Re­think­ing Treat­ments for GAD: Progress in Sight for Pa­tients in Need

Gen­er­al­ized Anx­i­ety Dis­or­der (GAD) is a de­bil­i­tat­ing con­di­tion that af­fects mil­lions of in­di­vid­u­als world­wide – a dis­or­der that has been over­looked for many years but is per­va­sive and rapid­ly grow­ing. While it may not al­ways man­i­fest with the same in­ten­si­ty as oth­er men­tal health con­di­tions, GAD can of­ten be de­bil­i­tat­ing.  De­spite its preva­lence and the pro­found im­pact it has on in­di­vid­u­als, fam­i­lies, and com­mu­ni­ties, there re­mains a high de­gree of un­met need in GAD, where there has been lit­tle in­no­va­tion to de­vel­op new treat­ments for al­most two decades.  This is set to change as the re­nais­sance of re­search in­to psy­che­delics turns its sights on GAD with key da­ta on the most stud­ied psy­che­del­ic – a pro­pri­etary form of LSD – to be re­port­ed by the end of 2023.

In­ter­mit­tent sit­u­a­tion­al wor­ry is a nor­mal re­sponse to the stress­es of dai­ly life, how­ev­er, when anx­i­ety be­comes chron­ic and ex­pands be­yond iden­ti­fi­able stres­sors, it can be func­tion­al­ly im­pair­ing. In­di­vid­u­als with GAD ex­pe­ri­ence a range of symp­toms in­clud­ing rest­less­ness, fa­tigue, ir­ri­tabil­i­ty, mus­cle ten­sion, sleep dis­tur­bances, and oth­er psy­cho­log­i­cal and so­mat­ic man­i­fes­ta­tion. These symp­toms in­ter­fere with dai­ly ac­tiv­i­ties, im­pair so­cial re­la­tion­ships, im­pact ca­reers, and re­duce over­all qual­i­ty of life.

A re­cent epi­demi­o­log­i­cal study found that 10% of US adults have symp­toms con­sis­tent with GAD, mak­ing it the sec­ond most com­mon men­tal health dis­or­der among adults be­hind ma­jor de­pres­sive dis­or­der. In com­par­i­son to his­tor­i­cal stud­ies on GAD, the preva­lence of the con­di­tion ap­pears to have tripled in the last two decades, with women twice as like­ly to be af­fect­ed as men. Whether this rep­re­sents a change in re­port­ing, more com­fort with dis­clo­sure, or a true in­crease in anx­i­ety, the im­pli­ca­tions are pro­found.  Pa­tients and pay­ors are poor­ly served by the cur­rent lack of treat­ment op­tions; an­nu­al health care costs for peo­ple with a psy­chi­atric di­ag­no­sis are 3.5 times high­er than for those with­out one.

Giv­en the preva­lence of GAD, the sig­nif­i­cant bur­den it places on in­di­vid­u­als and so­ci­ety, and the lim­i­ta­tions of cur­rent ther­a­pies, there con­tin­ues to be a sub­stan­tial un­met need in the treat­ment and man­age­ment of GAD. The phar­ma­ceu­ti­cal treat­ment land­scape is dom­i­nat­ed by sero­tonin re­up­take in­hibitors (SRIs), ben­zo­di­azepines, and in more lim­it­ed cas­es, an­tipsy­chotics. For decades, GAD has been an over­looked in­di­ca­tion pre­cise­ly be­cause the most com­mon treat­ment op­tions, such as SRIs, have his­tor­i­cal­ly un­der­per­formed. This is ev­i­dent both in the rel­a­tive­ly low­er re­sponse to SRIs in GAD ver­sus Ma­jor De­pres­sive Dis­or­der (MDD), and in that MDD pa­tients with height­ened anx­i­ety typ­i­cal­ly re­spond less to the cur­rent stan­dard of care. De­spite their wide­spread use, rep­re­sent­ing rough­ly $3 bil­lion in an­nu­al US rev­enues, many ex­ist­ing ther­a­pies can take 6 weeks or more to pro­vide ben­e­fit and even then have lim­it­ed ef­fi­ca­cy, while safe­ty and tol­er­a­bil­i­ty chal­lenges lead to low rates of ad­her­ence.

In­no­va­tion in the treat­ment of GAD has been lim­it­ed, with Cym­bal­ta hav­ing been the last ther­a­py ap­proved for GAD in 2004. There is a sig­nif­i­cant de­mand for new phar­ma­co­log­i­cal class­es that of­fer more ro­bust, rapid, and durable ef­fi­ca­cy, as well as a fa­vor­able safe­ty and tol­er­a­bil­i­ty pro­file. This is par­tic­u­lar­ly true for the seg­ment of pa­tients who, de­spite hav­ing been pre­scribed cur­rent­ly avail­able ther­a­pies, con­tin­ue to ex­pe­ri­ence in­tol­er­a­ble anx­i­ety. It is es­ti­mat­ed that half of those treat­ed with a front-line ther­a­py for GAD, do not sus­tain an ad­e­quate re­sponse to that ther­a­py.

Against this back­drop, the re­nais­sance of re­search in­to the psy­che­del­ic drug class has shown enor­mous promise, lead­ing to a boom of con­tem­po­rary stud­ies. The phar­ma­ceu­ti­cal po­ten­tial of psy­che­delics was first dis­cov­ered in the 1940s by a San­doz re­searcher named Al­bert Hoff­man, who syn­the­sized ly­ser­gic acid di­ethy­lamide (LSD or ly­sergide), which end­ed up be­ing the most stud­ied and sto­ried drug in the psy­che­del­ic class. It al­so hap­pens to be one of the most po­tent neu­ropsy­chi­atric mol­e­cules ever stud­ied.

The pro­found psy­cho­log­i­cal mod­u­la­tion im­part­ed by even mod­est dos­es of LSD was uti­lized ex­ten­sive­ly in lega­cy re­search with strong pos­i­tive clin­i­cal re­sults across dozens of stud­ies, hun­dreds of pa­tients, and a wide range of dis­or­ders – from anx­i­ety and de­pres­sion to sub­stance use and pain dis­or­ders.  A se­ries of re­cent, ground­break­ing stud­ies have con­firmed the promis­ing find­ings from these lega­cy stud­ies, with par­tic­u­lar promise of strong and durable ef­fects in anx­i­ety and de­pres­sion.

In 2022, a place­bo-con­trolled in­ves­ti­ga­tor-ini­ti­at­ed tri­al demon­strat­ed sig­nif­i­cant, durable and ben­e­fi­cial ef­fects of LSD re­veal­ing the drug’s po­ten­tial to safe­ly mit­i­gate symp­toms of anx­i­ety and de­pres­sion. The study showed a clin­i­cal­ly and sta­tis­ti­cal­ly sig­nif­i­cant re­sponse for the pri­ma­ry end­point, change from base­line in State Trait Anx­i­ety In­ven­to­ry (STAI-G) scores, six­teen weeks af­ter treat­ment. Ad­di­tion­al­ly, 65% of pa­tients in the LSD arm showed at least a 30% re­duc­tion in STAI-G scores com­pared to on­ly 9% in the place­bo arm.

MindMed’s pro­pri­etary form of LSD, MM-120 (ly­sergide D-tar­trate), builds on this ex­ten­sive body of re­search with the goal of bring­ing a nov­el treat­ment op­tion to the mil­lions of peo­ple liv­ing with GAD.  MM-120 is ad­min­is­tered at psy­choac­tive dos­es un­der the close su­per­vi­sion of health­care prac­ti­tion­ers in a safe and sup­port­ive set­ting.  A sim­i­lar ap­proach of episod­ic, per­cep­tu­al in­ter­ven­tion has achieved sig­nif­i­cant up­take with the wide and in­creas­ing adop­tion of Janssen’s Spra­va­to (in­tranasal es­ke­t­a­mine) — though the short du­ra­tion of clin­i­cal ef­fect re­quires fre­quent and ex­ten­sive treat­ments.  In con­trast, the ex­tra­or­di­nary promise of MM-120 is char­ac­ter­ized by an acute, sin­gle dose in­ter­ven­tion that pro­duced rapid and durable anx­i­olyt­ic ef­fects that in some stud­ies have last­ed for up to a year.

MindMed’s Phase 2b study eval­u­at­ing MM-120 in GAD pa­tients – which en­rolled near­ly 200 par­tic­i­pants and is set to read­out by the end of this year – is the largest well-con­trolled study of ly­sergide ever con­duct­ed and in­cludes the most rig­or­ous as­sess­ment of the dose-re­sponse re­la­tion­ship of psy­che­delics that has been at­tempt­ed.  This is al­so the first large, mod­ern study to test the stand­alone phar­ma­co­log­i­cal ef­fects of a psy­che­del­ic drug can­di­date – i.e. in the ab­sence of psy­chother­a­peu­tic in­ter­ven­tion – the im­por­tance of which is em­pha­sized in the re­cent­ly pub­lished FDA Draft Guid­ance.

These study re­sults of MM-120 in GAD come at a crit­i­cal time for the drug class and for pa­tients strug­gling with brain health dis­or­ders. The preva­lence and im­pact of GAD cou­pled with the lim­i­ta­tions of cur­rent treat­ment op­tions, high­lights the im­por­tance and the po­ten­tial im­pact that MM-120 could rep­re­sent.  We are on the cusp of a rev­o­lu­tion in men­tal health­care and we be­lieve ly­sergide may once again as­sume its place at the front of the pack as a promis­ing treat­ment for pa­tients with anx­i­ety and oth­er brain health dis­or­ders.