Pharmacology of canabinoids in the treatment of epilepsy

Revi ew Phar maco logy o f canna binoid s in the trea tmen t of epilep sy Tyle r E. Gaston a , \u204e , Da niel Fri edm an b a Dep artmen t of Ne urol ogy, Di vis ion of Ep ilep sy, Un iver sity of Al abam a at Bir mingh am, Bi rmi ngham , AL, US A b Com prehe nsi ve Epil epsy Cent er, D epar tmen t of Neu rolo gy, NYU La ngon e Med ical C ente r, New Yo rk, NY , USA abstract article info Arti cle his tory : Rec eive d 17 Octo ber 20 16 Rev ised 9 Nove mber 201 6 Acce pted 1 1 Nove mber 201 6 Avai labl e onlin e xx xx The use o f cann abis pro duc ts in the tre atme nt of epil epsy ha s long be en of int eres t to rese arche rs and cli nic ians alik e; ho weve r, unt il rece ntl y very li ttl e publi she d data w ere av aila ble to s uppo rt it s use. Th is art icle summ ariz es the ava il ab le scie nt i \ufb01 c d ata of pha rmac ology fr om huma n and anim al studi es on the maj or canna bino ids whi ch have been of int erest in the trea tment of epilep sy, includ ing \u0394 9-tetrah ydrocanna binol ( \u0394 9-THC), can nabidiol (CBD), \u0394 9-tetrahydrocannabivarin ( \u0394 9-THCV), cannabidivarin (CBDV), and \u0394 9-tetrahydrocannabinolic acid ( \u0394 9-T HCA). It ha s long been kn own that \u0394 9-T HC has part ial agon ist activi ty at the endo canna binoid rece ptors CB1 an d CB2, tho ugh it also binds to oth er targe ts whic h may modu lat e neuro nal exci tabil ity an d neuro in \ufb02 am - mati on. Th e actio ns of \u0394 9-TH CV an d \u0394 9-TH CA are less w ell und erst ood. In con tra st to \u0394 9-THC , CBD ha s low af - \ufb01 ni ty for CB1 and CB2 re cep tors an d oth er targe ts have be en inve stig ated to ex plain it s antic onvu lsan t proper tie s incl udi ng TRPV1 , volt age gate d potas sium an d sodiu m chan nels , and GPR5 5, among o ther s. We des crib e the ab- sorp tio n, dist ribu tion, me tab olis m, and ex cretio n of eac h of the above me ntion ed comp oun ds. Can nabi noid s as a whol e are very li pophi lic, r esult ing in decr ea sed bioav aila bili ty, wh ich pres ent s challe nges in op timal dr ug deliv - ery. Fina lly, we di scuss the lim ited drug- drug inter action dat a availab le on THC and CB D. As canna binoids an d cann abis -bas ed produ cts ar e studie d for ef \ufb01 cacy as an ticon vuls ants , more inve stig atio n is need ed rega rdin g the spec i \ufb01 c tar get s of ac tio n, optima l drug del iver y, and pot ent ial dru g-dru g inter actio ns. This ar tic le is part of a Spec ial Is sue title d Cann abin oid s and Epile psy Pub lish ed by Elsev ier In c. Keywords : Cann abin oid s Tet rahy droca nnab inol Tet rahy droca nnab ivar in Cann abid ivar in Tet rahy droca nnab inol ic acid Pha rmaco logy 1. Int rod uctio n There has long been intere st in the use of cannabis pro ducts in the trea tmen t of various me dica l conditi ons, inc ludi ng epileps y. After ce n- turies of anecdotal reports of improvemen t with cannabis products but lim ited hu man data to suppor t their use , ther e has bee n a vast ex- pansi on of resea rc h (includin g recent do ub le -b li n de d, placebo c on - trolle d trials ) investig ating the pharmacol og ic poten ti al of various cannabis products as anti-epileptic drugs (AEDs). The cannabis plant ( Canna bi s sativ a ) consi s ts of around 100 compound s known as phy toca nna bino ids , and the vas t major ity of re sear ch on can nabis prod- ucts in the treat men t of epilepsy ha s been done on th e main psycho acti ve compone nt, \u0394 9-Tet rahydr ocanna bidiol ( \u0394 9- THC). Th ere has been more recen t inte re st in inve st ig a ti n g thos e compo un ds whi ch do no t ha ve psy cho acti ve pr oper tie s as pot ent ial A EDs [1 ] ,n a m e - ly cann ab idio l (CBD) , but also inc lu ding \u0394 9- tetr ahy droca nna biv ari n ( \u0394 9-TH CV), cann abidi varin (C BDV), an d \u0394 9-tetr ahydro cannab inoli c acid ( \u0394 9-T HCA). These ph ytoca nnabino ids are structu rally simil ar (see Fig. 1 ), but diff er in regards to th eir pharma cology and acti ons by which they have antic onvulsa nt effect. Here , we summarize th e literature to date on th e mech ani sms of ac tion, metabo lism , and int erac tions of the abo ve list ed majo r phytoc anna bino ids, in or der to gai n a bett er unde r- standi n g of the proposed pharm ac olo gy of cann ab i s produc ts whi ch hav e pote ntia l for th e trea tm ent of ep ilep sy . 2. Mec hani sm of actio n 2.1. \u0394 9-TH C The pharm acolog y of \u0394 9-THC is perh aps the bes t understoo d of all the phytoc an n ab in oid s and has been st ud ie d ext en si ve ly sin ce its syn the sis in 1 964 [2 ] . The co mp ound i s respo ns ible fo r the ma in p sych o- tropic effects of cannab is and use of synthetic, high-af \ufb01 nity analogues led to th e disc ov er y of its CNS targe ts and id ent i \ufb01 c ati on of the Epi leps y & Beha vio r xxx (201 6) xxx \u2013 xxx Abbrev iation s: (AED) , Anti-epile ptic drug; (T HC), \u0394 9- Tetrahy drocanna bidio l; (CBD), cann ab idio l; ( \u0394 9- TH C V ), \u0394 9-te trahy d r oc annab iv arin ; (CBDV ), can n ab idiva r in ; ( \u0394 9- THCA ), \u0394 9- tetra hydr ocan nabi noli c acid ; (TR P), tra nsie nt re cept or pote ntia l; (V GCC) , volt - age ga ted calc ium chan nel; ( VGSC ), volt age gate d sodi um chann el; (V GKC) , volta ge gated pota ss ium chann el ; (PPAR \u03b3 ) , pero xi some prol i fe r at or-ac ti vated rec e p to r gamma; (DL G \u03b1 ), dia cylg lyce rol li pase al pha; (C OX), cy cloo xyge nase. \u204e Corr esp ondin g aut hor at : UAB Epi leps y Cent er, Un iver sit y of Al abama at Birm ingh am, Depa rtm ent of N eurolo gy, 1 719 6 th Aven ue So uth, CI RC 312 , Birm ingh am, AL 3 5249 -002 1, USA. E-m ail ad dress : tegaston@uab mc.edu (T. E. Gas ton) . YEBE H- 0511 0; No of Pag es 6 htt p:// dx.d oi.or g/10 .10 16/j. yebe h.20 16. 11.0 16 1525 -50 50/P ubli shed by Els evie r Inc. Cont ent s lists av ai labl e at Scie nceD ire ct Epil epsy & Be havio r journal homepage: www.elsevier.com/locate/yebeh Please cite this arti cle as: Gaston TE, Friedman D, Pharmacology of cann abinoids in the treatment of epilepsy, Epilep sy Behav (2016), http:// dx. doi. org/1 0.1 016/ j.ye beh. 2016. 11. 016 endoca nnab inoid syst em [3,4 ] . The best stud ied tar gets of \u0394 9-TH C are the end oc anna bino id receptors, CB 1R and CB2R, where it se rve s as a partial agonist at sub-micromolar concentrations [5] . Primarily found in the presynap tic terminals of CNS neuro ns, CB1 receptors are highly exp res sed in limb ic stru ctu res (amy gda la, hip poc ampu s, cing ulat e) , ce- rebr al cor tex , basal ga ngli a and sel ect are as of the mi dbr ain and me dul la [6] an d are a G-prote in-cou pled re ceptor s which can modu late neur o- tra nsmi tter r elea se. Syna pti c acti vity mod ula tes the on- de mand sy nthe - sis of anan da mi d e (AE A) and 2-arac h idon oy l- glycero l ( 2 -AG) , th e endo geno us ligan ds for the CB -rece ptors in the post-s yna ptic ter mina l and this signalin g m ec ha n is m med ia te s sever al forms of shor t- and long -t erm sy nap tic pl astic ity [7] . The cr yst al st ruct ure of th e CB1 r ecep - tor has re cently be en descri bed, whi ch may facili tate the de sign of the new CB 1 recep tor li gands fo r ther ape uti c use [8] . The m ajo r expr essi on of CB2 rec epto rs is in perip h er al immune tissues such as the spleen, lymph nodes , and bone marr ow as well as on B-cells , macro ph ages, and microglia where activa ti on may lead to immun osup press iv e re- spons es [9] . The re is a lso li mi t ed CB 2- re c ep to r ex pres sion in CNS neur ons includ ing in the brai nstem [1 0] and hippo campus [1 1] wher e activation can affect neuron al excitability. In addition to its effects on the ca noni cal endo cann abin oid rec eptor s, \u0394 9- THC bin ds to an d modu - lates several ot her receptor targets in submi cro mo la r or micromo la r conce ntratio ns including th e transient rece ptor poten tial (TRP) catio n chan ne ls TRP A1, TRP V2, an d TRPM 8; the or phan G -co uple d prote in re- cept or GPR55; 5- HT 3A recept or; the perox isome prol iferat or-acti vated recep to r gamma (PPAR \u03b3 ); \u03bc -a n d \u03b4 -opioid recep to rs , \u03b2 - adr eno rece pto rs, some su bty pes of Ca ,Ka n dN ac h a n n e l s [5 ] . The fu nc- tio nal co nseq ue nces o f acti vat ion o f these targe ts by \u0394 9 -TH C in viv o are not co mp lete ly unde rst ood. Eve n befo re th e pharm ac ology of \u0394 9- THC was d eline at ed, in vivo an d in vitro studie s demonstra ted that the compoun d may have eff ects on experime ntal models of sei zures. Many of th e studies in acute seiz ure mode ls demons trat ed antico nvulsa nt effect s of \u0394 9-THC o r modu latio n of a ntico nvu lsa nt eff ect s of trad iti ona l ant i-se izu re dru gs tho ug h othe rs demons tr a te d no ef fe c ts , mix ed ef fects or pr oc onv ulsant ef fe c ts [1 ] . Ther e is CB1-r ecep tor exp ressi on in huma n and exper ime ntal epi lepsy Chemical Structure Potential Targets of Action in Epilepsy \u0394 9-tetrahydrocannabidiol (THC) CB1 CB2 TRPA1 TPRV2 TRPM8 GPR55 5-HT 3A PPAR \u03b3 \u03bc -a n d \u03b4 -opioid receptors \u03b2 -adrenoreceptors VGCC, VGKC, VGSC \u0394 9- tetrahydrocannabinolic acid (THCA) TRPA1 TRPV4 TRPM8 DLG \u03b1 COX 1, COX 2 \u0394 9- Tetrahydrocannabivarin (THCV) CB1 CB2 GPR55 TRPA1 TRPV1-4 Cannabidiol (CBD) TRPV1 VGCC, VGSC 5-HT 1A , 5-HT 2A GPR55 Adenosine receptors A 1 and A 2 VDAC1 TNF \u03b1 Cannabidivarn (CBDV) CB1 and CB2 \u2013 independent \u2013 more data needed Fig . 1. Chemic al st ruct ures of majo r phyt ocan nabi no ids an d their pos sible t arge ts by wh ich t hey exe rt an ticon vuls ant e ffect s. 2 T.E . Gast on, D. Fr iedm an / Epi leps y & Beh avio r xxx (20 16) xx x \u2013 xxx Please cite this arti cle as: Gaston TE, Friedman D, Pharmacology of cann abinoids in the treatment of epilepsy, Epilep sy Behav (2016), http:// dx. doi. org/1 0.1 016/ j.ye beh. 2016. 11. 016 [12] . The anti-seiz ur e effects of synthetic CB1-re c ep to r blocke rs and modu lat ors of endoca nnab ino id metabo lism ha ve also sh own anti con- vulsant effect s in some but not all studies [1,13] . The mixed results in sei zure an d epile psy mo del s of \u0394 9 -T HC and i ts a na lo gu es l ik ely r e \ufb02 ects the co mplic ate d phar maco logy of the co mpo und as wel l as the di verse effects of endocannabinoid signaling in the CNS, including impact on both GABAergic and glutamatergic signaling [12] . Furthermore, there is eviden ce of homeostati c control of CB1-r eceptor express ion and ef- fect s in acu te seizu re mod els ma y diffe r from chr oni c model s. Dow nre g- ulation of CB1-receptor expression with chronic act ivation may alter drug ta rge ts or change t he func tiona l impac t of \u0394 9-TH C. Only one ca se serie s of 5 patients exa mine d the effects of iso lated \u0394 9- THC in human epil epsy [1 4] and most ca se repo rts and ca se serie s sugg estin g ef \ufb01 ca cy have us ed ex tr act s from cann ab i s or ot h er pr ep ar a ti on s contain in g othe r can nabi noi ds [15] . 2.2 . \u0394 9-THCA Delta -9 -t et rahydro c a nn a bi nol ic acid ( \u0394 9 -T H CA)i s the metab olic precur sor of \u0394 9-T HC, an d it is foun d in hi gh conc ent rat ions i n livi ng can - nab is pl an ts . I t i s decar bo xy la te d t o \u0394 9-TH C throu gh dry ing or bur ning of the plant and it is thought to hav e little psychoactive pro perties. In vitro experiments have demonstrated activ ation of TRPA1 and TRPV4 chan nels and bl ockade of TR PM8 chan nels at low mic romola r concen - trations. It inhibits diac ylglycerol lipase alpha (DLG \u03b1 , the key biosyn- thetic enzyme for the endocannabinoid 2-AG) and cyclooxygenase-1 and 2, al bei t at conce ntr atio ns N 10 \u03bc M [16 ] . Litt le is know n about the ef - fects of th is c om po un d on epil epsy thou gh there are anecdo te s an d clai ms o n the int ern et su gges ting an ti -sei zur e effec ts [1 7] . 2.3 . \u0394 9-THCV Delt a-9- tetr ahydr ocan nabi var in ( \u0394 9 -THC V) is anot her ca nnab inoid fou nd in canna bis in var ying am oun ts. Li ke \u0394 9-TH C, it is a par tial ag oni st of CB 1/2 r ecep tors an d has s ome ac ti vity o n GPR55 , TR PA1 and TRP V1 \u2013 4 rece pt ors at su bmi cro molar or low micr omo lar co ncent rat ion s [5] .O n e study has shown anti -seizu re effe c ts in in vitro and in vivo anima l mod els [1 8] . 2.4 . CBD Unlike \u0394 9-TH C, CBD ha s a very low af \ufb01 nit y for the e ndoca nn abino id rece ptors by wh ich \u0394 9-TH C exerts i ts most me anin gful an ticonv ulsa nt effects [19 ] . A series o f exper ime nts sho wed th e anti conv uls ant pro per - ties of THC a nd CBD in the m ax ima l electr os hock and pilocarp in e models of epilepsy, elucidate d that the anticonvulsant activity of THC was mo dul ate d by it s act ions o n the C B1 rece pt or, and tha t the m echa - nism by whi c h C BD ha s anti convu ls a nt p ro pe rt ie s wa s di f fe re n t [20 \u2013 22] . Therefore, resear ch on CBD mechanisms has mainly been fo- cuse d on CB1 - and CB 2-de pend ent m echan ism s of acti on. To date, a num ber of propo sed mecha nisms of act ion for CB D with pote ntiall y antico nvulsa nt prop ertie s have been iden ti \ufb01 ed , thoug h the exact mechanism by which CBD possesses anticonvulsant activity re- mai ns unk now n. Can na bidi ol act s as an ago nist at huma n TRP cha nnel s, spe ci \ufb01 ca ll y in the TRPV 1 chann el, whi ch is in par t resp onsi ble for ca lci - um cha nn el modulation [23,24] . How the TRPV1 cha nn el may be in- volved in ep ile psy and th us how this acti on of CB D may carry anticon vulsant effec ts is less clear [25] . Curren tly, there is not enough evidence to support that CBD's agonist activity at TRPV1 can account for it s antico nv ulsan t effe ct [26 ] . Cannabi diol has a numbe r of action s on ion cha nnels whi ch are tar get ed by othe r anti -seiz ure dr ugs. C anna bid iol blo cks hu man T-t ype volta ge ga ted cal c iu m ch a nn el s ( VG CC ) [27] . Th es e low vo lt a ge - activated channels are also blocked by a sel ect number of AEDs su ch as zoni sami de and et hosuxi mide , thou gh othe rs such as lev etir aceta m, lamotrigine, and eslica rbazepine target other VGCCs (L-, P/Q-, and N- type ) [2 8] . Can nab idio l also has vo ltag e gat ed so diu m chan nel (V GS C) bl ocki ng abilities in vi tro , but this ac ti on doe s not ap pear to nece ssar ily co nfer an ant ico nvul san t effect in v ivo . Recent r ese arch ha s indica te d that CBD ca n pre fere nti all y targe t resur gen t sodi um curr ent s over pe ak tra nsie nt cur- rent s gene rat ed by both w ild- type Na v1.6 as w ell as the abe rra nt res ur- gent and pe rs is tent current generat ed by Nav 1 .6 mutant channel s (whi ch can be se en in synd romi c epile psi es such as Dr avet Sy ndro me) [29] . Given that recent Phase 3 Tri als of CBD for the treatme nt of both Dravet and L ennox -Ga staut Syndrome [30,31] have been completed, the action on VGSCs should certainly be investigated further and is a plausib le mec h an is m of action by whic h CBD exer ts anticonvu ls a n t properties in th ese disorders. Other potential mechanisms for CBD's anticonvulsant abi lities in- clud e modu lati on of var ious re cept ors. Ca nnab idiol e xhib its af \ufb01 nity fo r sero to n in rec ep to rs 5- H T 1A and 5 -HT 2A . Tho ugh thi s is no t a conv enti on- al targ et for AE Ds, the d rug fen \ufb02 ur amine (w hich i s a poten t 5-HT re leas - er activating mul tiple 5-HT receptor sub types, including 5-HT 2A ) may be an effec tive tre atm ent for se iz ures in Dra ve t Sy n dr om e [3 2, 3 3] . Other sugge st ed mecha n is ms of CBD which could be an ti - epi lept oge nic inc lude an tag oni sm at G-co upl ed pro tein re cep tor pro tei n 55 (GPR55), modulation of adenosin e (A 1 and A 2 ) receptors, voltage- depen dent anion -sele ctive chann el protei n 1 (VDAC1), an d tumor ne- crosi s fac to r a lp ha ( TNF \u03b1 ) release , th ou gh mo re data are needed in order to determine not only CBD \u2019 s act ion on these but als o th e ro le the y may play i n epile psy an d other me dica l cond itio ns [34 \u2013 37] . 2.5. C BDV Ver y litt le dat a ex ist on the pro pose d mech an isms of acti on of C BDV (the propy l vari ant o f CBD) , tho ugh i t is pre sum ed its ac ti ons ar e simi lar to CBD. Of im porta nce, howev er, is tha t CBDV in isol ation h as been show n to ha ve ant iconvu lsan t pro perti es in ma xima l elect rosho ck and audi og enic se izu re mode ls in mice an d PTZ and pi loca rpi ne-i nduc ed sei - zur es in rat s [38] . And, t houg h sp eci \ufb01 c mecha nis ms for CBD V's an tico n- vulsant properties have not yet been elucidated be yon d its chemical simil ar it y to CB D, CB DV 's mec hanism al s o se em s to be CB rece ptor- indepe ndent. A study com paring the an ticonvu lsant activity in ca nna- bis -de riv ed bot anica l dr ug subs tan ces (B DS s) rich in CB DV bu t also co n- tainin g THC and p uri \ufb01 ed CBDV s how ed that the BDS s had gr ea te r af \ufb01 nit y to the CB1 re cept or th an the pur i \ufb01 ed C BDV [39] . 3. Metabo lism 3.1. TH C The p harma co kine tics o f \u0394 9-THC ar e perha ps bes t stu died of al l the phy toca nna bino ids . Abso rpt ion of \u0394 9-TH C i s signi \ufb01 cant ly depe nd ent on the route of administr at ion . Smoked \u0394 9-T HC has a bi oa vaila bi li ty of ~ 25% with a rapi d time t o pea k plas ma le vel s (6 \u2013 10 min) . Inha led or va- porized \u0394 9-THC has simi lar absorption an d single dose kinetics with bio ava ilabi li ty of 10 \u2013 3 5% repo rte d in the lite ratur e. Or al admi nis trat ion has a bi oavai labi lity of ~ 6% and va riabl e thou gh solu tio ns wit h sesame oil or glycoch ol ate may show improve d ab so rp tio n . Time to Cmax is much longe r than for smok ed or vaporiz ed \u0394 9-THC, be tw ee n 2 an d 6h [40] . Sublingual admini stration using an oral mucos al spray such as nabiximo ls, show similar bioavailabili ty and single dos e kinetics as oral \u0394 9- THC th oug h per haps w ith l ess var iab ili ty [41 ] . Highly lipophilic, \u0394 9- THC is r apid ly di str ibut ed thr oug hout t he bo dy. The vol ume of distr ibut ion is estima ted to be 3.4 L/kg and 95 \u2013 99% is pro tein-b ound [42] . Signi \ufb01 cant am ount of \u0394 9- THC i s store d in adip ose tiss ue w here i t can be s lowl y rele ased i n the bl ood ov er day s in ch roni c users [43] . \u0394 9- THC can al so cros s the plac ent a [40] . \u0394 9-TH C is hydrox ylated i n the liver by CYP2 C9, 2C19 , and 3A4 iso- zymes into 11-OH-THC which is then further transformed to over 30 3 T.E . Gast on, D. Fr iedm an / Epi leps y & Beh avio r xxx (20 16) xx x \u2013 xxx Please cite this arti cle as: Gaston TE, Friedman D, Pharmacology of cann abinoids in the treatment of epilepsy, Epilep sy Behav (2016), http:// dx. doi. org/1 0.1 016/ j.ye beh. 2016. 11. 016 meta bolit es. In add ition , glucor onidat ion is res pons ible for mo st of the phase II metabol ism of \u0394 9-THC. About 65 % of \u0394 9-THC metabo lites are exc rete d in the fece s and 25 % in the uri ne. The re is also e vid ence of ex - trahepatic metabolism of \u0394 9-THC in tissues that express cytochrome P450 enzy mes such as the brain [42] . The termina l half-li fe of \u0394 9-THC is esti mat ed to be 25 \u2013 36 h [44] . 3.2 . \u0394 9- THCA an d \u0394 9-THCV Littl e is known about the pharmac okin etics of \u0394 9-THCA and \u0394 9- THCV in h uman s though a phase II trial of \u0394 9-THCV in patients with typ e II di abet es wa s rece ntl y comp let ed (N CT02 053 272) . 3.3 . CBD/ CBDV Like \u0394 9-T HC, CB D and CB DV ha ve lo w wate r sol ubil ity an d poo r oral bio avai lab ilit y, esti mate d to be 6% in huma ns [45 ] , maki ng oral ad min is- trat ion less th an favor able. Th is is due to signi \ufb01 cant \ufb01 rs t-pas s meta bo- lism in the liver and erratic absorption from the gastrointestinal tract leadi ng to unreliab le pharmacokin etics [34] . Despite this, CBD and CBDV have relatively rapid absorption with peak concentra tions seen aro und 2 h af ter o ral ad mini str atio n in an imal ph ar maco kine tic s tud ies [46] . Cannabi diol has and is bein g delivered in oil- based capsules and oil-ba sed suspen sions in hu man studies , notably the se same oil-ba sed suspe nsion Epi diolex ®. Other ro utes of admi nistrat ion of CBD for pa in indic ati on s have b ee n inve st ig a te d inclu d in g nasa l, s ubl in gu a l, an d transd er m al applic a ti on . In an animal study, intr a nas al CBD wa s absorbed within 10 mi n with a bio ava ilability of 34 \u2013 46%, and ste ady stat e pla sma co nc entr ati ons we re achi ev ed wit h tran sd ermal gel ap pli - cat ion at a mean o f 15.5 h [47 ] . Cannabi di ol has a h ig h vo lu m e of distri but ion (a ppro x im a te ly 32 L/ kg), and is v ery l ipo phil ic and highl y pr otei n-bo und , whi ch di ctat es its patte rn of distribu tion. There is rap id distribu tion to brain and adi- pos e tiss ue and abo ut 10% is boun d to red bl ood cel ls [48 ] . Given its lipo- philic it y, concer n has been rais ed rega rd in g th e po ss ib il it y of accu mu lati on ov er time with c hroni c use , espe cial ly in thos e with hi gh adi posi ty [3 4] . Like o ther ca nna bino ids , CBD is hepat ic ally me tabo lize d, with e xte n- siv e invo lvem ent of the cy toch rome P 450 sy stem. A fte r absor pti on, it is rap idl y hydr oxy late d to 7-OH- CBD. Th e enzy mes CY P2C 19 and CYP 3A4 are p rim aril y resp ons ibl e for the hydr ox ylat ion, with pot enti al inv olv e- ment o f CYP1A 1, CY P1A 2, CYP2 C9, an d CYP2D 6 [49] . 7 -O H-C a nn abi di ol is the n furt her met abo lize d by the liv er and then th es e meta boli tes are excr eted in th e feces, wi th a small po rtion be ing excre ted in the ur ine. Half-life in humans is estimated to be 18 \u2013 32 h [48] . Metabolism data on CBDV are scant, but in an animal pharmacokinetic study, the half- life w as note d to be si milar to t hat of C BD [46] . 4. Int eract io ns 4.1 . \u0394 9- THC Beca use it is prim arily me taboli zed by CYP 2C9, 3A4 an d, to a lesser ext ent , 2C19, dru gs whi ch ind uce or inh ibi t these cy to chro me P45 0 iso- zyme s may af fect \u0394 9- THC me tabo li sm. Fo r insta nce, co admi ni strat ion o f valproate, a potent CYP2C9 inhibitor, can theoretically potentiate the psy cho trop ic effe ct s of \u0394 9-T HC by decr eas ing pla sma cl earan ce . Some in vitr o ev idence exists th at \u0394 9- THC is an inh ibi tor of CY P2C 9, 2C19 , 3A4, and 1A2 at conc entr ations of 26 \u2013 44 \u03bc M [50, 51] th ough on e in vitro study dem onst rate that \u0394 9-THC increased the metabolism of phe nyt oin, a CYP 2C9 su bstr ate [5 2] . The cl inic al sig ni \ufb01 cance of thi s i n hi- bit ion i n huma ns is no t kno wn and t here w ere no signi \ufb01 ca nt drug -dr ug int erac tio ns repo rte d in the clini cal de velo pmen t of nabi xamo ls, whi ch cont ai ns 50% 9-T HC [51] . How eve r, the re ar e no hu man da ta o n the i m- pact of \u0394 9- THC on se rum ant i-se izu re drug l evel s. 4.2. C BD Cannabidiol has a potent effect on particular CYP enzymes, which cou ld ha ve im plica tion s fo r phar mac olog ic int erac tio ns wi th ot her med - ica tio ns (part icu larl y AEDs) . CBD has be en sho wn to be a potent i nhib- itor of CYP2 C19 , CYP2D6, a nd CYP 2C 9, an d ma y inh ib it memb ers of the C YP3 family [28 ,49, 53, 54] . Repeat ed ad mini str atio n of CBD may in- duce me mbers of the CYP 2B famil y in animal mod els [34] . No int erac- tion d ata ex ist on CBDV. To dat e, t here ar e lit tle da ta on dru g int erac tio ns wi th CBD , parti cu- larly in humans. A ph a rm a cod yn amics a nim a l s tu dy using maxi ma l elec tr ic sho ck and a udi ogeni c sei zur e mode ls sho wed t hat CBD pot enti - ate d the ant iconv ulsa nt ef fect s of pheny toin by t wo-f old, an d mode stly potentiated the effect of phenobarbital. Cannabidiol also reduced the antic on vuls a nt proper ti es of chlordia zep ox id e, clon azep a m, and ethosuxi mide [55] . A recently published article revealed a clear drug- drug intera ctio n betw een CB D and cl obaza m in a gr oup of 1 3 pedia tri c patien ts . C lob az a m and N -d esmeth yl cl ob azam (acti ve m et a bo li te of clo baza m) leve ls incr ease d in respo nse to incre asi ng dose s of CBD, and subjects more frequently repor ted sedation [56] . This interaction was als o ide nti \ufb01 ed in a g roup o f 11 ad ults a nd 6 ch ildr en tak ing co nc omit ant CBD and cloba zam in an open-lab el study [57] In terac tions w ith other AEDs have not been investigated, though one could hypothesize that AED s which ar e met abol ized by en zyme s that ar e indu ced or inh ibi ted by CBD could be affected . Once pote nti a l inte ra ct ion s are identi \ufb01 ed , they then need to be evaluated in the c lin ica l setting to determine if the y are cli nica lly si gni \ufb01 cant . 5. Conc lusio n Ther e is accumu lating evide nce that so me can nabino ids have ant i- convu lsant prope rties in animal model s of seizures and emergin g evi- dence for ef \ufb01 cacy in human epil epsies. Despite thi s empiric evidence, the mecha nisms by which these com pounds exe rt anti-seizu re effects are poorly understood. The major canna binoids have multiple targets wit hin th e CNS an d can mo dul ate ac tiv ity of neuro ns, g lia, a nd micr og lia and it is unknow n which me chani sm(s ) are crit ical fo r therap eutic ac- tions. Th e pharm a cok in etic prope rt ie s of \u0394 9-T HC , \u0394 9-T HCA , \u0394 9- THCV, CBD, and CBDV also present unique challenges to use as thera- peutic agents including low bioavailability and potentially erratic ab- sorptio n in oral formul ations, signi \ufb01 cant accumu lation in adipose and othe r tiss ue s, and i nter act ions w ith ot her d rugs me ta boli zed by t he cy- tochrome P45 0 system. Some of the se problems may be ove rcome by nov el de live ry sys tems (or omuc osal , tran sde rma l) or thr oug h syn the sis of rela ted comp ound s with opt imi zed prop erti es. Howe ver, t he poten- tial i nter act ions wi th othe r ant i-se izu re drug s pose a par ticu lar pr oblem for pa tie nts wi th treat ment -r esis tant e pile psy for w hom po lyph arm acy is th e norm. For ins tan ce, in t he case of cl oba zam, e ffec ts on t he meta b- olism of the metabolite N -de smet hylcl oba zam ma y pot enti ate me dica - tion side effects or confound interpretation of ef \ufb01 cacy results [26,56] Finally , as the recre ati on al use of cannabis expa nd s, it will becom e mor e impo rt ant to u nder sta nd ho w com pou nds in the p lant may af fect the rape uti c agen ts an d bett er scr ee ning , coun sel ing an d mon ito ring w ill be ne cess ar y. Disc losu re s Dr . Gasto n recei ves sa lary sup po rt from t he State o f Alaba ma (Car ly 's Law ) for her wor k in the UAB CBD pr ogr am, an ope n-lab el stu dy of CBD in the tr eat ment of ref rac tory epi le psy. Dr . Frie dma n rece ive s sala ry su ppo rt for co ns ultin g an d cli nica l tri al related activities performed on behalf of The Epilepsy Study Consor - tium, a non-pro \ufb01 t organiza tion. Dr. Fried man receive s no personal in- come for the se activities. NYU rece ives a \ufb01 xed amount from the Epilepsy Study Consortium tow ards Dr. Friedman's salary. Within the past year, The Epil ep sy Stud y Con sort ium receive d pay men ts fo r 4 T.E . Gast on, D. Fr iedm an / Epi leps y & Beh avio r xxx (20 16) xx x \u2013 xxx Please cite this arti cle as: Gaston TE, Friedman D, Pharmacology of cann abinoids in the treatment of epilepsy, Epilep sy Behav (2016), http:// dx. doi. org/1 0.1 016/ j.ye beh. 2016. 11. 016 rese ar ch serv ice s perfo rme d by Dr. Frie dma n from: Al exz a Pharma ceu - tical s , Ac or da , Eisai Medic al Resea rc h, P \ufb01 zer, Upsher Smit h, and Zyner ba . He ha s a ls o s er ve d as a pa id cons ul ta nt fo r UC B, Inc. an d Liv aNov a as well as pa rti cipa ted in ad vis ory boar ds fo r GW Phar mac eu- tica ls and Su pern us. He has re cei ved hono rari um from Ne uropa ce, In c. He re ceive s researc h support from U CB , Inc., NINDS, CD C, a n d the Epi leps y Fou nda tion. Ref ere nces [1] Rosen be rg EC, Tsi en RW , Wh al ley BJ, Dev i n s ky O. Canna bi noids a nd ep i le psy. Neur othe rape utic s 201 5;12: 747 \u2013 68. [2] Gaoni Y, Mechoulam R. Isolation, structur e, and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86: 1646 \u2013 7. [3] Matsuda LA, Lolait SJ, Browns tein MJ, Young AC, Bo nner TI. Structure of a ca nnabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561 \u2013 4. [4] Wilson RI, Nicoll RA. Endocannabino id signali ng in th e brain. Science 2002;296 : 678 \u2013 82. [5] Pe rtwee RG, Ca scio MG . Know n pharma colog ical ac tions of delt a-9- tetrah ydro can- nabin ol and of four other ch emical con stituen ts of cannabi s that acti vate canna bi- noid recepto rs. In: Pertwee RG, editor. Handbo ok of cannabis. Oxford , UK: Oxford Univ ersi ty Pre ss; 2014 . p. 115. [6] T sou K, Bro wn S, Sanudo -Pen a M, Mack ie K, Walk er J. Immu nohi stoch emic al dis tri- but ion of ca nnab inoi d CB1 rece ptor s in the ra t cent ral ne rvou s syste m. Neur osci ence 1998 ;83: 393 \u2013 411. [7] Ca stil lo PE, Yo unts TJ, Ch avez AE , Hashim otod ani Y. En doca nnabi noid s igna ling an d syn aptic f unct ion. Neur on 20 12;76 :70 \u2013 81. [8] Hu a T, Vemuri K, Pu M, Qu L, Ha n GW, Wu Y, et al. Crys tal stru ctur e of the human cann abin oid re cept or CB1. Cell 20 16;1 67:7 50 \u2013 62:e14. [9] Ga lièg ue S, Mary S, M arch and J, Duss osso y D, Carr ière D, Cara yo n P, et al. Expre ssio n of ce ntra l and pe riph era l cann abin oid r ecep tors in human immun e tis sues and leu- koc yte sub popu latio ns. Eur J Bi oche m 1995; 232: 54 \u2013 61 . [10] Va n Sickle MD , Dunc an M, King sley PJ , Mouih ate A, Urba ni P, Mack ie K, et al. Iden ti- \ufb01 ca tion an d func tiona l cha ract eriz atio n of bra inst em cann abino id CB 2 recept ors . Sci- ence 2 005;3 10:3 29 \u2013 32. [11] St empe l AV, St umpf A, Zhang HY, Oz doga n T, Pa nnas ch U, The is AK , et al. Cannabi - noid type 2 recepto rs mediate a cell type-speci \ufb01 c plasticity in the hippocampus. Neur on 20 16 ;9 0: 795 \u2013 809. [12] Alg er BE. Sei zing an opportunit y for th e endocannabin oid system. Epileps y Curr 2014 ;1 4: 27 2 \u2013 6. [13] Hi ll AJ, Hill TDM, Wh alley BJ. Th e developme nt of cannabi noid bas ed therap ies for epil eps y. In: Ona ivi ES, Dar mani N A, Wagne r E, edito rs. Endo ca nnab inoid s: mole cu- lar, pha rmaco lo gical , b e h av i or al and cli n i ca l fea tures . Bentham S c ie nce; 20 1 3. p. 164 \u2013 204. [14] Da vis JP, R amsey HH . Antie pile ptic act ion of mari jua na-a ctiv e subs tance s. Fede rati on of Am erican , Soc E xp Biol 19 49;8: 284 \u2013 5. [15] Frie dman D, Devinsky O. Cannabi noids in the treatment of epilepsy. N Engl J Med 2015 ;373 :104 8 \u2013 58 . [16] Cascio MG, Pertwee RG. Known pharmacolo gical actions of nine nonps ychotropic phyt ocan nabin oids . In: Pe rtwe e RG, ed itor. H andb ook of ca nnab is. Ox ford, UK : Ox- ford Un vers ity Pre ss; 2014 . p. 137. [17] P aren ts: THCA tin ctur e work s just as wel l as CBD for pedi atri c seizur es. Here 's how to make it ; 2014 ht tps:/ /to kesig na ls.co m/pa rent s-th ca-t inct ure- work s-j ust-a s-w ell- as-c bd-f or-p edia tri c-sei zur es-he res -how -to-m ake- it/ . [18] Hi ll AJ, Weston S E, Jones NA, Sm ith I, Bevan SA, Wil liamson EM, et al. 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[33] So urbron J, Schnei der H, Kecskes A, Liu Y, Buening EM, Lag ae L, et al. Serotoner gic modul ation as eff ec tive trea tmen t for Dr a v et sy n d rome in a zebra \ufb01 sh mu ta nt mode l. ACS Ch em Neur osci 20 16;7: 588 \u2013 98. [34] De vins ky O, Cili o MR, Cr oss H, Fer nand ez-R uiz J, Fr ench J, Hi ll C, et al . Cann abidio l: phar mac ology and pot entia l the rape utic ro le in e pile psy an d other neuro psyc hiat ric dis orde rs. Epi leps ia 2014 ;55: 791 \u2013 802. [35] Durin g MJ, Spencer DD. Adenos ine: a po tenti a l mediat or of sei zure arrest and pos ticta l refr act orin ess. An n Neu rol 1 992;32 :61 8 \u2013 24. [36 ] Rimm erman N, Ben- Hail D, Po rat Z, Ju knat A, Ko zela E, Da niel s MP, et al. Dire ct mo d- ulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell de ath. Ce ll Death Di s 2013;4: e94 9. 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Importa n c e of monito r i n g clob az a m and N - desm e th ylclo ba zam le v e ls in treatm ent wi th cannabi d i ol (CBD) for epileps y (S14 .001). Ne urol ogy 2016; 86(16) htt p:// www.n eurolo gy.o rg/con tent/ 86/16_ Sup- plem ent/ S14 .001 .abs tract . 6 T.E . Gast on, D. Fr iedm an / Epi leps y & Beh avio r xxx (20 16) xx x \u2013 xxx Please cite this arti cle as: Gaston TE, Friedman D, Pharmacology of cann abinoids in the treatment of epilepsy, Epilep sy Behav (2016), http:// dx. doi. org/1 0.1 016/ j.ye beh. 2016. 11. 016

Pharmacology of canabinoids in the treatment of epilepsy

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