Neurology

Click here to read about AUTISM SPECTRUM DISORDER

Click here to read about EPILEPSY

Click here to read about TOURETTE’S SYNDROME

Click here to read about MULTIPLE SCLEROSIS

Click here to read about PARKINSON’S DISEASE


AUTISM SPECTRUM DISORDER

A summary of the available clinical evidence for the use of medicinal cannabis in addressing autism spectrum disorder can be found below.

EFFICACY AND EXPECTED BENEFITS

Large-scale, high quality, double-blind, randomised controlled trials (RCTs) are needed to establish the safety and efficacy of cannabis products for treating autism spectrum disorder (ASD). There has been an increase in cannabis use in the ASD-affected population due to anecdotal evidence of benefit. The results of clinical studies are mixed, with some evidence of benefit along with reports of adverse events (AEs), some severe. Earlier studies tended to use extracts with high Δ9-tetrahydrocannabinol (THC) concentrations, which may well explain some of the AEs.1

Cannabidiol (CBD) is potentially a good candidate for treatment of ASD, based on recent reports on observational studies showing efficacy and safety.2-4

EVIDENCE REVIEWS

Agarwal et al, 2019

A review of the current state of evidence for cannabis in the treatment of ASD assessed systematic reviews, reports, and experimental studies. The authors identified three large-scale clinical trials at varying stages of progress, and only five small studies that specifically examined cannabis use in ASD. Consequently, they also included studies reporting effects of cannabis on shared pathological symptoms of ASD.1

The assessed studies revealed mixed and inconclusive findings for the effects of cannabis, except in epilepsy. The reported adverse effects included increased agitation, somnolence, decreased appetite, irritability, and one case of transient psychosis in a 13-year-old girl, see below. A wide range of cannabis compositions and doses were used in the studies, making clear and reliable general guidance difficult. The authors concluded that there is currently insufficient evidence for cannabis use in ASD, and hence an urgent need for large-scale controlled studies to increase understanding of risks and benefits.1

Poleg et al, 2019

This review suggested that CBD might be a candidate for treatment of ASD, although at the time, there was no reliable clinical evidence for its efficacy and safety, with current evidence for benefit based on the efficacy of CBD in ASD-related pathological conditions. The authors concluded that CBD may be effective as a monotherapy or additional treatment in some of the most common ASD co-morbidities, and that further studies are needed.2

PRIMARY LITERATURE

Aran et al, 2016

In a retrospective feasibility study, CBD-rich cannabis oil was given as an adjuvant therapy to 60 children (5–18 years of age) with ASD and severe behavioural problems. Sublingual doses of a whole plant extract (containing a 20:1 ratio of CBD:THC in olive oil) were given 2–3 times per day. The starting dose of CBD (1 mg/kg/day) was up-titrated over 2–4 weeks, according to individual effect and tolerability, to a maximum CBD dose (10 mg/kg/day). Assessments included the Home Situations Questionnaire–Autism Spectrum Disorder (HSQ-ASD) and the Autism Parenting Stress Index (APSI).2

Efficacy

Cannabis treatment improved behavioural outbreaks from baseline following the cannabis treatment in 61% of patients:

  • HSQ scores improved from 4.74 ± 1.82 to 3.36 ± 1.56 (29%)—Mean improvement 1.38 ± 1.79 (median = 0.81)
  • APSI scores improved from 2.04 ± 0.77 to 1.37 ± 0.59 (33%)—Mean improvement 0.66 ± 0.74 (median = 0.53).

This led to the following modifications to concomitant treatments: 12 (24%) ceased therapy, 16 (33%) reduced therapy and 4 children (8%) increased therapy (dose or number of agents).2

In 29 patients with an insufficient response to initial treatment, lower CBD:THC ratios were tried (ratio ≤ 6:1, to a maximum CBD dose of 5 mg/kg/day). The lower CBD:THC ratio was reported by parents to be much better for 13 patients, slightly better in 7, no change in 6, and worse in 3.2

Based on these promising results of high-CBD extracts in ASD, the authors have commenced a placebo-controlled cross-over trial to assess CBD-rich cannabis in 150 children with ASD and disruptive behaviour, and another large placebo-controlled study of cannabidivarin (CBDV)—a related cannabinoid from cannabis—in 100 children with ASD.2

Safety

The CBD-rich treatment was generally well tolerated, although AEs were reported in 51% of patients, with 3 children (5%) stopping treatment due to AEs: in 2 cases marked irritability after treatment onset, and a transient psychotic event in a 13 year-old girl who received 6.5 mg/kg/day CBD with no other medications. Her THC dose had been gradually increased, and at 0.72 mg/kg/day of THC she developed an abrupt behavioural change, at which point she stopped taking CBD-THC and symptoms resolved after 9 days of antipsychotic medication.2

The authors note that strains with a relatively high THC concentration (CBD:THC ratio of 6:1) might lead to a serious psychotic episode requiring treatment with an antipsychotic.2

Fleury-Teixeira et al, 2019

A recent observational study included 18 ASD patients aged 6–17 years who received a standardised CBD-enriched cannabis extract (CBD:THC ratio of 75:1). Individualised starting doses of CBD (2.30–3.60 mg/kg/day) were up-titrated over 150 days to a maximum tolerated CBD dose (3.75–6.45 mg/kg/day).3

Three patients abandoned treatment in the first month. Of the 15 remaining in the study, 5 had a diagnosis of epilepsy and had experienced seizures in the previous month, while the other 10 had either never been diagnosed with epilepsy or had no clinical seizures for ≥ 12 months before cannabis treatment.

Each patient’s parent/caregiver filled out a standardised form at baseline and monthly during the cannabis treatment. They evaluated the severity of each of 8 symptom categories with a score between 0 and 100, with 0 for the lowest level of performance (maximum level of deficit and impairment) and 100 for maximum performance (complete absence of deficit and impairment).3

Efficacy

After 6–9 months of treatment, most patients showed some improvement in more than 1 of the 8 symptom categories evaluated. The range of therapeutic benefits for several distinct autistic symptoms extended to non-epileptic patients. The strongest improvements were reported for seizures, ADHD, sleep disorders, and communication and social interaction deficits. Improvements of ≥ 30% were found for 9 patients in at least 1 of the 8 categories, 6 patients in at least 2 categories, and 4 patients in at least 4 categories. Ten of the 15 patients were using concomitant medications for ASD, 9 of whom reported continued improvements after reducing or withdrawing those medications.3

Safety

Treatment was well tolerated with infrequent and mild AEs in most patients. Three participants dropped out in the first month due to AEs, and only 1 of the 15 patients (10 non-epileptic and 5 epileptic) who continued treatment showed no improvement in ASD symptoms.3

Bar-Lev Schleider et al, 2019

In a recent prospective observational study (subjective self-report by parents of patients), between 2015 and 2017, 188 ASD patients (mean age 12.9 ± 7.0 years) were treated sublingually with cannabis oil containing 30% CBD, 1.5% THC (CBD:THC ratio of 20:1). The extract also contained minor cannabinoids, including CBDV and cannabigerol (CBG), terpenes and flavonoids. Dosing started at 1 drop 3 times per day (45 mg CBD, 2.25 mg THC daily) with gradual up-titration according to individual response, with some patients receiving as much as 20 drops 3 times per day (900 mg CBD, 45 mg THC daily).4

Efficacy

Of the 155 patients still in active treatment at six months, 93 (60%) responded to the questionnaire with the following observations of improvement: 28 (30.1%) significant, 50 (53.7%) moderate, 6 (6.4%) slight, and 8 (8.6%) no change in condition. The cannabis treatment had mixed effects on concomitant chronic medication use: 6 patients (8.9%) reported an increase, 38 (56.7%) reported no change, and 23 (34.3%) decreased concomitant medication.4

Safety

Twenty-three patients (25.2%) experienced at least one moderate and easy to manage AE. The most common AE was restlessness (6.6%). The authors concluded that their study suggests cannabis treatment is safe and can improve ASD symptoms and quality of life, although RCTs are crucial to improve understanding.4

CLINICAL CONSIDERATIONS

Dosing

CBD

Although there was variation in the CBD dosage across the small number of observational studies, the clinical approach of up-titrating slowly from a low starting dose according to individual response was consistent.2-4

Two of the studies reported CBD doses in the range 1.0–10.0 mg/kg/day; typically starting with 1.0–3.6 mg/kg/day and titrating to a maximum dose of 3.6–10.0 mg/kg/day until ASD symptoms are reduced or the patient experiences adverse effects.2,3

While one study reported CBD doses starting at 45 mg/day and up-titrating to an optimal dose (79.5 ± 61.5 mg CBD, 3 times a day) with a maximum daily dose of 900 mg. The cannabis dose was not significantly associated with weight, age, or sex.4

Cannabidiol: Tetrahydrocannabinol (CBD:THC), THC and Cannabis sativa

The authors of one study noted cannabis extracts containing a relatively high THC concentration (CBD:THC ratio of 6:1) might lead to a serious psychotic episode.2

Interactions with antipsychotic and other drugs

Medicinal cannabis in the treatment of autism spectrum disorder (ASD) has been reported as an add-on therapy to existing medications, the most common including antipsychotics, antiepileptics, antidepressants, hypnotics and sedatives. The authors did not report any specific concerns regarding concomitant medication use in autism. However, all patients must be monitored for adverse events and tolerability when altering any therapeutic regimen.4

References

  1. Agarwal R, Burke SL, Maddux M. Current state of evidence of cannabis utilization for treatment of autism spectrum disorders. BMC Psychiatry. Oct 29 2019;19(1):328. doi: 10.1186/s12888-019-2259-4
  2. Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. Mar 2019;49(3):1284-1288. doi: 10.1007/s10803-018-3808-2
  3. Fleury-Teixeira P, Caixeta FV, Ramires da Silva LC, Brasil-Neto JP, Malcher-Lopes R. Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use. Front Neurol. 2019;10:1145. doi: 10.3389/fneur.2019.01145
  4. Bar-Lev Schleider L, Mechoulam R, Saban N, Meiri G, Novack V. Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Sci Rep. Jan 17 2019;9(1):200. doi: 10.1038/s41598-018-37570-y
  5. Poleg S, Golubchik P, Offen D, Weizman A. Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry. Mar 8 2019;89:90-96. doi: 10.1016/j.pnpbp.2018.08.030

Abbreviations
AE, adverse event; ASD, Autism Spectrum Disorder; APSI, Autism Parenting Stress Index; CBD, cannabidiol; CBG, cannabigerol; CBDV, cannabidivarin; ECS, endocannabinoid system; HSQ-ASD, Home Situations Questionnaire–Autism Spectrum Disorder; THC, ∆-9-tetrahydrocannabinol.


EPILEPSY

The Therapeutic Goods Administration (TGA) of Australia has prepared clinical guidance documents for prescribers of medicinal cannabis products for numerous conditions. A link to the guidance document for epilepsy can be found here.

Additional clinical evidence that has been published since the release of the TGA’s guidance documents is being developed into summaries that will be available soon.


TOURETTE’S SYNDROME

Summaries of the available clinical evidence for the use of medicinal cannabis in addressing Tourette’s syndrome be found below.

EFFICACY AND EXPECTED BENEFITS

Large-scale, high quality, double-blind, randomised controlled trials (RCTs) are needed to establish the safety and efficacy of cannabis products for treating Tourette syndrome (TS). The majority of studies have been on the main psychotropic cannabinoid, ∆-9-tetrahydro-cannabinol (THC). Case studies have reported effective and well tolerated use of CBD in combination with THC, for treatment-resistant TS. This suggests potential for CBD as an effective option for patients with treatment-resistant TS.1-3

EVIDENCE REVIEWS

Hoch et al, 2019

A systematic review of the efficacy and safety of medicinal cannabis in treating mental disorders found a consistent improvement of tics and behavioural problems in three small-scale prospective placebo controlled RCTs (2 crossover trials), with insufficient statistical power. Both medicated and unmedicated treatment-resistant TS patients were administered THC (2.5–10 mg/day). Non-serious adverse effects (AEs) were reported in these studies, such as dizziness, tiredness, dry mouth and headache. However, in the non-crossover trial, 7 of the 24 patients dropped out of the study or had to be excluded, but only 1 due to side effects—restlessness and anxiety.4

Black et al, 2019

A systematic review and meta-analysis of cannabinoids in the treatment of mental disorders reported on two small-scale RCTs of adjuvant THC extract in the treatment of TS, which were considered to be low/very low-grade evidence with pooled analysis finding no significant benefit compared to placebo. A crossover RCT on safety, which was reviewed, indicated that smoked cannabis (13% THC) increased the risk of acute psychotic symptoms.5

PRIMARY LITERATURE

Trainor et al, 2016

In a single case report on cannabinoids for treatment-resistant TS, a 26-year-old male was treated with twice daily cannabis extract (oromucosal spray, 10.8 mg THC and 10 mg CBD daily) for four weeks. No other drugs were being taken during this study.3

Efficacy

Subjective and objective assessment at weeks 1, 2 and 4 of treatment showed marked improvements in the frequency and severity of motor and vocal tics compared to baseline. At each assessment, a 30-minute videotape of the patient was recorded completing maths then reading tasks, and then sitting in silence (each for 10 minutes). Two observers blinded to the treatment phase rated the subject using the Original Rush Videotape Rating Scale (ORVRS). Changes from baseline to week four were:3

  • 85% reduction in motor tics from 176 to 27
  • vocal tics improved by 90% from a score of 20 to 2

Safety

The THC-CBD treatment was well tolerated with no adverse effects.3

Kanaan et al, 2017

A case study reported on a 22-year-old male patient with treatment-resistant TS who was treated with an oromucosal spray of cannabis extract containing THC and CBD. Treatment commenced at a dose of 1 spray/day (2.7 mg THC and 2.5 mg CBD) and slowly increased to 3 x 3 sprays/day (24.3 mg THC and 22.5 mg CBD daily).1

Efficacy

Treatment resulted in major improvements of both tics and premonitory urges, as well as in measures of global impairment and health-related quality of life. The largest improvements were observed for quality of life from baseline to 2-week follow up: 1

  • Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL) from 51 to 11 (78.4%)
  • Visual Analogue Scale for satisfaction of the GTS-QOL (QoL-VAS) from 50 to 85 (70%)

Safety

Treatment was well tolerated with no AEs of note.1

Pichler et al, 2019

A case study reported on a 47-year-old woman who had failed to manage her TS symptoms with standard antipsychotic pharmacotherapy, self-grown THC-rich cannabis and pure synthetic THC. The authors of this study reported treatment of this patient with a standardised cannabis tincture containing THC and CBD at a ratio of 1:2, an appreciably higher ratio than reported in earlier studies. A divided (3 x) daily dose totalling 10 mg THC and 20 mg CBD per day was administered.2

Efficacy

Before treatment the patient scored 73/100 on the Yale Global Tic Severity Scale (YGTSS). After two months of treatment, while taking no other drugs or psychotropic substances, her tic severity and frequency were reduced to a YGTSS score of 44/100. She reported a subjective increase in quality of life and slightly enhanced social activity.2

Safety

No significant AEs were observed, only light xerostomia (dry mouth).2

Discussion

The authors speculated that in view of this patient’s previously unsuccessful THC-rich cannabis and pure THC treatments, the beneficial effects of the cannabis tincture could be due to the presence of CBD, and synergies between the cannabinoids, with CBD reducing the psychotropic effects of THC while enhancing its positive therapeutic actions. They also suggest that beneficial effects of CBD itself cannot be ruled out, through action on the endocannabinoid system, an area needing further research.2

CLINICAL CONSIDERATIONS

Dosing

CBD

Cannabis extracts containing THC appear to be more effective in the presence of CBD.1-5 However, there are currently no studies reporting use of high-CBD, low-THC cannabis extracts in the treatment of TS, thus no clear dosing protocol for CBD itself.

Because CBD dosed as high as 50 mg/kg/day was found to be safe and well tolerated in treatment resistant epilepsy,6 it is worth considering high-CBD, low-THC cannabis extracts for TS, using doses of CBD higher than used in THC-CBD-containing extracts for treatment-resistant TS to date. Careful up-titration from a low starting dose of CBD would, of course, be prudent in any such treatment.

Cannabidiol:Tetrahydrocannabinol (CBD:THC), THC and Cannabis sativa

From the available data, THC-containing cannabis extracts or pure THC do not appear to be effective in the treatment of TS.4,5 Benefits have been reported in single case studies using cannabis extracts of THC combined with CBD; benefits were observed with CBD in the range of 10–22.5 mg per day.1-3 In the highest dosing TS case study, the combined THC-CBD dose was up-titrated from 2.5 to 22.5 mg per day.1

Interactions with antipsychotic and other drugs

There is a lack of data available to advise on concomitant medications with CBD for the treatment of TS. In two of the three case studies of treatment-resistant TS, no other medications were taken.2,3 In the other case, it was not stated whether other drugs were taken during treatment, although previous treatments with other drugs had been either ineffective or caused intolerable side effects.1

However, in the treatment of autism spectrum disorder (ASD), medicinal cannabis has been reported as an add-on therapy to existing medications, the most common of which included antipsychotics, antiepileptics, antidepressants, hypnotics and sedatives. The authors did not report any specific concerns regarding concomitant medication use in autism. Nonetheless, all patients must be monitored for adverse events and tolerability when altering any therapeutic regimen.7

References

  1. Kanaan AS, Jakubovski E, Muller-Vahl K. Significant Tic Reduction in An Otherwise Treatment-Resistant Patient with Gilles de la Tourette Syndrome Following Treatment with Nabiximols. Brain Sci. Apr 26 2017;7(5). doi: 10.3390/brainsci7050047
  2. Pichler E-M, Kawohl W, Seifritz E, Roser P. Pure delta-9-tetrahydrocannabinol and its combination with cannabidiol in treatment-resistant Tourette syndrome: A case report. Int J Psychiatry Med. 2019;54(2):150-156. doi: 10.1177/0091217418791455
  3. Trainor D, Evans L, Bird R. Severe motor and vocal tics controlled with Sativex(R). Australas Psychiatry. Dec 2016;24(6):541-544. doi: 10.1177/1039856216663737
  4. Hoch E, Niemann D, von Keller R, et al. How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review. European archives of psychiatry and clinical neuroscience. 2019;269(1):87-105. doi: 10.1007/s00406-019-00984-4
  5. Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6(12):995-1010. doi: 10.1016/s2215-0366(19)30401-8
  6. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. Mar 2016;15(3):270-278. doi: 10.1016/S1474-4422(15)00379-8
  7. Bar-Lev Schleider L, Mechoulam R, Saban N, Meiri G, Novack V. Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Sci Rep. Jan 17 2019;9(1):200. doi: 10.1038/s41598-018-37570-y

Abbreviations
AE, adverse event; ASD, autism spectrum disorder; CBD, cannabidiol; GTS-QOL, Gilles de la Tourette Syndrome-Quality of Life Scale; QoL-VAS, Visual Analogue Scale for satisfaction of the GTS-QOL; ORVRS, Original Rush Videotape Rating Scale; THC, ∆-9-tetrahydrocannabinol; TS, Tourette syndrome; YGTSS, Yale Global Tic Severity Scale

MULTIPLE SCLEROSIS

The Therapeutic Goods Administration (TGA) of Australia has prepared clinical guidance documents for prescribers of medicinal cannabis products for numerous conditions. A link to the guidance document for multiple sclerosis can be found here.

Additional clinical evidence that has been published since the release of the TGA’s guidance documents is being developed into summaries that will be available soon.

PARKINSON’S DISEASE

Summaries of the available clinical evidence for the use of medicinal cannabis in addressing Parkinson’s disease be found below.

EFFICACY AND EXPECTED BENEFITS

Large-scale, high quality, double-blind, randomised controlled trials (RCTs) are needed to establish the safety and efficacy of cannabis extracts (CEs) for treating the symptoms of Parkinson’s Disease (PD). Currently, results from RCTs on both motor and non-motor symptoms are inconsistent. While a number of uncontrolled trials and case reports indicate benefits of cannabinoids in PD, the range of cannabis products investigated, the different methods of intake, and varying doses and treatment durations make data comparison difficult.1-3

Cannabidiol (CBD), the main non-intoxicating cannabinoid from Cannabis sativa, is a promising candidate for the treatment of some of the symptoms associated with PD. Preclinical animal models have shown a neuroprotective effect of CBD, which appears to be due to its anti-inflammatory and antioxidant actions, and its ability to inhibit microglial activation in the substantia nigra. This remains to be clearly demonstrated in humans.2,3

CBD has shown a wide range of biological effects in preclinical and clinical studies of neurological and neuropsychiatric conditions, including psychosis, anxiety, depression, sleep disorders, and cognitive decline.2,3

Studies to date, although small, suggest that CBD is well tolerated with low risk of toxicity; large-scale clinical trials are needed to assess the long-term efficacy and safety of CBD.2 There is encouraging preliminary clinical evidence for benefit of CBD in treating the symptoms of PD, particularly non-motor symptoms; however, further research is needed to establish its specific role.3

Importantly, due to the ‘entourage effect’ (synergies between the numerous trace chemicals in Cannabis sativa extract), standardised CBD-rich whole plant extracts may be more therapeutically beneficial than pure CBD.4 This is supported by the preclinical findings that pure CBD follows a bell-shaped dose-response curve, while a CBD-enriched standardised cannabis extract (CE) follows a linear dose-response curve.5

EVIDENCE REVIEWS

Crippa et al, 2019

A review of cannabinoid treatment of PD, with a focus on CBD, concluded that non-motor PD symptoms are highly prevalent, that they are debilitating, and that existing drugs are of limited efficacy and associated with significant adverse reactions. Based on the limited evidence available, the authors considered CBD to be a promising, multi-target drug for treating non-motor symptoms of PD. Large RCTs investigating different disease stages are needed to elucidate CBD efficacy and mechanisms involved for motor and non-motor PD symptoms, as well as CBD’s safety, potential for antiparkinsonian drug (APD) interactions, and long-term effects. The authors cautioned that clinical studies involving CBD should use pure and pharmaceutical-grade products, and that patients should be advised about the potential hazards of consuming unregulated products labelled as CBD.2

Included in their evidence review were the following studies:

  • Seven preclinical studies of CBD in PD: 6 mouse/rat models showed a neuroprotective effect of CBD, while in a human neuroblastoma model of PD-related abnormalities, no protective effects of CBD (0.01–1.0 μM) were observed on cells exposed to 3 toxins.2
    • Four small RCTs assessing cannabinoid receptor 1 (CBR1) agonists/antagonists in PD:2
    • Two placebo-controlled, crossover RCTs administered a single oral daily dose nabilone, a synthetic THC analogue and CBR1 agonist, at a dose of 0.03 mg/kg to PD patients (n = 7) and patients (n = 15) with generalized and segmental primary dystonia (GSPD), respectively.
      • In the study of PD patients, nabilone significantly reduced levodopa-induced dyskinesia (LID) according to the Rush Dyskinesia Disability Scale (RDDS), and was reported to be safe, although 2 patients discontinued treatment due to vertigo (n = 1) and symptomatic postural hypotension (n = 1)—other, transient, adverse events (AEs; n = 5) included mild sedation, ‘floating sensation’, dizziness, and visual hallucinations.6
      • In the study of GSPD patients, nabilone was not associated with significant reductions in dystonia according to the Marsden Dystonia Scale, although 4 patients described subjective improvements in dystonia severity 2–3 days after treatment. While nabilone was well tolerated, 2 patients withdrew from the study due to significant postural hypotension (n = 1) and marked sedation (n = 1)—no other AEs were reported.7
    • In a parallel-arm RCT, PD patients (n = 8) with motor fluctuations and LID for at least 6 months received placebo or a single oral dose (20 mg) of the CB1 receptor antagonist, rimonabant (SR 141716). No significant difference was observed on motor symptoms and dyskinesia assessed with the UPDRS.8
    • A small crossover RCT with CE versus placebo in PD patients is discussed below, under Primary Literature.9
  • Three clinical studies involving CBD and PD were also identified:2 an open-label study,10 an RCT,11 and a case series,12 which are discussed below, under Primary Literature.
Ferreira Junior et al, 2020

A review of CBD and cannabinoid compounds as potential strategies for managing the symptoms of PD and LID found that clinical and preclinical evidence suggests therapeutic effects in PD and LID for CBD and other cannabinoids. The pharmacology and neuroprotective effects of CBD and other cannabinoids are discussed. Also discussed is the modulation of pro- or anti-inflammatory factors, which are possible mechanisms for the therapeutic/neuroprotective potential of cannabinoid compounds from cannabis, and their synthetic analogues, in motor disorders.3

The authors reviewed the same 4 small CBR1 agonist/antagonist RCTs, and 3 clinical studies of CBD as the above review, reporting similar findings. They note that, to date, no clinical study has been undertaken specifically to observe the effects of CBD on alleviation of LID in PD patients. The few investigations on the effects of cannabis/cannabinoids on PD-related motor dysfunctions such as LID have generated conflicting results. However, several single-case reports have indicated that cannabinoids can provide benefit in PD treatment-related motor symptoms.3

PRIMARY LITERATURE

de Faria et al, 2020

A recent placebo-controlled, crossover RCT of 24 patients with idiopathic PD receiving concomitant APDs, investigated the effects of acute CBD administration on anxiety and tremors induced by a simulated public speaking test (SPST). Patients with atypical Parkinsonism and dementia or current psychiatric disorders (DSM-5) were excluded. The mean age of participants was 64 years.13

Two experimental sessions at a 15-day interval were conducted for each participant who undertook the SPST in each session after taking a capsule containing 99.9% pure CBD (300 mg) in corn oil or corn oil placebo. Data were collected at baseline, pre-test, and post-stress to measure heart rate, blood pressure, a tapping test, and tremor frequency and amplitude (with an accelerometer). The Visual Analog Mood Scales (VAMS) and Self-Statements during Public Speaking Scale were also applied.13

Efficacy

Statistically significant differences in anxiety were observed between CBD and placebo measured by the VAMS (F(1, 21) = 6.27; p = .021). Bonferroni post hoc analysis found mean values for anxiety at the anticipatory, performance, and post-stress phases of the SPST were lower for CBD than for placebo (results are presented in Figure 1 of the article).13

Significant decreases between CBD and placebo in this anxiogenic situation were also seen for tremor amplitude recorded by the accelerometer (results are presented in Figure 2 of the article).13

Safety

No AEs were reported.13

CBD is generally considered to be safe, although clinical trials with higher participant numbers and longer CBD administration are needed. Given CBD use as an adjunct treatment, elucidation of drug interactions would also be valuable.14

Carroll et al, 2004

A small crossover RCT assessed standardised ethanolic CE (2.5 mg THC: 1.25 mg CBD capsules) versus placebo in PD patients (n = 19). The maximum daily dose of THC was 0.25 mg/kg.9

Efficacy

No significant differences were observed between CE and placebo on dyskinesia as measured by the Unified Parkinson Disease Rating Scale (UPDRS).9

Safety

The CE was well tolerated, and no serious AEs were reported. Both CE and placebo produced transient and mild AEs, such as feeling ‘drowsy/lethargic’ and ‘dizzy/light-headed’, musculoskeletal pain, and dry mouth. While only the CE caused nausea, constipation, feeling ‘detached’, paranoia, vivid dreams/nightmares, confusion, panic attacks, and poor concentration. The incidence of AEs was dose related.9

Zuardi et al, 2009

In a 4-week, open-label study of PD patients (n = 6) with psychotic symptoms for ≥ 3 months prior to study entry, oral CBD was administered at doses ranging from 150 mg daily at week 1 to a maximum of 400 mg daily at week 4, according to individual response.10

Efficacy

Compared to baseline, CBD was associated with significant improvements in psychotic symptoms at week 4 assessed by

  • The Brief Psychiatric Rating Scale: mean total score at baseline = 18.5, and at four weeks = 5.5 (p < .001)
  • The Parkinson Psychosis Questionnaire: mean total score at baseline = 13, and at four weeks = 1.5 (p = .001)

And in global functioning assessed by

  • The UPDRS: mean total score at baseline = 67.5, and at four weeks = 51.5 (p = .046), and
  • The Clinical Global Impressions scale (very much improved = 1, no change = 4, very much worse = 7): mean score at baseline = 4, and at four weeks = 1.5 (p = .001)

No other significant effects were observed.10

Safety

No adverse effects were reported during the study.10

Chagas et al, 2014

A 6-week RCT parallel-group study of PD patients (n = 21) with no dementia or comorbid psychiatric conditions assessed the safety and efficacy of daily CBD (75 mg), CBD (300 mg) or placebo (n = 7 per treatment arm). Motor and general PD symptoms, well-being and quality of life were assessed according to the UPDRS and the Parkinson’s Disease Questionnaire–39 (PDQ–39) at baseline and at week 6.11

Efficacy

Compared to placebo, CBD (300 mg/day) was associated with significant improvements in the PDQ–39 total score:

Total scores for placebo = 5.5, and CBD = 25.57 (p = .05).

Significant differences were also observed for both CBD doses versus placebo in the PDQ–39 scale factors ‘activities of daily living’ (ADL) and ‘stigma’

  • For ADL, placebo = –0.69, CBD (75 mg/day) = 16.07, and CBD (300 mg/day) = 21.43,
  • For stigma, placebo = 3.13, CBD (75 mg/day) = –4.46, CBD (300 mg/day) = 15.18,
  • For groups taking placebo and CBD 300 mg/day, p = 0.02,
  • For groups taking CBD 75 mg/day and 300 mg/day, p = 0.04.

No significant effects were observed for other measures (including the motor score of the PDQ-39). These results suggest that PD patients may experience improvement in their well-being and quality of life with CBD.11

Safety

No AEs were reported.11

Chagas et al, 2014

A case series reported on 4 of the PD patients who had participated in the RCT outlined above, and had a rapid eye movement sleep behaviour disorder. They received CBD treatment (75 mg [n = 3] or 300 mg [n = 1] for 6 weeks). Inclusion criteria included a clinical assessment by a sleep disorder neurology specialist plus ≥ 2 episodes of complex sleep-related behaviours per week (nightmares and active behaviour during dreaming).12

Efficacy

All 4 patients experienced a rapid and persistent reduction in the frequency of symptoms, including swearing, talking, yelling, pushing, kicking, punching, and gesturing with CBD treatment.

Three patients (75 mg CBD) experienced symptoms 2–4 (n = 2) or 7 (n = 1) times per week at baseline and had no symptoms at all after the 6-week treatment period. The remaining patient (300 mg CBD) experienced symptoms 2–4 times per week at baseline and only one symptom per week after the 6-week treatment period. Following treatment discontinuation, symptoms returned to the same frequency and intensity as at baseline.12

Safety

CBD was well tolerated in this group.12

CLINICAL CONSIDERATIONS

Dosing

CBD

Oral dosing of CBD in the studies reviewed ranged from 75–400 mg daily according to patient clinical response; CBD was well tolerated in these studies.2,3 However, as individual response to CBD varies, the clinical approach of ‘start low and go slow’ is recommended; that is, weekly up-titration according to individual response.

Cannabidiol: Tetrahydrocannabinol (CBD:THC), THC and Cannabis sativa

Two studies used a relatively low daily dose of 0.03 mg/kg of synthetic THC, resulting in only transient and non-serious AEs. Another study dosed a 2:1 ratio of THC:CBD (THC, 2.5 mg and CBD, 1.25 mg per capsule) at a maximum daily dose of 0.25 mg/kg of THC. No serious AEs were reported.2,3

Interactions with APDs

Based on the available data, no APD interactions were apparent at the reported doses of CBD. However, further investigation of CBD safety and long-term effects, and its interaction with APDs are still needed.2,3,14

No clinical information relating to negative interactions between THC and APD was found.

References

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  11. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. Nov 2014;28(11):1088-1098. doi: 10.1177/0269881114550355
  12. Chagas MH, Eckeli AL, Zuardi AW, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series. J Clin Pharm Ther. Oct 2014;39(5):564-566. doi: 10.1111/jcpt.12179
  13. de Faria SM, de Morais Fabricio D, Tumas V, et al. Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease. J Psychopharmacol. Feb 2020;34(2):189-196. doi: 10.1177/0269881119895536
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