This is a list of all the studies published on Epilepsy and cannabis.



With a growing awareness of the potential benefits of cannabis as a medical treatment for those who have been diagnosed with a form of epilepsy or seizure disorder, we thought it would be a good idea to help arm our readers with as much knowledge as possible on the subject.



We are constantly told that there is not enough research on any medical condition when it comes to cannabis, but anyone that knows how to search for published medical studies using google knows that this just isn’t the case!



Our team of clinical researchers and medical professionals have compiled this list of over 100 published studies on cannabinoids and epilepsy. It is well worth a browse of the many study titles just to get an idea of what kind of research has taken place.



If you have epilepsy, we encourage you to take a read of the intro and conclusion of the studies that interest you in order to gain perspective of what the study involved and what the scientist found with some of their thoughts about what it could mean or lead on to for further studies. This can give you a foot up when talking to your neurologist about looking at cannabinoid treatment options if you are one of the many patients that have already been trying the AED (anti epileptic drugs) that are prescribed as conventional treatment.



Epilepsy is a disorder that impacts the lives of children and adults with over 500,000 having the diagnosis in the UK. Current medications include, sodium valproate, carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, ethosuximide, topiramate. These have side effects of drowsiness, a lack of energy, agitation, headaches, uncontrollable shaking (tremor), hair loss or unwanted hair growth, swollen gums, sickness and rashes.



Cannabis oil is a natural plant extract which main active ingredient compounds are THC (delta 9 tetrahydrocannabinol) and CBD (cannabidiol). Patients with different forms of epilepsy find that the ratios needed vary from patient to patient and there is no one size fits all cannabis medicine for anyone. It requires a level of self titration and this is an area most patients or parents treating a child have concern over.



Cannabis Social Clubs have become a first point of contact for many patients in the UK who operate shared cultivation collectives or the ability to access safe cannabis oils that have been tested by a lab, These lab tests allow patients to know the mg of THC in the extract so that tinctures and other cannabis preparations can be made with consistent dosing batch to batch and crop to crop.



Some members find that cannabis extracts have kept them in remission for a number of years and free of all seizures, others have found that it has reduced them greatly but not completely.



So, take a look below at this giant list of evidence to show the potential benefit and interactions of cannabis with epilepsy.



Medical Cannabis and Epilepsy



1. Cannabinoid therapy in epilepsy.

2. Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.

3. Successful use of pure cannabidiol for the treatment of super-refractory status epilepticus.

4. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models.

5. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial.

6. CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway.

7. Simultaneous quantification of thirteen cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients.

8. Cannabis-based products for pediatric epilepsy: A systematic review.

9. Emerging drugs for the treatment of Dravet syndrome.

10. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

11. Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

12. Epilepsy and Cannabis: A Literature Review.

13. The Endocannabinoid System and Oligodendrocytes in Health and Disease.

14. Cannabis Therapeutics and the Future of Neurology.

15. Efficacy of cannabinoids in paediatric epilepsy.

16. Medical cannabis: A needs analysis for people with epilepsy.

17. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.

18. Cannabis and epilepsy.

19. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

20. Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

21. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

22. Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

23. Cannabis for the Treatment of Epilepsy: an Update.

24. Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.

25. Cannabidiol for Epilepsy: New Hope on the Horizon?

26. Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders.

27. Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System.

28. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

29. Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

30. Cannabis for pediatric epilepsy: protocol for a living systematic review.

31. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

32. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

33. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

34. Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

35. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment.

36. Addition of Cannabidiol to Current Antiepileptic Therapy Reduces Drop Seizures in Children and Adults With Treatment-Resistant Lennox-Gastaut Syndrome.

37. Investigational cannabinoids in seizure disorders, what have we learned thus far?

38. Review of the neurological benefits of phytocannabinoids.

39. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

40. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study.

41. Treatment Strategies for Dravet Syndrome.

42. Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

43. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.

44. Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia.

45. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.

46. Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

47. Cannabis for paediatric epilepsy: challenges and conundrums.

48. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

49. Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

50. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

51. Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

52. Cannabinoids for epilepsy: What do we know and where do we go?

53. Efficacy and safety of cannabis for treating children with refractory epilepsy.

54. The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.

55. Medical Cannabinoids in Children and Adolescents: A Systematic Review.

56. A resurging boom in new drugs for epilepsy and brain disorders.

57. [Cannabis use in Epilepsy. Current situation in Argentina and abroad].

58. The potential role of cannabinoids in epilepsy treatment.

59. Interactions between cannabidiol and commonly used antiepileptic drugs.

60. Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

61. [Cannabidiol: its use in refractory epilepsies].

62. Assessing the role of serotonergic receptors in cannabidiol’s anticonvulsant efficacy.

63. Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

64. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.

65. Cannabidiol in Patients With Intractable Epilepsy Due to TSC: A Possible Medication But Not a Miracle.

66. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions.

67. Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome.

68. Neurological Disorders in Medical Use of Cannabis: An Update.

69. Neurological Aspects of Medical Use of Cannabidiol.

70. Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy.

71. The current status of artisanal cannabis for the treatment of epilepsy in the United States.

72. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.

73. Social correlates of health status, quality of life, and mood states in patients treated with cannabidiol for epilepsy.

74. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

75. Treatment issues for children with epilepsy transitioning to adult care.

76. Cannabinoids in treatment-resistant epilepsy: A review.

77. Are cannabinoids effective for epilepsy?

78. Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy.

79. Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s.

80. Pharmacology of cannabinoids in the treatment of epilepsy.

81. Cannabis and epilepsy: An ancient treatment returns to the fore.

82. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.

83. Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol.

84. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

85. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases.

86. From Cannabis to Cannabidiol to Treat Epilepsy, Where Are We?

87. The Utility of Cannabidiol in the Treatment of Refractory Epilepsy.

88. Cannabidiol and epilepsy: Rationale and therapeutic potential.

89. Is the medical use of cannabis a therapeutic option for children?

90. Plant-Derived and Endogenous Cannabinoids in Epilepsy.

91. Cannabinoids for pediatric epilepsy? Up in smoke or real science?

92. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

93. The Pharmacological Basis of Cannabis Therapy for Epilepsy.

94. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

95. Cannabidiol as potential treatment in refractory pediatric epilepsy.

96. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy.

97. Cannabis and Endocannabinoid Signaling in Epilepsy.

98. Marijuana Use in Epilepsy: The Myth and the Reality.

99. Cannabinoids and Epilepsy.

100. Cannabinoids: is there a potential treatment role in epilepsy?

101. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

102. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

103. Use of cannabis in severe childhood epilepsy and child protection considerations.

104. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

105. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.

106. Phytocannabinoids and epilepsy.

107. Medical marijuana in neurology.

108. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia’s survey.

109. Seizing an opportunity for the endocannabinoid system.

110. Cannabis, cannabidiol, and epilepsy–from receptors to clinical response.

111. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability.

112. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

113. The case for medical marijuana in epilepsy.

114. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.

115. Cannabinoids for epilepsy.

116. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.

117. Cannabis and other illicit drug use in epilepsy patients.

118. Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.

119. Cannabinoids for epilepsy.

120. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

121. Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain.

122. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention.

123. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

124. Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus.

125. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

126. The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

127. Not too excited? Thank your endocannabinoids.

128. Endocannabinoids and their implications for epilepsy.

129. Cannabinoids as potential anti-epileptic drugs.

130. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

131. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center.

132. On the application of cannabis in paediatrics and epileptology.

133. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.

134. Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

135. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy.

136. Hypnotic and antiepileptic effects of cannabidiol.

137. The cannabinoids as potential antiepileptics.

138. Chronic administration of cannabidiol to healthy volunteers and epileptic patients.

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138 of 138 saved results

1. Cannabinoid therapy in epilepsy.

Author(s): Billakota S; Devinsky O; Marsh E

Source: Current opinion in neurology; Jan 2019

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30676535

Abstract:PURPOSE OF REVIEW: To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy.RECENT FINDINGS: Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (>99% of CBD and <0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data.SUMMARY: Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

Database: PubMed



2. Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.

Author(s): Chen JW; Borgelt LM; Blackmer AB

Source: The Annals of pharmacotherapy; Jan 2019 ; p. 1060028018822124

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30616356

Abstract:OBJECTIVE: To review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).DATA SOURCES: Relevant information was identified through EMBASE and Ovid MEDLINE (1946 to October 2018). Product labeling and https://www.clinicaltrials.gov were also reviewed.STUDY SELECTION/DATA EXTRACTION: English language articles evaluating efficacy and safety in humans with treatment-resistant epilepsies were reviewed; additional pharmacology and pharmacokinetic studies in humans, animals, and in vitro were also included.DATA SYNTHESIS: Pure, plant-based CBD is a pharmaceutical grade extract that exhibits clinically significant antiseizure properties, with a hypothesized multimodal mechanism of action. In the GWPCARE trial series, CBD displayed superior efficacy in reducing key seizure frequencies (convulsive seizures in DS; drop seizures in LGS) by 17% to 23% compared with placebo as adjunctive therapy to standard antiepileptic drugs in patients 2 years of age and older. Common adverse effects were somnolence, diarrhea, and elevated hepatic transaminases. Noteworthy drug-drug interactions included clobazam, valproates, and significant inducers/inhibitors of CYP2C19 and 3A4 enzymes. Relevance to Patient Care and Clinical Practice: A discussion regarding CBD dosing, administration, adverse effects, monitoring parameters, and interactions is provided to guide clinicians. CBD offers patients with DS and LGS a new treatment option for refractory seizures.CONCLUSION: This is the first cannabis-derived medication with approval from the US Food and Drug Administration. This CBD formulation significantly reduces seizures as an adjunct to standard antiepileptic therapies in patients ≥2 years old with DS and LGS and is well tolerated.

Database: PubMed



3. Successful use of pure cannabidiol for the treatment of super-refractory status epilepticus.

Author(s): Rajaraman RR; Sankar R; Hussain SA

Source: Epilepsy & behavior case reports; 2018; vol. 10 ; p. 141-144

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30596011

Available at Epilepsy & behavior case reports – from Europe PubMed Central – Open Access

Abstract:We present the case of a child with long-standing, super-refractory status epilepticus (SRSE) who manifested prompt and complete resolution of SRSE upon exposure to pure cannabidiol. SRSE emerged in the context of remote suspected encephalitis with previously well-controlled epilepsy. We discuss the extent to which response may be specifically attributed to cannabidiol, with consideration and discussion of multiple potential drug-drug interactions. Based on this case, we propose that adjunctive cannabidiol be considered in the treatment of SRSE.

Database: PubMed



4. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models.

Author(s): Patra PH; Barker-Haliski M; White HS; Whalley BJ; Glyn S; Sandhu H; Jones N; Bazelot M; Williams CM; McNeish AJ

Source: Epilepsia; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30588604

Available at Epilepsia – from Wiley

Available at Epilepsia – from IngentaConnect

Abstract:OBJECTIVE: Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizures (RISE-SRS) model of temporal lobe epilepsy (TLE).METHODS: We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6-Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine-induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE-SRS model of TLE.RESULTS: CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine-induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD’s acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time-dependent increase in seizure burden and improved TLE-associated motor comorbidities of epileptic rats in the RISE-SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task.SIGNIFICANCE: The present study illustrates that CBD is a well-tolerated and effective antiseizure agent and illustrates a potential disease-modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE.

Database: PubMed



5. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial.

Author(s): Devinsky O; Nabbout R; Miller I; Laux L; Zolnowska M; Wright S; Roberts C

Source: Epilepsia; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30582156

Available at Epilepsia – from Wiley

Available at Epilepsia – from IngentaConnect

Abstract:OBJECTIVE: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.RESULTS: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient’s overall condition on the Subject/Caregiver Global Impression of Change scale.SIGNIFICANCE: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Database: PubMed



6. CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway.

Author(s): Cao Q; Liu X; Yang F; Wang H

Source: Experimental and therapeutic medicine; Dec 2018; vol. 16 (no. 6); p. 4784-4790

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30542433

Abstract:Epilepsy is a chronic brain disease caused by abnormal discharging in the brain, which induces momentary brain dysfunction. Cannabinoid 2 receptor (CB2R) is expressed in central nervous system (CNS) and serves an important role in the pathogenesis of CNS diseases. The aim of the present study was to explore the effects of CB2R activation on phosphoinositide 3-kinase (PI3K) 110α-protein kinase B (AKT) signaling in an astrocyte model of epilepsy. Rat CTX TNA2 astrocytes were treated with Mg free solution to establish a cell model of epilepsy and were subsequently treated with a CB2R agonist (JWH133) and antagonist (AM630). Cell cycle analysis revealed that treatment using Mg free solution inhibited cell cycle transition. JWH133 facilitated cell cycle progression while AM630 inhibited it. Western blotting results demonstrated that treatment with Mg free solution downregulated the expression of cyclin D1, cyclin E, phosphorylated Retinoblastoma (p-Rb), B-cell lymphoma 2 (Bcl-2), PI3K 110α, p-AKT and p-mammalian target of rapamycin, whereas JWH133 treatment upregulated these proteins. AM630 ameliorated the JWH133-induced upregulation of these proteins. To confirm the involvement of AKT signaling, the AKT inhibitor wortmannin was used. The results revealed that wortmannin inhibited the effect of JWH133 on p-AKT, cyclin D1, p-Rb and Bcl-2 expression. In addition, the effects of JWH133 and AM630 on PI3K 110α-AKT signaling were verified using a rat model of epilepsy. In conclusion, the present study demonstrates that CB2R activation induces astrocyte proliferation and survival via activation of the PI3K 110α-AKT signaling pathway.

Database: PubMed



7. Simultaneous quantification of thirteen cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients.

Author(s): Roslawski MJ; Remmel RP; Karanam A; Leppik IE; Marino SE; Birnbaum AK

Source: Therapeutic drug monitoring; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30520828

Abstract:BACKGROUND: A sensitive, robust method was developed and validated to quantitate thirteen major natural cannabinoid parent and metabolite compounds in human plasma at or below 0.5 ng/mL.METHODS: A liquid chromatography-tandem mass spectrometry method was developed and validated to measure thirteen cannabinoid compounds: cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), Δ-tetrahydocannabinol (THC), Δ-tetrahydrocannabinolic acid A (THCA), Δ-tetrahydrocannabivarin (THCV), 11-hydroxy-Δ-tetrahydrocannbinol (11-OH-THC), 11-nor-9-carboxy-Δ-tetrahydrocannbinol (THC-COOH), and 11-nor-9-carboxy-Δ-tetrahydrocannabinol-glucuronide (THC-COOH-glu). Samples (200 µL) were extracted via protein precipitation and separated with a Kinetex-EVO C18 column and a 65%-95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy receiving cannabis for the treatment of seizures.RESULTS: The extracted lower limit of quantification was 0.05 ng/mL for CBD, CBDV, CBN, and 11-OH-THC; 0.10 ng/mL for CBDA, CBG, CBC, CBGA, THC, THCA, and THCV; 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean QC intra-day accuracy and precision for all analytes ranged 96.5-104% and 2.7-4.9% respectively while inter-day accuracy and precision ranged 98-103.3% and 0.2-3.6%, respectively. An absolute matrix effect was observed for some analytes, however, with minimal relative matrix effect. Lack of nonspecific drug binding to extraction glass and plasticware was verified. Patient CBD levels ranged from 0.135-11.13 ng/mL.CONCLUSIONS: The validated method met FDA guidelines for Bioanalytical Assays precision and accuracy criteria. The assay reliably confirmed the use of particular medical cannabis formulations in patient samples as well as reliably measured low CBD concentrations from single dose CBD exposure.

Database: PubMed



8. Cannabis-based products for pediatric epilepsy: A systematic review.

Author(s): Elliott J; DeJean D; Clifford T; Coyle D; Potter BK; Skidmore B; Alexander C; Repetski AE; Shukla V; McCoy B; Wells GA

Source: Epilepsia; Jan 2019; vol. 60 (no. 1); p. 6-19

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30515765

Available at Epilepsia – from Wiley

Available at Epilepsia – from IngentaConnect

Abstract:OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy.METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome.RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported.SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Database: PubMed



9. Emerging drugs for the treatment of Dravet syndrome.

Author(s): Brigo F; Striano P; Balagura G; Belcastro V

Source: Expert opinion on emerging drugs; Nov 2018

Publication Date: Nov 2018

Publication Type(s): Journal Article

PubMedID: 30482063

Abstract:INTRODUCTION: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment. Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS. Expert Opinion/Commentary: A recent large randomized controlled-trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.

Database: PubMed



10. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

Author(s): Sands TT; Rahdari S; Oldham MS; Caminha Nunes E; Tilton N; Cilio MR

Source: CNS drugs; Jan 2019; vol. 33 (no. 1); p. 47-60

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30460546

Abstract:BACKGROUND: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks.OBJECTIVE: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy.METHODS: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures.RESULTS: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free.CONCLUSION: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.

Database: PubMed



11. Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

Author(s): James Huntsman R; Tang-Wai R; Acton B; Alcorn J; William Lyon A; David Mousseau D; Seifert B; Laprairie R; Prosser-Loose E; Ondrej Hanuš L

Source: Paediatrics & child health; Sep 2018; vol. 23 (no. 6); p. 368-373

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30455572

Available at Paediatrics & child health – from ProQuest (Hospital Premium Collection) – NHS Version

Available at Paediatrics & child health – from Europe PubMed Central – Open Access

Abstract:The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

Database: PubMed



12. Epilepsy and Cannabis: A Literature Review.

Author(s): Zaheer S; Kumar D; Khan MT; Giyanwani PR; Kiran F

Source: Cureus; Sep 2018; vol. 10 (no. 9); p. e3278

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30443449

Available at Cureus – from Europe PubMed Central – Open Access

Abstract:Epilepsy is considered to be one of the most common non-communicable neurological diseases especially in low to middle-income countries. Approximately one-third of patients with epilepsy have seizures that are resistant to antiepileptic medications. Clinical trials for the treatment of medically refractory epilepsy have mostly focused on new drug treatments, and result in a significant portion of subjects whose seizures remain refractory to medication. The off-label use of cannabis sativa plant in treating seizures is known since ancient times. The active ingredients of this plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the latter considered safer and more effective in treating seizures, and with less adverse psychotropic effects. Clinical trials prior to two years ago have shown little to no significant effects of cannabis in reducing seizures. These trials seem to be underpowered, with a sample size less than 15. In contrast, more recent studies that have included over 100 participants showed that CBD use resulted in a significant reduction in seizure frequency. Adverse effects of CBD overall appear to be benign, while more concerning adverse effects (e.g., elevated liver enzymes) improve with continued CBD use or dose reduction. In most of the trials, CBD is used in adjunct with epilepsy medication, therefore it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications. Future trials may evaluate the efficacy of CBD in treating seizures due to specific etiologies (e.g., post-traumatic, post-stroke, idiopathic).

Database: PubMed



13. The Endocannabinoid System and Oligodendrocytes in Health and Disease.

Author(s): Ilyasov AA; Milligan CE; Pharr EP; Howlett AC

Source: Frontiers in neuroscience; 2018; vol. 12 ; p. 733

Publication Date: 2018

Publication Type(s): Journal Article; Review

PubMedID: 30416422

Available at Frontiers in neuroscience – from Europe PubMed Central – Open Access

Abstract:Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.

Database: PubMed



14. Cannabis Therapeutics and the Future of Neurology.

Author(s): Russo EB

Source: Frontiers in integrative neuroscience; 2018; vol. 12 ; p. 51

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30405366

Available at Frontiers in integrative neuroscience – from Europe PubMed Central – Open Access

Abstract:Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

Database: PubMed



15. Efficacy of cannabinoids in paediatric epilepsy.

Author(s): Ali S; Scheffer IE; Sadleir LG

Source: Developmental medicine and child neurology; 2019; vol. 61 (no. 1); p. 13-18

Publication Date: 2019

Publication Type(s): Journal Article; Review

PubMedID: 30402932

Available at Developmental medicine and child neurology – from Wiley

Abstract:There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of ∆9 -tetrahydrocannabinol. CBD does not act via cannabinoid receptors and its antiepileptic mechanism of action is unknown. Despite considerable community interest in the use of CBD for paediatric epilepsy, there has been little evidence for its use apart from anecdotal reports, until the last year. Three randomized, placebo-controlled, double-blind trials in Dravet syndrome and Lennox-Gastaut syndrome found that CBD produced a 38% to 41% median reduction in all seizures compared to 13% to 19% on placebo. Similarly, CBD resulted in a 39% to 46% responder rate (50% convulsive or drop-seizure reduction) compared to 14% to 27% on placebo. CBD was well tolerated; however, sedation, diarrhoea, and decreased appetite were frequent. CBD shows similar efficacy to established antiepileptic drugs. WHAT THIS PAPER ADDS: Cannabidiol (CBD) shows similar efficacy in the severe paediatric epilepsies to other antiepileptic drugs. Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD.

Database: PubMed



16. Medical cannabis: A needs analysis for people with epilepsy.

Author(s): Kerai A; Sim TF; Emmerton L

Source: Complementary therapies in clinical practice; Nov 2018; vol. 33 ; p. 43-48

Publication Date: Nov 2018

Publication Type(s): Journal Article

PubMedID: 30396625

Available at Complementary therapies in clinical practice – from ClinicalKey

Abstract:BACKGROUND AND PURPOSE: Medical cannabis may be effective treatment for refractory epilepsy. It is timely to seek users’ and potential users’ opinions in regard to its place in the management of epilepsy.MATERIALS AND METHODS: An online survey was administered to members of an epilepsy support organisation in Western Australia. Experience with cannabis for management of epilepsy was explored, along with desire to trial a particular pharmaceutical formulation(s).RESULTS: People with epilepsy (33/71) and carers (38/71) participated. Fifty-four participants indicated no experience with medical cannabis, although 35, mainly with inadequate response to prescription medicines, were willing to ask for a prescription. Concerns included difficulty accessing cannabis and high cost of this treatment. Tablets/capsules was the most acceptable dosage form for development.CONCLUSION: These findings suggest wide interest in trialling medical cannabis in individual cases of refractory epilepsy, despite the developing body of literature and some concerns about cost and procurement.

Database: PubMed



17. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.

Author(s): Lattanzi S; Brigo F; Trinka E; Zaccara G; Cagnetti C; Del Giovane C; Silvestrini M

Source: Drugs; Nov 2018; vol. 78 (no. 17); p. 1791-1804

Publication Date: Nov 2018

Publication Type(s): Journal Article; Review

PubMedID: 30390221

Abstract:BACKGROUND: Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.OBJECTIVE: The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.METHODS: Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).RESULTS: Four trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1-31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8-28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07-2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55-8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28-7.41; p = 0.657) and 4.20 (95% CI 1.82-9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87-16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22-12.86; p = 0.626) and 6.89 (95% CI 2.28-20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11-1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.CONCLUSIONS: Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Database: PubMed



18. Cannabis and epilepsy.

Author(s): Thomas RH; Cunningham MO

Source: Practical neurology; Dec 2018; vol. 18 (no. 6); p. 465-471

Publication Date: Dec 2018

Publication Type(s): Journal Article; Review

PubMedID: 30337476

Available at Practical neurology – from BMJ Journals – NHS

Abstract:Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs. It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in 2018 there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic. We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in 2019.

Database: PubMed



19. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

Author(s): Pamplona FA; da Silva LR; Coan AC

Source: Frontiers in neurology; 2018; vol. 9 ; p. 759

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30258398

Available at Frontiers in neurology – from Europe PubMed Central – Open Access

Abstract:This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/223, 36%), with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.56) between treatments with CBD-rich extracts (97/255, 38%) and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346, p < 0.0001) and severe (23/285 vs. 77/346, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.

Database: PubMed



20. Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

Author(s): Klotz KA; Schulze-Bonhage A; Antonio-Arce VS; Jacobs J

Source: Frontiers in neurology; 2018; vol. 9 ; p. 731

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30258395

Available at Frontiers in neurology – from Europe PubMed Central – Open Access

Abstract:Background: The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner’s attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available. Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy. Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018. Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1-35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient’s quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option. Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment.

Database: PubMed



21. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

Author(s): McCoy B; Wang L; Zak M; Al-Mehmadi S; Kabir N; Alhadid K; McDonald K; Zhang G; Sharma R; Whitney R; Sinopoli K; Snead OC

Source: Annals of clinical and translational neurology; Sep 2018; vol. 5 (no. 9); p. 1077-1088

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30250864

Available at Annals of clinical and translational neurology – from Europe PubMed Central – Open Access

Abstract:Introduction: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.Methods: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.Results: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.Conclusions: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Database: PubMed



22. Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

Author(s): Ghovanloo MR; Shuart NG; Mezeyova J; Dean RA; Ruben PC; Goodchild SJ

Source: The Journal of biological chemistry; Oct 2018; vol. 293 (no. 43); p. 16546-16558

Publication Date: Oct 2018

Publication Type(s): Journal Article

PubMedID: 30219789

Abstract:Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD’s anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD’s mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.

Database: PubMed



23. Cannabis for the Treatment of Epilepsy: an Update.

Author(s): Gaston TE; Szaflarski JP

Source: Current neurology and neuroscience reports; Sep 2018; vol. 18 (no. 11); p. 73

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30194563

Abstract:PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Database: PubMed



24. Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.

Author(s): Friedman LK; Wongvravit JP

Source: Journal of neuropathology and experimental neurology; Oct 2018; vol. 77 (no. 10); p. 904-919

Publication Date: Oct 2018

Publication Type(s): Journal Article

PubMedID: 30169677

Abstract:Anticonvulsant effects of cannabidiol (CBD), a nonpsychoactive cannabinoid, have not been investigated in the juvenile brain. We hypothesized that CBD would attenuate epileptiform activity at an age when the brain first becomes vulnerable to neurotoxicity and social/cognitive impairments. To induce seizures, kainic acid (KA) was injected either into the hippocampus (KAih) or systemically (KAip) on postnatal (P) day 20. CBD was coadministered (KA + CBDih, KA + CBDip) or injected 30 minutes postseizure onset (KA/CBDih, KA/CBDip). Hyperactivity, clonic convulsions, and electroencephalogram rhythmic oscillations were attenuated or absent after KA + CBDih and reduced after KA + CBDip. NeuN immunohistochemistry revealed neuroprotection. Augmented reactive glia number and expression were reversed in CA1 but persisted deep within the dentate hilus. Parvalbumin-positive (PV+) interneurons were reduced in both models, whereas immunolabeling was dramatically increased within ipsilateral and contralateral dendritic/neuropilar fields following KA + CBDih. Cannabinoid receptor 1 (CB1) expression was minimally affected after KAih contrasting elevations observed after KAip. Intracranial coadministration data suggest that CBD has higher efficacy in epilepsy with hippocampal focus rather than when extrahippocampal amygdala/cortical structures are triggered by systemic treatments. Inhibition of surviving PV+ and CB1+ interneurons may be facilitated by CBD implying a protective role in regulating hippocampal seizures and neurotoxicity at juvenile ages.

Database: PubMed



25. Cannabidiol for Epilepsy: New Hope on the Horizon?

Author(s): Sanmartin PE; Detyniecki K

Source: Clinical therapeutics; Sep 2018; vol. 40 (no. 9); p. 1438-1441

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30150078

Available at Clinical therapeutics – from ClinicalKey

Available at Clinical therapeutics – from ProQuest (Hospital Premium Collection) – NHS Version

Abstract:Epilepsy is a common neurologic disorder; it is estimated that ∼50million people are affected worldwide. About one third of those patients are drug resistant, defined as failure to stop all seizures despite adequate trials of at least 2 appropriate medications. There has been an enormous interest in developing antiepileptic drugs with novel mechanisms of action. This review discusses the evidence supporting the anticonvulsant properties of cannabis in humans, focusing on cannabidiol. We begin by exploring the early and somewhat anecdotal evidence that was recently replaced by high-quality data from randomized controlled studies, which subsequently led to the US Food and Drug Administration approval of a purified cannabidiol extract for the treatment of 2 highly refractory pediatric epilepsy syndromes (Dravet and Lennox-Gastaut).

Database: PubMed



26. Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders.

Author(s): Sagredo O; Palazuelos J; Gutierrez-Rodriguez A; Satta V; Galve-Roperh I; Martínez-Orgado J

Source: Biochemical pharmacology; Nov 2018; vol. 157 ; p. 85-96

Publication Date: Nov 2018

Publication Type(s): Journal Article; Review

PubMedID: 30118663

Abstract:The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases. In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds. This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity.

Database: PubMed



27. Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System.

Author(s): Schonhofen P; Bristot IJ; Crippa JA; Hallak JEC; Zuardi AW; Parsons RB; Klamt F

Source: CNS drugs; Aug 2018; vol. 32 (no. 8); p. 697-712

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30109642

Abstract:The endocannabinoid retrograde signaling pathway is widely expressed in the central nervous system, where it plays major roles in regulating synaptic plasticity (excitatory and inhibitory) through long-term potentiation and long-term depression. The endocannabinoid system (ECS) components-cannabinoid receptors, endocannabinoids and synthesis/degradation enzymes-are expressed and are functional from early developmental stages and throughout adolescent cortical development, regulating progenitor cell fate, neural differentiation, migration and survival. This may potentially confer increased vulnerability to adverse outcomes from early cannabinoid exposure. Cannabidiol (CBD) is one of the most studied exogenous cannabinoids, and CBD-enriched Cannabis extracts have been widely (and successfully) used as adjuvants to treat children with refractory epilepsy, and there is even a Food and Drug Administration (FDA)-approved drug with purified CBD derived from Cannabis. However, there is insufficient information on possible long-term changes in the central nervous system caused by cannabinoid treatments during early childhood. Like the majority of cannabinoids, CBD is able to exert its effects directly and indirectly through the ECS, which can perturb the regulatory processes mediated by this system. In addition, CBD has a large number of non-endocannabinoid targets, which can explain CBD’s effects. Here, we review the current knowledge about CBD-based therapies-pure and CBD-enriched Cannabis extracts-in studies with pediatric patients, their side effects, and their mechanisms of action regarding the central nervous system and neurodevelopment aspects. Since Cannabis extracts contain Δ9-tetrahydrocannabinol (Δ9-THC), we consider that pure CBD is possibly safer for young patients. Nevertheless, CBD, as well as other natural and/or synthetic cannabinoids, should be studied in more detail as a therapeutic alternative to CBD-enriched Cannabis extracts for young patients.

Database: PubMed



28. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

Author(s): Szaflarski JP; Bebin EM; Cutter G; DeWolfe J; Dure LS; Gaston TE; Kankirawatana P; Liu Y; Singh R; Standaert DG; Thomas AE; Ver Hoef LW; UAB CBD Program

Source: Epilepsy & behavior : E&B; Aug 2018

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30100226

Available at Epilepsy & behavior : E&B – from ClinicalKey

Abstract:The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Database: PubMed



29. Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

Author(s): Chen KA; Farrar M; Cardamone M; Gill D; Smith R; Cowell CT; Truong L; Lawson JA

Source: The Medical journal of Australia; Aug 2018; vol. 209 (no. 5); p. 217-221

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30092753

Available at The Medical journal of Australia – from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print Holdings: Latest Five years.[location] : RDH,Derby Hospitals NHS Foundation Trust., [location] : Print Holdings Latest Five years. RDH,Derby Hospitals NHS Foundation Trust.

Abstract:OBJECTIVE: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.STUDY DESIGN: Prospective, open label cohort study.SETTING: Three tertiary NSW referral centres with paediatric neurology services.PARTICIPANTS: First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures.INTERVENTION: Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks.OUTCOME MEASURES: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity.RESULTS: Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.CONCLUSION: Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.

Database: PubMed



30. Cannabis for pediatric epilepsy: protocol for a living systematic review.

Author(s): Elliott J; DeJean D; Clifford T; Coyle D; Potter B; Skidmore B; Alexander C; Repetski AE; McCoy B; Wells GA

Source: Systematic reviews; ; vol. 7 (no. 1); p. 95

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 30021618

Available at Systematic reviews – from ProQuest (Hospital Premium Collection) – NHS Version

Available at Systematic reviews – from BioMed Central

Available at Systematic reviews – from Europe PubMed Central – Open Access

Abstract:BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers.METHODS: We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings.DISCUSSION: Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755.

Database: PubMed



31. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

Author(s): Devinsky O; Verducci C; Thiele EA; Laux LC; Patel AD; Filloux F; Szaflarski JP; Wilfong A; Clark GD; Park YD; Seltzer LE; Bebin EM; Flamini R; Wechsler RT; Friedman D

Source: Epilepsy & behavior : E&B; Sep 2018; vol. 86 ; p. 131-137

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30006259

Available at Epilepsy & behavior : E&B – from ClinicalKey

Abstract:OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016.RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Database: PubMed



32. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

Author(s): Szaflarski JP; Bebin EM; Comi AM; Patel AD; Joshi C; Checketts D; Beal JC; Laux LC; De Boer LM; Wong MH; Lopez M; Devinsky O; Lyons PD; Zentil PP; Wechsler R; CBD EAP study group

Source: Epilepsia; Aug 2018; vol. 59 (no. 8); p. 1540-1548

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 29998598

Available at Epilepsia – from Wiley

Available at Epilepsia – from IngentaConnect

Abstract:OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Database: PubMed



33. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

Author(s): Reithmeier D; Tang-Wai R; Seifert B; Lyon AW; Alcorn J; Acton B; Corley S; Prosser-Loose E; Mousseau DD; Lim HJ; Tellez-Zenteno J; Huh L; Leung E; Carmant L; Huntsman RJ

Source: BMC pediatrics; Jul 2018; vol. 18 (no. 1); p. 221

Publication Date: Jul 2018

Publication Type(s): Journal Article

PubMedID: 29981580

Available at BMC pediatrics – from ProQuest (Hospital Premium Collection) – NHS Version

Available at BMC pediatrics – from BioMed Central

Available at BMC pediatrics – from Europe PubMed Central – Open Access

Available at BMC pediatrics – from EBSCO (MEDLINE Complete)

Abstract:BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects.DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Database: PubMed



34. Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

Author(s): Suraev A; Lintzeris N; Stuart J; Kevin RC; Blackburn R; Richards E; Arnold JC; Ireland C; Todd L; Allsop DJ; McGregor IS

Source: Scientific reports; Jul 2018; vol. 8 (no. 1); p. 10154

Publication Date: Jul 2018

Publication Type(s): Journal Article

PubMedID: 29977078

Available at Scientific reports – from ProQuest (Hospital Premium Collection) – NHS Version

Available at Scientific reports – from Europe PubMed Central – Open Access

Available at Scientific reports – from Nature Publishing Group – Open Access

Abstract:Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child’s seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as “effective” versus those rated “ineffective”. Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as “effective”, with no clear differences between extracts perceived as “effective” and “ineffective”. Contrary to family’s expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

Database: PubMed



35. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment.

Author(s): Álvarez Bravo G; Yusta Izquierdo A

Source: Seizure; Aug 2018; vol. 60 ; p. 68-70

Publication Date: Aug 2018

Publication Type(s): Case Reports; Journal Article

PubMedID: 29929108

Available at Seizure – from ClinicalKey

Abstract:Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult that is why Cannabidiol emerged as valid option for treatment of this condition.

Database: PubMed



36. Addition of Cannabidiol to Current Antiepileptic Therapy Reduces Drop Seizures in Children and Adults With Treatment-Resistant Lennox-Gastaut Syndrome.

Author(s): Ostrovsky DA; Ehrlich A

Source: Explore (New York, N.Y.); 2018; vol. 14 (no. 4); p. 311-313

Publication Date: 2018

Publication Type(s): Journal Article; Comment

PubMedID: 29887290

Database: PubMed



37. Investigational cannabinoids in seizure disorders, what have we learned thus far?

Author(s): Ružić Zečević D; Folić M; Tantoush Z; Radovanović M; Babić G; Janković SM

Source: Expert opinion on investigational drugs; Jun 2018; vol. 27 (no. 6); p. 535-541

Publication Date: Jun 2018

Publication Type(s): Journal Article; Review

PubMedID: 29842819

Abstract:INTRODUCTION: The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin, and Δ9-tetrahydrocannabinolic acid. Areas covered:In this review, the authors look at the results of preclinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR, and SCINDEX databases. Expert opinion: Preclinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy-resistant seizures associated with Dravet syndrome and in patients with Lennox-Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future.

Database: PubMed



38. Review of the neurological benefits of phytocannabinoids.

Author(s): Maroon J; Bost J

Source: Surgical neurology international; 2018; vol. 9 ; p. 91

Publication Date: 2018

Publication Type(s): Journal Article; Review

PubMedID: 29770251

Available at Surgical neurology international – from ProQuest (Hospital Premium Collection) – NHS Version

Available at Surgical neurology international – from Europe PubMed Central – Open Access

Available at Surgical neurology international – from Unpaywall

Abstract:Background: Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.Methods: In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.Results: Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.Conclusions: In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.

Database: PubMed



39. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

Author(s): Devinsky O; Patel AD; Cross JH; Villanueva V; Wirrell EC; Privitera M; Greenwood SM; Roberts C; Checketts D; VanLandingham KE; Zuberi SM; GWPCARE3 Study Group

Source: The New England journal of medicine; May 2018; vol. 378 (no. 20); p. 1888-1897

Publication Date: May 2018

Publication Type(s): Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov’t

PubMedID: 29768152

Available at The New England journal of medicine – from Massachusetts Medical Society

Available at The New England journal of medicine – from ProQuest (Hospital Premium Collection) – NHS Version

Available at The New England journal of medicine – from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print holdings: Latest five years: UHDB – Derby site<br><br>Print holdings: 2000 – 2018: UHDB – Burton site

Abstract:BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, an