School of Chemistry, Food Biosciences & Pharmacy Cannabis and epilepsy from recreational abuse to therapeutic use B. Whalley © University of Reading 2007 www.reading.ac.uk Epilepsy and public health • Chronic, progressive neurological disorder characterised by spontaneous, recurrent seizures. • ~10% of people will have a seizure in their lifetime of which ~30% will subsequently develop epilepsy. • Lifetime prevalence ~1%. • Third most prevalent neurological disorder after migraine and Parkinson’s Disease (both ~0.7- 1.2%). • Affects 50 million people worldwide and accounts for 1% of the global burden of disease. 2 Banerjee & Hauser, 2006 Aetiology of epilepsy • ~60% of cases are idiopathic (WHO, 2012) • Remainder are cryptogenic or secondary to insults such as hypoxia (or other trauma) at birth, head trauma, drug use, stroke and CNS infection or tumour. • Age is an independent risk factor and febrile seizure specific to childhood • A small minority are due to specifically identifiable molecular/genetic causes. Rate ratio <1 = protective Banerjee & Hauser, 2006 3 Disease burden and co-morbidities • Example disease burden: $15.5 billion per year in US (CDC, 2008) • Premature mortality is 2-3 times higher in epilepsy patients (maximum reported: 8.8). – Significant causes: SUDEP, status epilepticus, accidents as a consequence of seizure, aspiration pneumonia after seizure, drug toxicity and idiosyncratic ADRs and suicides (Lhatoo et al, 2006) • Co-morbidities include: – Cognitive decline (drug and disease-related) – Anxiety – Depression – Agitation, anger and emotional outbursts – Suicide (5-15x more likely) – ADHD – Reproductive problems (make and female) – Insomnia – Migraine • Co-morbidities more frequent and severe in refractory patients 4 Clinical need for new AEDs • The introduction of new AEDs since 1990 onwards has had no effect upon the number of pharmacologically intractable/refractory epilepsy patients. – Of 525 people with newly diagnosed epilepsy with 2–16 years of follow up, 37% still exhibited seizures at the final clinic visit whilst the remainder were seizure free for Ʀ1 year. – Seizure-free rate did not differ significantly between those treated with a single established drug (67%) and those treated with a single new drug (69%). Thus, new AEDs have not reduced pharmacoresistance (Kwan & Brodie, 2000). • New AEDs achieve some benefit via improved side-effect profiles. • New, better tolerated and more effective AEDs are clearly required to benefit the 15- 20M people experiencing pharmacologically refractory seizures. http://www.ncbi.nlm.nih.gov 5 Rational drug design • How have successful drugs been discovered? – Serendipity e.g. valproate, levetiracetam – Secondary use of existing drugs e.g. phenobarbital – Screening related compounds e.g. phenytoin, ethosuximide • ‘me too’ drugs – Modification of existing drugs e.g. oxcarbazepine, pregabalin – “Rational”/target oriented design e.g. vigabatrin, tiagabine • The least successful have come from rational/target-based development. • Related and modified compounds are typically only effective in epilepsies that already respond to existing treatments. 6 Historical use of cannabis in epilepsy • 1100AD: al-Mayusi makes first written record of its use for this purpose • C15th: Ibn al-Badri notes “the epileptic son of the caliph's chamberlain” was treated with Cannabis and “it cured him completely, but he became an addict who could not for a moment be without the drug” • C19th: O’Shaughnessy, McMeens, Moreau and Reynolds independently tested the efficacy of a crude extract against seizures. • J.R. Reynolds, Queen Victoria’s personal physician said Cannabis is “the most useful agent with which I am acquainted” in the treatment of “attacks or violent convulsions,” which“may recur two or three times in the hour,” claiming that such attacks “may be stopped with a full dose of hemp” 7 Evidence from preclinical models Publis hed resu lts of cannabinoid effects upon w hole animal models of seiz ure and epileps y Grosseffect ( pr oco nvul s an t = Si ngl e comp oun d o r co- C ann abi noi d dos e s RED, Speci es S t r a in A ge M odel ty pe D ise as e mode l Method ad ministration tested D os e t imi ng R o u te E ffe ct an ti con vul s ant = N ot es Ref er e nce GREEN,no effect = BLAC K) Phy to can nab inoi ds ' 9-T HC 1 0mg/kg 5- 13 5 mi ns bef or e t es t s t i m ul us 1 0 mg/ k g 15- 45 m i ns bef or e t es t s t i m ul us re duce d n um be r of a ni m als s how i ng s i gns of sei z ur e s 2 .5- 10 m g / k g r e du c e d num b e r o f a n im a l s s h ow i ng s i g n s of Mouse C57B L/6 A dul t A cute G ene ra li sed sei zur e Audiogenic priming 1.25-10 mg/kg 15 m i ns bef or e t es t st i m ul us i. p. M od e l us e s a pr i m in g s t i m ul us a t P+ 1 9 Bog gan et al . , 1973 se izu r es followed by atest stimulus at P+28 1 0 mg/ k g 15- 45 m i ns bef or e pr i m in g st i m ul us s how ed THC 1 0mg/kg 15 - 90 m in s be f or e pr im i ng s t im u lu s r e duce d si gns of s ei z ur es 1 0- 50 mg/k g 15 - 90 m in s a f t e r pr im i ng s t im u lu s N o ef f ect Mouse QS A dul t A cute G ene ra li sed sei zur e PTZ 1-80mg/kg 30 m i ns bef or e t es t i ng N o ef f ect PT Z thr es h ol d m ode l 30 m i ns bef or e t es t i ng p. o. > 160 m g/ kg p r ot ect ed agai ns t hi ndl i m b e xt ens i on 2 5 - 200 mg /kg 30 m i ns bef or e t es t i ng 2 0- 75 m g / kg s i gni f i cant ly i ncr eas e d hin dl imb e xt ens i on St an dar d MES mo del 2 0mg/kg 30 m i ns bef or e t es t i ng i.v. Significantlydecreased hindlimb extension 5 0 m g / k g T H C, 50m g / kg TH C p. o. w as pr ocon vul s ant alo ne TH C pl us C BD pl us CBN 5 0mg/kg CBD , 50 30 m i ns bef or e t es t i ng p. o. Significantlydecreased hindlimb extension a n d 5 0 m g / k g CB D nor CBN p .o . a r e m g / kg C BN an ticon vulsant at these d oses Che sher et al . , 1974 Mouse QS A dul t A cute G ene ra li sed sei zur e MES 50mg/kg THC (with a Aproconvulsant THC dose (50 mg/kgp.o.) r ed uces AED ED 50. S uppo r ts ear l i er pr o pos al TH C pl us P HN r an ge on phe nyt oi n 30 m i ns bef or e t es t i ng p. o. S ign if i cant l y r e duce d p hen yt oi n E D50 t hat canna bi s an d p hen yt oi n i nt e ract d oses) synergistically (Loewe et al.,1947) 5 0 m g / k g T H C, 50 A ED ED50 f ur t he r r edu ced f ro m t hat mg/kgCBD (with a T H C pl us P HN p lu s CB D range ofphenytoin 30 m i ns bef or e t es t i ng p. o. S ign if i cant l y r e duce d p hen yt oi n E D50 ach ie ved by coad m ini s t r at io n of TH C wi t h ph eny to in d oses) Mouse CF-1 A dul t A cute G ene ra li sed sei zur e MES THC 1 -1 00mg/kg 12 0 mi ns bef or e t es t i ng i. p. S ign if i cant pr ot ect i on agai ns t s ei z ur es Bl ock ed by SR141 716A Wal lace e t al ., 2001 2 5- 50 mg/k g TH C pl us T H C: 1 20 m i ns ; P BL : 60 m i ns b e f or e THC:p.o., Po t ent i at io n g re at er t ha n th at caus e d by CBD TH C pl us P BL S ignificant potentiation of PBL effect 9 .3-40 mg/kg PB L testing PBL: i . p. r ep or t ed in s am e s t udy Mouse QS A dul t A cute G ene ra li sed sei zur e MES 2 5 m g / k g T H C, 25 Che sher et al .