Can CBD tem­per Parkin­son's-re­lat­ed psy­chosis? UK re­searchers will look for an­swers in PhII study

Cannabid­i­ol (CBD), the cannabi­noid com­pound found in the cannabis plant, has been tried and test­ed in pa­tients with rare forms of epilep­sy, in­spir­ing the ap­proval of GW Phar­ma’s $GW­PH land­mark plant-de­rived Epid­i­olex. Its resur­gence in re­search — and its ubiq­ui­tous pres­ence in oils, creams, and gum­my bears — is on the ba­sis that it is not ad­dic­tive, like its in­tox­i­cat­ing cousin THC, and re­tains the ther­a­peu­tic po­ten­tial for a plant that was once tout­ed as a cure-all in In­dia. Re­searchers at King’s Col­lege Lon­don have been study­ing the ef­fect of CBD on psy­chosis, and on Mon­day sig­naled they are prep­ping to be­gin a large-scale Phase II tri­al in pa­tients with Parkin­son’s-re­lat­ed psy­chosis, char­ac­ter­ized by hal­lu­ci­na­tions and delu­sions.

The re­search team, led by Pro­fes­sor Sag­nik Bhat­tacharyya from the In­sti­tute of Psy­chi­a­try, Psy­chol­o­gy & Neu­ro­science, will as­sess the safe­ty and ef­fec­tive­ness of CBD by track­ing psy­chot­ic, mo­tor and non-mo­tor symp­toms, along­side brain imag­ing.

The emer­gence of dopamine D2 re­cep­tor an­tag­o­nists in the 1950s trans­formed the treat­ment of psy­chot­ic dis­or­ders — and they per­sist as one of the main tools in the treat­ment ar­se­nal for psy­chosis. How­ev­er, tra­di­tion­al an­tipsy­chotics car­ry a litany of side ef­fects and a sig­nif­i­cant pro­por­tion of pa­tients do not de­rive ad­e­quate ben­e­fit from the class of drugs.

CBD casts a wide net be­cause it acts through en­do­cannabi­noid re­cep­tors; CB1 and CB2, as well as oth­er re­cep­tors, such as GPR18, GPR55, GPR 119, 5HT1A, and TR­PV2. This sug­gests ther­a­peu­tic val­ue in a pletho­ra of con­di­tions due to its neu­ro­pro­tec­tive and im­munomod­u­la­to­ry prop­er­ties.

Pre­clin­i­cal stud­ies sug­gest CBD may have an­tipsy­chot­ic prop­er­ties, al­though cannabis use, in gen­er­al, is as­so­ci­at­ed with an in­creased risk of de­vel­op­ing psy­chosis. Bhat­tacharyya, of King’s Col­lege Lon­don, has been un­pack­ing the ev­i­dence sup­port­ing CBD’s ben­e­fit in psy­chosis pa­tients.

In a study pub­lished last year, Bhat­tacharyya et al in­ves­ti­gat­ed the neu­rocog­ni­tive mech­a­nisms that un­der­lie the pur­port­ed ther­a­peu­tic ef­fects of CBD in psy­chosis in a small place­bo-con­trolled tri­al (n=16 par­tic­i­pants with a clin­i­cal high risk (CHR) of psy­chosis re­ceived a sin­gle oral dose of 600 mg of CBD; n=17 such par­tic­i­pants re­ceived a place­bo, and n=19 con­trol par­tic­i­pants were not giv­en any drug). Each par­tic­i­pant was then stud­ied us­ing func­tion­al mag­net­ic res­o­nance imag­ing while per­form­ing a ver­bal learn­ing task. The re­searchers found that CBD could par­tial­ly nor­mal­ize al­ter­ations in parahip­pocam­pal, stri­atal, and mid­brain func­tion as­so­ci­at­ed with the CHR state.

Now, with a $1.2 mil­lion grant from Parkin­son’s UK, Bhat­tacharyya will lead the Parkin­son’s study, sched­uled to start in ear­ly 2020. There are cur­rent­ly 145,000 peo­ple liv­ing with Parkin­son’s in the Unit­ed King­dom, and da­ta sug­gest more than half will suf­fer from psy­chosis at some point.

The tri­al will be­gin with a six-week pi­lot to as­sess the safe­ty, tol­er­a­bil­i­ty, and ef­fec­tive­ness of phar­ma­ceu­ti­cal-grade CBD in pa­tients with Parkin­son’s-re­lat­ed psy­chosis.

CBD will be de­liv­ered oral­ly in cap­sules at a dose of up to 1,000 mg/day — in a bid to find an op­ti­mum dose. In the sec­ond tranche of the study, 120 pa­tients will be re­cruit­ed to a 12-week dou­ble-blind, place­bo-con­trolled study.

Re­cent­ly, there was one an­tipsy­chot­ic ap­proved for Parkin­son’s dis­ease psy­chosis, which is de­signed to work by in­ter­act­ing with 5HT2A re­cep­tors and to a less­er ex­tent 5HT2C re­cep­tors — in­stead of tar­get­ing the over­pro­duc­tion of dopamine.

Aca­dia’s $ACAD Nu­plazid was ap­proved in 2016, al­though an in­de­pen­dent pan­el to the FDA sug­gest­ed its ef­fi­ca­cy was not as ro­bust as it would have liked. It was al­so ap­proved with a black box warn­ing — which most an­tipsy­chotics car­ry — high­light­ing the high­er risk of death as­so­ci­at­ed with its use in the el­der­ly.

Nu­plazid, which gen­er­at­ed sales of about $146 mil­lion in the first half of this year, gained no­to­ri­ety af­ter a se­ries of re­ports sug­gest­ed its mak­er had mis­rep­re­sent­ed the dan­gers of us­ing the drug and em­ployed ques­tion­able tac­tics to mar­ket it, prompt­ing an FDA re­view, which even­tu­al­ly reaf­firmed the drug’s safe­ty pro­file.

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Jackie Fouse, Agios CEO

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Adeno-associated virus-1 illustration; the use of AAVs resurrected the gene therapy field, but companies are now testing the limits of a 20-year-old technology (File photo, Shutterstock)

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George Yancopoulos (L) and Len Schleifer (Regeneron)

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Hal Barron, GSK via YouTube

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