria

Selection criteria are as follows: (1) age 18-65 years, (2) diagnosis of GTS confirmed by the treating neurologist (S.A.) based on the DSM-V criteria [39], (3) eligibility to receive MOH MC license for GTS, (4) provided written informed consent, (5) did not regularly use cannabis in any form of self-medication prior to entering the study, (6) were not pregnant or lactating women, (7) did not have a tic disorder other than GTS, and (8) did not have concurrent physical or mental disease that could interfere with the study.

2.3. Assessment Procedure

Assessment of symptoms was based on clinical or telephone interviews conducted by one of the authors (S.A. or C.Z.). The primary efficacy outcome was based on the Yale Global Tic Severity Scale (YGTSS) [40]. The YGTSS is a clinician completed rating instrument and is currently the gold standard for assessing the severity of tics in children and adults. The YGTSS Tic Score (YGTSS-TS) scale quantifies the number, frequency, intensity, complexity, and interference of motor and phonic tics that occurred during the prior week. Each section is given a score from 0 to 5, for a potential total of 50. The YGTSS Impairment (YGTSS-I) scale is used to describe the impact of tics on quality of life; it is given a score from 0 to 50. Global severity score (YGTSS-Total) was calculated as the sum of the YGTSS-TS and YGTSS-I, range 0–100. Premonitory Urge for Tic Scale (PUTS) is a self-reported 9-item measurement used in the study to assess the intensity and frequency of premonitory sensory phenomena (scale of 1-4, total score 9-36) [41]. Two Likert-type scales (range 1-7, 1 = very dissatisfied, 2 = moderately dissatisfied, 3 = slightly dissatisfied, 4 = neutral, 5 = slightly satisfied, 6 = moderately satisfied, 7 = very satisfied), one for “subjective report of treatment effect on tics” and the other for “subjective report of treatment effect on general quality of life (QoL),” were used as tools to measure the subjective effectiveness of MC. Patients were additionally asked to rate the impact of MC on symptoms commonly associated with GTS, such as restlessness, tempered behavior, OCB/OCD, attention, mood, sleep, and sexual function. Lastly, participants were asked about SEs of MC treatment including psychiatric, neurological, and other somatic symptoms. During the baseline visit, data were collected on demographics, disease characteristics, previous and current pharmacological and nonpharmacological treatments, baseline YGTSS, and PUTS scales. Each patient was instructed on MC titration to implement for the following 12 weeks. Visits two and three, at 4 weeks and 12 weeks, respectively, were conducted by S.A. and C.Z. either in the clinic or by telephone. During those visits, participants were assessed using YGTSS, PUTS, and two Likert-type scales, and information about method of MC use, frequency of use, dose in grams, percentage of THC and CBD, and SE profile was collected.

2.4. Primary Outcomes

The primary outcomes were (1) a significant reduction in YGTSS-TS, YGTSS-I, and YGTSS-Total, (2) a significant decrease in PUTS, (3) subjective improvement of tics and QoL using a Likert-type scale, and (4) subjective percentage of improvement of tics compared to baseline. Additional aims of this study were to examine the patient’s consumption habits including way of administration (smoked, inhaled, or sublingual oil extraction), dose in grams/month of MC, the percentage of THC and CBD in the formulation consumed, the frequency of use each day, and the quantity of puffs/drops per use.

2.5. Statistical Methods

The statistical analyses included all 18 patients who signed informed consent and completed the first baseline visit of this study. Descriptive statistics were used for demographic variables including mean, median, standard deviation (SD), and range. Friedman’s two-way analysis, a nonparametric test, was used to compare the primary outcome measures between visit 1, visit 2, and visit 3 (YGTSS-TS/I/Total and PUTS change). The nonparametric Wilcoxon test was used to compare the change of MC dose, frequency, and quantity of use, as well as MC efficacy and QoL between visits 2 and 3. Significance level of nonparametric testing was 0.05. All statistics were done with SPSS version 27.

3. Results

3.1. Subjects

A total of 18 patients with a diagnosis of GTS who fulfilled the inclusion criteria were recruited at our GTS clinic between July 01, 2020, and January 01, 2021. Table 1 gives the demographic characteristics of our patient cohort. The majority of participants were male (61%), and the median age was 30.5 and disease duration 23.5 years. Comorbidities in our cohort included a diagnosis of ADHD for 14 patients (77.8%), obsessive compulsive symptoms/disorder (OCS/OCD) for 12 patients (66.7%), history of depressive episodes for 7 patients (38.9%), and anxiety for 10 patients (55.6%). Twelve patients (66.4%) had tried pharmacological therapy for GTS (including alpha-2 agonists, dopamine blockers, benzodiazepines, and antiepileptic drugs) in the past, while only one person (5.5%) entered the study while currently being medicated for GTS (aripiprazole).

Table 1

Demographic characteristics of study participants.

Characteristics Cohort group (N = 18)
Sex
Male 11
Female 7
Age (years)
Median 30.5
Range 20-50
Disease duration (years)
Median 23.5
Range 8-44
Level of education (years)
Median 12.5
Range 8-17
Employment
Unemployed 6
Marital status
Married 9
Single 9
Family history of tics 7
Diagnosis of ADHD 14
OCS 12
History of depressive episode/s 7
Anxiety 10

Abbreviations: OCS: obsessive compulsive symptoms; ADHD: attention deficit hyperactive disorder.

3.2. Premature Termination

Three of the 18 patients (16.7%) terminated the trial prematurely. The reasons for an early discontinuation were a severe depressive episode following recruitment before cannabis use in one patient, presumed lack of efficacy and dislike for the smell of cannabis (withdrew after the first visit), and worsening of obsessive thinking and compulsions in one patient (withdrew just before the second visit).

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3.3. Primary Outcomes

Our analysis showed a significant (p = 0.003) reduction in YGTSS-TS following 4 weeks of MC treatment. On average, an over 8-point reduction (25.3 at baseline to 17.0) in the YGTSS-TS was achieved, equitable to a 32.8% reduction in the motor and vocal tic score. Further decrease of YGTSS-TS to an average of 16.4 points was demonstrated following 12 weeks of MC use, signifying an average of 9-point reduction compared to baseline (p = 0.002), equitable to greater than 35% decrease in YGTSS-TS compared to baseline ( Figure 1(a) ). A nonsignificant (p = 0.248) average reduction of 10 points, from 35.0 to 25.0, was observed in YGTSS-I following 4 weeks of MC treatment. 12 weeks after treatment initiation, there was a further reduction in impairment due to tics, to a nadir of 40% according to YGTSS-I, statistically significant compared to baseline (p = 0.013, Figure 1(b) ). YGTSS-Total revealed a significant (p = 0.001) reduction of roughly 38% in the burden of disease after 12 weeks of MC use ( Figure 1(c) ). A more modest but significant (p = 0.043) reduction was observed in PUTS from 22.9 points on average before cannabis treatment to 18.3 points on average after 12 weeks of use ( Figure 1(d) ). Using a Likert-type scale, we intended to subjectively estimate each patient’s experience with cannabis on the influence on tics and QoL. After just 4 weeks of MC use, there was an overwhelmingly positive response demonstrated by a score of 5.1 points out of 7. Following 12 weeks, there was an even stronger indication of satisfaction, with reported scores of 5.5 and 5.7 (out of 7) for cannabis effect on tics and QoL, respectively ( Figure 2 ). The mean subjective tic improvement following 12 weeks of MC was 53.9%. These primary results are outlined in Table 2 .

Primary outcome measures at baseline and following 4 and 12 weeks of MC use. (a) YGTSS-TS (score 0-50). (b) YGTSS-I (score 0-50). (c) YGTSS-Total (score 0-100). (d) PUTS (score 4-36). ∗ Compared to baseline. † N = 12, 3 subjects failed to complete midtrial evaluation, 3 subjects terminated the trial prematurely. ‡ N = 15. Abbreviations: MC: medical cannabis; YGTSS-TS: Yale Global Tic Severity Scale Tic Score; TGYSS-I: Yale Global Tic Severity Scale Impairment; PUTS: Premonitory Urge for Tic Scale.

Subjective effectiveness of MC on tics and QoL using a 7-point Likert-type scale. Abbreviations: MC: medical cannabis; QoL: quality of life.

Table 2

Primary outcome efficacy measures (baseline and week 4 and 12 weeks after treatment initiation) for MC treatment.

Rating scale Baseline 4 weeks † 12 weeks ‡
Mean SD Mean SD Baseline to 4-week change p value (Friedman two-way analysis) Mean SD Baseline to 12-week change p value (Friedman two-way analysis)
YGTSS-TS 25.3 10.5 17.0 10.7 0.003 ∗ 16.4 10.1 0.002 ∗
YGTSS-I 35.0 11.0 25.0 7.9 0.248 21.0 10.0 0.013 ∗
YGTSS-Total 60.3 17.1 42.0 13.3 0.032 ∗ 37.4 14.6 0.001 ∗
PUTS 22.9 5.5 19.4 6.7 0.043 ∗ 18.3 7.4 0.043 ∗
Subjective percentage of tic improvement following treatment 50.0 23.8 53.9 28.8

N = 12, 3 subjects failed to complete midtrial evaluation, 3 subjects terminated the trial prematurely. ‡ N = 15; ∗ statistically significant. Abbreviations: MC: medical cannabis; YGTSS-TS: Yale Global Tic Severity Scale Tic Score; TGYSS-I: Yale Global Tic Severity Scale Impairment; PUTS: Premonitory Urge for Tic Scale; SD: standard deviation.

3.4. Cannabis Consumption Characteristics

One of our goals in this open-label study was to examine our patient’s consumption habits including way of administration (smoked, inhaled, or sublingual oil extraction), dose in grams/month of MC, the percentage of THC and CBD in the formulation consumed, the frequency of use each day, and the quantity of puffs/drops per use. Our results showed that the majority of patients (93%) who completed 12 weeks of cannabis use chose to consume MC through their lungs (smoking or inhalation). One patient (7%) used both sublingual oil and smoked cannabis. Another patient (7%) solely used the oil extract via sublingual administration. After 4 weeks, the average dose consumed was 16.8 grams/month. After 12 weeks, the average dose increased to 18 grams/month. All patients started on the same THC : CBD ratio (10 : 2). At the end of the study, the average ratio was 12.3 : 3.6, suggesting a higher percentage of THC was needed for our patients to achieve clinical significance. There was also a small increase in the frequency of MC per day, from 2.7 times per day after 4 weeks to 2.9 times per day on average after 12 weeks. Moreover, in proportion to more frequent, patients consumed more puffs/drops of MC with each use; at 4 weeks 7.7 puffs/drops were used on average, which rose to 10.1 puffs/drops with each use after 12 weeks. Dose, ratio, frequency, and quantity of MC used can be seen in Table 3 .

Table 3

MC consumption characteristics during trial.

Baseline 4 weeks † 12 weeks ‡
Mean SD Mean SD Mean SD
MC average monthly dose (grams) 16.8 5.4 18.0 5.6
THC/CBD % 10/2 12.3/3.6 5.3/3.5
MC use times per day 2.7 0.8 2.9 1.4
Quantity in each use (puffs/drops) 7.8 5.4 10.1 4.7

N = 12, 3 subjects failed to complete midtrial evaluation, 3 subjects terminated the trial prematurely. ‡ N = 15. Abbreviations: MC: medical cannabis; THC: tetrahydrocannabinol; CBD: cannabidiol; SD: standard deviation.

3.5. Cannabis Influence on Comorbid Conditions and Life Habits

We asked patients to report any benefit from MC use on comorbid conditions associated with GTS and life habits, such as sleep and sexual function. Interestingly, 40% of patients reported at least 50% improvement in mood compared to baseline. There was a significant improvement in sleep, with 9 patients reporting improved sleep preservation and 10 reporting improved sleep onset. Sexual function was improved in 47% of our patients, with reports of improved libido and two reports of improved erection. See summarized data on MC influence on comorbid conditions and life habits in Figure 3 .

Treatment-related side effects and influence on comorbidities and life habits. Abbreviations: OCS: obsessive compulsive symptoms; OCD: obsessive compulsive disorder; ADHD: attention deficit hyperactive disorder.

3.6. Adverse Events

The adverse events reported during the trial are shown in Figure 3 . The most common adverse event was dry mouth (67%), followed by fatigue (53%), and sedation and dizziness (47%). A substantial number (40%) reported cognitive SEs including altered time perception (n = 1), visuospatial orientation (n = 1), attention (n = 1), confusion (n = 2), and speed of processing (n = 1). Three patients suffered from anxiety secondary to cannabis use, and one additionally suffered from a panic attack soon after initiation of treatment. The panic attack was due to titration practices that differed from what was instructed with the use of a high dose (more than 10 puffs) soon after initiation. With a substantial reduction of THC content (from 10% to 3%) of his MC, he had no panic attacks, but he felt little improvement of tics. Of note, after study termination he continued follow-up, and through slow titration and gradual increase in THC percentage to 10%, he was able to achieve a better response with no SEs. One patient had to stop the study due to worsening of his OCD, as mentioned above.

4. Discussion

The results of this pilot open-label prospective study are in line with our clinical impression that MC may be an effective treatment for patients with GTS. The main outcome measures YGTSS-TS, YGTSS-I, and YGTSS-Total showed a significant improvement of 35, 40, and 38 percent, respectively, after 12 weeks of use. PUTS showed significant improvement as well with a modest decrease of 20% after 12 weeks of MC. Using Likert-type scales [1–7], patients self-reported significant satisfaction with cannabis with tics and QoL with scores of 5.5 and 5.7, respectively. To illustrate the results clinically, according to YGTSS scale, a typical patient with moderate-marked severity of tics and impairment successfully improved to mild-moderate severity through a course of treatment with MC. Several previous reports of GTS improvement with the use of MC have been published. Two small placebo-controlled studies with 36 participants [18, 19] suggested that THC capsules may significantly improve tic severity in patients with GTS compared with placebo. Analysis of placebo effect in those studies showed no average reduction in clinical global improvement (CGI), YGTSS, and premonitory urge in the 6-week randomized trial [18], and in the single-dose crossover trial, 25% of the placebo group showed mild improvement (average of 7% global improvement) compared to 83% of patients treated with THC capsules (average of 35% global improvement) [19], manifesting a very mild placebo effect. A more recent publication from the same group [25] found that cannabis-based treatment (for medical cannabis, THC : CBD ratio was not published) resulted in a subjective improvement of tics of about 60% in 85% of treated cases. In this study, our patients collaborated with the treating neurologist to select the method of administration of MC that best fits personal preferences. Interestingly, patients had a predilection for cigarette smoking/inhaled buds via a designated vaporizer (93%) over the extracted oil. This could be explained by the pharmacokinetics of THC. THC when inhaled reaches the peak plasma concentration in 8-12 minutes, while sublingual oil takes longer to absorb with the first measurable plasma levels at 30 minutes and peak concentration at 3-4 hours [42, 43]. Additionally, smoking THC achieves a higher plasma concentration (C(max), (microgram/L) 6 ) compared to sublingual oil [43, 44]. Collectively, this may show a benefit in prescribing inhaled cannabis, specifically, to reduce the symptoms of GTS. It is important to evaluate the increase in THC percentage and MC total monthly dose during the trial. During the study, patients were able to request for a change in THC percentage if they did not feel the maximum effects of cannabis with their current prescription. After 4 weeks, patients on average used 16.8 g/month of 10 : 2 THC : CBD, which corresponded to 8.9 mg THC/day. After 12 weeks, patients showed a preference for a higher THC percentage (12.33%) compared to baseline (the baseline default was 10%, which is the recommended starting point in the Israeli guidelines for using MC for GTS) and an increase in dose to 18 grams/month, which corresponded to 12 mg THC/day. In a cohort of 25 GTS patients with chronic MC use (average time of use 4.8 ± 3.0 years) in our MDU, the average THC percentage is 15.5 ± 4.6 and monthly cannabis use is 33.7 g/month (~1.1 g/day), corresponding to 27 mg THC/day. Both sets of data support the findings of other studies that showed “THC-rich” MC strains to be more effective and better tolerated compared to nabiximols (containing 2.7 mg THC and 2.5 mg CBD per puff) and dronabinol (oral synthetic form of THC) [25, 37]. This suggests that a higher THC percentage and total daily dose may work better in GTS. We hypothesize that if further followed, our patients would increase their daily and monthly cannabis dose and achieve further improvement in their symptoms. The influence of MC on comorbid conditions was less impressive in our cohort. Symptoms of ADHD were reported to improve in only one patient and OCS/OCD in two patients. That contrasts with a recent report suggesting a 53% improvement for ADHD and 38% for OCS/OCD [25]. However, as previously mentioned, several other comorbid conditions did substantially improve. Forty percent of our patients reported improved mood, and 72% reported improvement in sleep. In the available literature, there are contradicting results about the influence of cannabis on sexual function, with some articles indicating improvement [45, 46] and others highlighting hazardous effects like erectile dysfunction in men [47–49]. In our study, 39% of patients reported that cannabis contributed to improvement in sexual function (desire/libido, erection), which may be in part due to mood improvement. The most common SEs reported by our patients were neurological. About 50% reported dizziness and sedation, and 40% reported cognitive SEs such as altered time perception, visuospatial orientation, confusion, and speed of processing; all have been previously described before [50, 51]. Our results show higher rates of neurological SEs compared to those reported by Milosev et.al [25]. In contrast to our high rate of reported cognitive SEs, the study done by Muller-Vahl et al. found that treatment up to 10 mg delta(9)-THC over a 6-week period has neither acute nor long-term cognitive deficits [18]. This discrepancy in SEs with MC use may be due to the subjective components of our data collection and patient autonomy in the titration process. It is important to note that while 2 patients (11%) reported improvement in anxiety following treatment, 3 patients (17%) suffered from anxiety following the initiation of cannabis, one patient terminated his participation in the study, and one patient suffered from panic attacks which resolved after a substantial decrease in THC percentage. The role of CBM in the treatment of anxiety is an ongoing debate with an increasing amount of literature investigating its impact [52]. A large meta-analysis of more than 100,000 people from the general population suggests a positive association between anxiety disorders and cannabis use [53], while another large review proposes that cannabis may be effective in alleviating anxiety, although current evidence is equivocal [52]. In a recent review published in JAMA Psychiatry, there was found to be an increase in the risk of developing depression with adolescent use of cannabis, but no associations were mentioned about anxiety [54]. Our study has several limitations: (1) this is an open uncontrolled study based on clinical and telephone interviews; however, since all patients were investigated by an author experienced in GTS (S.A. and C.Z.), we believe the data to be reliable; (2) the sample size is still relatively small, yet all primary outcome measures reached statistical significance; (3) diagnoses of comorbidities were made only based on a semistructured clinical interview; (4) an effective dose of cannabis is difficult to quantify because of the different contents of cannabinoids and inhalation patterns; the bioavailability of THC following inhalation ranges between 2 and 56%, varying based on the subject’s length of inhalation, lung capacity, and temperature of cannabis heating [55]; (5) the follow-up period of this study was relatively short. When comparing to our chronic MC users, we suggest that higher doses of MC per day and stronger strands (with more THC percentage) could provide added benefit.

5. Conclusions

Our results are in line with a number of other studies suggesting that MC is effective and well tolerated in adults with GTS. From our data, it is suggested that MC might be a treatment option for resistant TS patients, and MC has a significant effect on tics, premonitory urges, and patients’ overall quality of life. In our sample, patients favored THC-rich cannabis strands and smoking/inhaling MC over sublingual oil. One has to be aware of the neurological and cognitive SEs of MC and monitor them during treatment. The limitations of our study due to the open, uncontrolled design emphasize the necessity for controlled studies to further evaluate the role of MC in this disorder.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Tic Disorder Management with Cannabis: A Family’s Tale Meets the Science

Shortly after the COVID pandemic hit in Winter 2020, life took a worrisome turn when my youngest son developed a severe motor tic disorder. My healthy son was 10 at the time. He suddenly became plagued with involuntary movements during all his waking hours. The lockdown and home schooling were almost a blessing. It meant that he wasn’t faced with the loss of his usual activities, like playing hockey and spending time with friends. Given the severity of his symptoms, these activities would have been impossible for him to do. Of course, it also raised the possibility that his condition had been triggered by the stress of the pandemic, which hit young people especially hard.

My son received an extensive medical diagnostic work up. He had a comprehensive blood analysis that included tests for strep antibodies (to rule out Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and autoimmune encephalitis. All blood work was normal. He had a normal EEG. He had two MRI’s which showed a large cerebellar subarachnoid cyst and a cervical spine syrinx. But these were deemed as incidental findings that were unrelated to the tics. After an almost a week long stay in a pediatric hospital, we were given a diagnosis of a severe provisional tic disorder. It was deemed to be neuropsychological in origin.

The treatments we were offered were twofold. First we were recommended psychotherapy with a therapist specializing in family health. But my son was unable to sit still to participate in Zoom appointments, so he couldn’t participate in this process. His dad and I worked with the therapist to learn strategies to help with the emotional aspects of this difficult experience, including Emotion Focused Family Therapy. This helped us all to cope better, but it did nothing to reduce the tic severity. I also worked with another therapist who specializes in Cognitive Behavioral Therapy for Tics. She helped me to better understand the disorder and provided support through this difficult period. But because my son was not able to work with her in person, the benefit was limited.

Secondly we were offered drug therapies. These are typically reserved for children experiencing severe tics due to their significant side effect profiles. We began using Clonidine, a first line treatment for moderate to severe tics. 1 It was almost entirely ineffective. Next, we tried Risperidone as a second line treatment. 2 At first the Risperidone was combined with Clonidine. Then Clonidine was discontinued leaving Risperidone as a monotherapy. The severity of the tics did reduce a bit with the Risperidone. But the side effects were awful.

Within ten weeks of starting the medication, my son gained 23 pounds. For a very thin child who weighed 72 pounds at the outset of this ordeal, this was significant. It was also traumatic for him. After doing an extensive review of the scientific literature, I asked his doctor to change our drug regimen from Risperidone to Aripiprazole because there is evidence that it is better tolerated and has comparable efficacy. 3 Unfortunately, it also causes weight gain. Within nine months of starting pharmacotherapy, our son had gained 40lbs. And the medications were also only minimally effective at reducing tic severity.

As our journey continued, so did my search for alternatives. I quickly discovered that cannabis has been used in the treatment of tic disorders for many years. After finding a physician who specializes in the use of cannabis for pediatric neurological disorders, we were given a prescription for a cannabinoid medicine. We started using cannabis concurrently with Aripiprazole about five months after the onset of symptoms. After doing this for two months, we began using cannabis-based medicine exclusively.

I will describe the state of the research on cannabis in the treatment of tic disorders, as well as what we have personally experienced using a variety of different cannabis products.

Tic Disorders, Cannabis, and the Pandemic

Tics are involuntary, repetitive twitches, movements and sounds. There are both motor and vocal tics. There are three tic disorders listed in the DSM-V, including Tourette’s Syndrome, Persistent/Chronic Vocal or Motor Tic Disorder, and Provisional Tic Disorder. Tourette’s syndrome (TS) includes both motor and vocal tics. Those with provisional and persistent type disorders have one or the other. The only difference between persistent and provisional disorders is the length of the condition. In persistent disorders, tics have been present for more than a year. In provisional disorders, tics have been present for less than a year. 4 While my son was initially diagnosed with a provisional disorder, it is now considered a persistent disorder due to its duration.

During the COVID pandemic, there has been an increase in tic-like behavior among young people, especially girls. This condition has been termed Functional Neurological Disorder and is thought to be related to psychological distress. The tic patterns are different from the three previously mentioned disorders listed in the DSM-V. The tics in Functional Neurologic Disorder are also unique in that they aren’t preceded by an urge. 5 Although my son’s condition presented during the COVID pandemic, it did not fit the pattern of this disorder.

What the Literature Says

There are many scientific publications related to the use of cannabinoids in the treatment of tic disorders. A PubMed search using the terms “Tourette’s and Cannabis” yields 80 results, many of which are relevant. A search for “Tic Disorder and Cannabis” yields fewer results. This shows that the bulk of the literature has focused on the TS diagnosis. I will touch on some of the most notable publications related to observational research, clinical trials, and treatment recommendations.

Several observational studies have investigated the association between the use of cannabis and the symptoms of tic disorders. In 2019, researchers in Europe conducted a survey of patients with a history of using cannabis-based medicine to treat TS. They found that many preferred cannabis to pharmaceutical drugs. The majority reported a subjective improvement of tics and associated co-morbidities. The most striking finding was an improvement in quality of life in 93% of subjects. Patients also reported that they preferred cannabis to either nabiximols (a preparation with a specified quantity of specific cannabinoids and other phytoconstituents) or dronabinol (isolated THC). 6 Also in 2019, an Israeli group reported that 38 of 42 TS patients taking medical cannabis reported reduced tic severity, better sleep, and improved mood with treatment. 7 Similarly, a study published in 2017 found that 18 of 19 TS patients using medical cannabis reported that they were “much improved” with the use of cannabis. However, many reported side effects including feeling impaired and experiencing decreased concentration. 8 Unfortunately these studies don’t provide reliable information on the effective doses or the chemical profiles of the cannabis being used.

Several clinical trials have studied cannabis-based medicine in the treatment of tic disorders using controlled conditions. Some of the first studies were published in the early 2000’s by a research group from Germany. Initially, researchers investigated whether treatment with THC impaired cognitive performance in adults with TS. 9 After finding that cannabis didn’t impair cognitive function, a single dose, randomized placebo-controlled trial was conducted in 2002. It examined doses of THC at 5mg, 7.5mg, or 10mg. It was found that tic severity was reduced when the 7.5 and 10mg groups were pooled and analyzed as a single group, as was associated obsessive-compulsive disorder. The changes were correlated to plasma levels of THC, 11-OH-THC, and THC-COOH. 10 The next year, a six-week randomized controlled trial found a slight reduction in tics with THC at levels up to 10mg per day. 11

A more recent 2019 systematic review and meta-analysis published in Lancet Psychiatry concluded that the quality of clinical research evidence on cannabis for TS was low. The resulting findings are considered neutral. 12 An earlier review by the Cochrane Collaboration cited similar methodological concerns. 13 Currently, the CANNA-TICS study is underway which is a high quality, large randomized multicenter controlled trial. It is investigating the effect of nabiximols on tics. 14 Results are expected to be published soon after the time of this writing.

More recently, a new cannabinoid pharmaceutical has been developed called THX-110 that incorporates THC with other compounds. This product is manufactured by Therapix Biosciences Ltd and is “based on Dronabinol” and PEA (an endocannabinoid-like molecule) to “induce the entourage effect”. THX-110 consists of up to 10mg THC with 800MG PEA. 15 In autumn of 2021, results from a phase-2 pilot study of THX-110 found an improvement in tic symptoms in 16 adults with TS over a 12-week treatment period. 16

Because of the extensiveness of research using cannabis-based medicine for the treatment of tic disorders, comprehensive evidence reviews and treatment guidelines are available. A 2019 systematic review of treatments for people with TS and chronic tic disorders concluded that people with tics receiving THC are “possibly more likely than those receiving placebo to have reduced tic severity”. This study also reviewed risk of harm, such as weight gain and sedation. It did not find risk associated with THC treatment, unlike for pharmaceutical drugs like clonidine, risperidone, and aripiprazole. 17

What about treatment guidelines? A 2021 review on the use of cannabis-based medicine in the treatment of TS reported that the European Society for the Study of Tourette Syndrome (ESSTS) and the American Academy of Neurology (AAN) recommend behavioral therapy and pharmacotherapy with antipsychotics as first line treatments for tics. Cannabis-based medicine is classified as “an experimental intervention that should be applied to patients who are otherwise treatment-resistant”. 18 Given the experience of my family, this is a troubling recommendation. There is a high prevalence of side effects associated with the recommended pharmacotherapies. This is not the case with cannabis-based medicine.

There is very limited research on CBD in the treatment of tic disorders. A 2016 case study assessed whether Sativex (10.8mg THC and 10mg CBD) reduced severe motor and vocal tics. Treatment was over a four week period. The treatment resulted in a “marked improvement” in both the frequency and severity of both types of tics. 19 Similarly, a 2019 case report found that a daily dose of 10mg THC with 20mg CBD resulted in a “rapid and highly significant” reduction in tics. 20

While most of the published literature has examined adult patients with tics, a 2019 case report in the journal Medical Cannabis and Cannabinoids looked at the effectiveness of cannabis-based medicine in a pediatric subject. 21 A 12-year-old boy with TS experienced an initial reduction in tics when consuming vaporized THC equivalent to 4.4 mg. When the boy’s condition worsened, oral THC drops were added to the regimen at a daily dose of 12.5mg THC. No adverse events were reported. However, the author noted that treatment with cannabis in pediatric populations should be regarded as a “last-line treatment when well-established treatments have failed to improve tics”. As already mentioned, I would challenge that statement given the high incidence of significant side effects associated with the first-line pharmacotherapies. This general approach is consistent with the reluctance to use cannabis-based medicine as a first line medical therapy.

A study measuring levels of endocannabinoids in the cerebrospinal fluid of adult TS patients found that anandamide (AEA), 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA) were significantly increased relative to controls. The authors hypothesize that this demonstrates alterations in endocannabinoid system function in patients with TS. This may be either a primary cause or a secondary change resulting from alterations in other systems. 23 A 2004 study investigated whether common polymorphisms in the CB1 gene were associated with TS. The researchers did not find an association in the population studied. 23 However, a 2020 study found a significant association between a CB1 gene variant and TS. 24 These results certainly implicate the ECS in TS, but this remains poorly understood.

Our Experience

CBD has been the primary cannabinoid that has been used for my son’s treatment over the last 15 months. We’ve mostly used oil-based preparations. These have taken several forms, including liquid products, gelcaps, water-soluble preparations, and inhalation. Here’s a breakdown the different modes of administration in regards to our experience:

Oils: Taking an oil preparation can be challenging for a child. At first, we used a broad-spectrum oil extracted from cannabis (not hemp). It had a very strong taste due to the terpene profile. To make it more palatable, I put it in some lemon syrup. Subsequently we moved onto a hemp-derived CBD isolate oil. It had a less diverse chemical profile but was mostly tasteless and odorless. I put the oil into his morning smoothie. Another challenge is the slow onset and poor bioavailability. When taken on an empty stomach, studies have shown that the bioavailability of oil soluble CBD is only about 6%. 25 If taken with a high fat meal, bioavailability goes up fourfold. 26 Peak levels of lipid-soluble CBD also take at least 90 minutes to achieve. 27 Tic severity varies widely during the day, waxing and waning in response to stress and fatigue. Therefore, when there is a flare, it is difficult to use CBD oil treatment because of the slow onset. However, it can be used on a regular dosing schedule. We use CBD oil in the morning as described. After school, he takes a CBD oil gel cap which makes consumption easier if we’re on the go with after school activities.

In our experience, oral CBD oil has only a modest effect on tic severity. The effects are complicated by issues including the “as needed” medicinal effects related to tic severity fluctuation. There is also the difficulty of timing peak concentrations due to limited absorption. However, we have noted an anxiolytic and calming effect.

My son noted that the CBD oil helps him to feel calm and focused in the morning. Our cannabis physician prescribed CBD oil starting at 20mg twice daily, with incremental increases to determine the optimal dose. We found that our optimal dose was 40mg twice daily.

Water-Soluble: Water-soluble CBD has been shown to be absorbed much faster than lipid soluble preparations. In fact, its bioavailability was shown to be 4.5 times greater in a recent pharmacokinetic study. It is also easily dissolved in water and has no taste or odor. In addition, it has a very fast onset and appears in the blood in as little as 15 minutes. 27 This makes it a viable option for treating “tic flares” when they arise.

I live in Canada. It is illegal to ship or transport cannabinoids internationally. There are water-soluble products available in my country. But their cost is extremely high. Also there has been limited research into the safety of nanoparticles. 28 Given my son’s young age, I prefer to err on the side of caution and avoid nano products. There are water-soluble CBD products that are in micromolar size. I have found that these provide a good alternative to lipid-soluble CBD. They have the added benefit of a quick onset and easy incorporation into any food or beverage.

See also  Best CBD Oil Australia

The micromolar CBD products have provided an anxiolytic and calming effect with a modest change on tic severity. Because of the higher bioavailability of water-soluble CBD, a lower dose can be taken. We find that 15mg of water-soluble CBD provides comparable benefits to 40mg of CBD oil as a liquid or in gelcaps. For tic flares, 30mg of water-soluble CBD provides a rapid calming effect.

Inhaled: The fluctuating nature of tic disorders makes therapies with a fast onset a primary goal. This will not be the case with any orally ingested product, although water-soluble products will have a much faster onset than lipid-soluble preparations. Inhaled cannabinoids provide the fastest onset and greatest bioavailability, with an onset and peak within minutes following ingestion. 26 To treat my son’s acute tic flares, we occasionally use a CBD “puffer” that uses the same technology and delivery method as an asthma inhaler. These are metered inhalers which provide a measured dose of CBD, usually less than 5 mg per puff. We use a CBD-only inhaler and find that it provides some relief from the tics and anxiolytic effects at a dose of approximately 10mg.

CBDA (cannabidiolic acid) is the precursor to CBD and the form found in the raw plant. CBDA undergoes degradation to CBD in the presence of heat, light, and oxidants, which begins spontaneously after the plant is harvested. 26 CBDA is more easily absorbed than CBD. CBDA decreases inflammation by inhibiting the activity of the enzyme cyclooxygenase-2 (COX-2) (which mediates the synthesis of pro-inflammatory prostaglandins) and is structurally similar to salicylic acid. 29,30

I became interested in trying CBDA after observing that my son’s tics were greatly diminished when taking Aleve to treat an ear infection. Like CBDA, Aleve is a COX2 inhibitor. Although I have been unable to find any published research looking at either Aleve or CBDA in the treatment of tics, NSAIDS have been found to decrease flares in the related conditions PANS and PANDAS. 31 Unfortunately, CBDA is not widely available outside of the United States. I did have access to it when we spent a few months living in Florida. We found CBDA to be quite effective at reducing tic severity.

In our experience, CBDA does a better job at reducing tic severity but does not have as much of a calming and anxiolytic effect as CBD. But they can be used together to complement each other. We use 10-15mg of CBDA per treatment dose.

As already described, research on using cannabinoids for tic disorders has primarily been focused on using whole plant cannabis and THC. I admit I had an initial reluctance to use THC with my son out of concern over its psychoactive effects. However, we found that he was able to take the initially prescribed dose of 2.5mg THC balanced with 5mg of CBD without any noticeable impairment. But this wasn’t a high enough dose to have much effect on the tics. We found that a dose of 5mg of THC was required for maximum effect. This is a level that induces some noticeable impairment. My son reports his eyes feel heavy and he becomes slightly lethargic. For this reason, we reserve the higher dose of THC only when we are in what I call a “tic crisis”. Also, THC can be balanced with CBD at a 2:1 ratio to reduce some of THC’s psychoactive effects.

We use THC taken in gelcaps, which presents the issue of delayed onset of action and low bioavailability. We have only ever used THC in the evenings for two reasons. First, we want to avoid any potential psychoactive effects in school. Second, my son’s tics are usually much worse in the evening. A more rapid onset of action could be achieved by using an inhalation delivery method. Inhalers are now available with different ratios of CBD and THC, but we have been unable to get one in Canada.

Pediatric Considerations and Product Safety Considerations

Using cannabis-based medication with a child can present challenges. It may be difficult to find a medical practitioner who has experience with pediatric populations. The coordination of care between the cannabis physician and regular pediatrician or GP can be tricky if they are not knowledgeable about these treatments. When we told our GP about our intention to medicate with cannabinoids, she seemed shocked. But she did not attempt to discourage us from doing so. Others may not be so lucky.

There is also a social stigma associated with pediatric cannabis use, which stems from the nearly 100-year prohibition of the plant. We have never had to ask our son’s school to administer cannabinoid medication because our dosing regimen does not require this. But if it does, one should be prepared with the appropriate medical documentation. Sharing this information with other parents can also be tricky. I always preface our son’s use of cannabis-based medication with a clarification that he has a medical cannabis prescription from a physician. I also share some of the research that has been done on cannabis and tic disorders. People with little knowledge about cannabis-based medicine may assume that products such as CBD and CBDA are psychoactive and think you are giving your child something to make them “high”. We should educate and inform others using the best available information.

When purchasing any cannabis product, it’s always important to do your due diligence. This is especially important when administering cannabinoids to children. Only buy products that have undergone third party testing for pesticides, residual solvents, molds, heavy metals, and mycotoxins and avoid unnecessary flavorings. Of course, you should buy products that have been recommended and prescribed by your physician. In Canada, the cannabis market is legalized and regulated which means that all products have undergone safety testing and approval. I always buy products through one of the dispensaries recommended by our cannabis physician. Although I have found on more than one occasion that the prescribed product has been unavailable through the dispensary. When this happens, I’ve had to purchase a comparable product through a government store.

Many people experience tic disorders decreasing in severity over time, especially into adolescence. 32 For us, the four-month period following sudden onset was very severe. Gradually the intensity of the tics lessened. When we started using cannabis-based medicine, we discontinued the use of pharmaceutical drugs. At that point, we found the condition to be quite manageable. My son does experience flare ups, though.

As described by the American Academy of Child & Adolescent Psychiatry, tics can be exacerbated by “anxiety, tiredness, and certain medications”. 33 We have certainly found this to be the case. Any stressful situation can bring on a tic flare. Late nights or early mornings are almost invariably followed by a “bad day” until sufficient rest is achieved. My son has also experienced an exacerbation following a concussion, probably due to the associated neuroinflammation. His most severe increase in symptoms was following the second dose of the COVID-19 vaccine. We managed it with cannabis-based medicine along with over-the-counter anti-inflammatories.

In Summary

With tic disorders, there are good days and bad days. Sometimes tics flare up when you least expect it. Thankfully, cannabis-based medicine is available in different forms for acute and ongoing treatment. For flare ups, delivery methods such as inhalation or water-soluble preparations provide a faster onset of action. Oils and gel caps can be taken on a regular schedule. CBD and CBDA are non-psychoactive cannabinoids that can help to reduce anxiety and tic severity. THC can be used when tics are more severe. We use a variety of different cannabinoids as our primary therapy and follow different regimens depending on the situation. This has been very effective and most of the time does not cause any side effects.

My family is grateful for the support of physicians who courageously support pediatric populations with cannabis-based medicine.

Dr. Genevieve Newton spent 19 years as a researcher and educator in the field of nutritional sciences. A series of personal health crises led her to discover the benefits of medicinal cannabis, and she soon found herself engrossed in studying the endocannabinoid system and therapeutic applications of cannabis/cannabinoids in mental health, pain, sleep, and neurological disorders. She is the Scientific Director at Fringe, a medical education company that is focused on whole person health.

More By Dr. Newton
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