From left to right: Charles Nichols, Meghan Hibicke and Shlomi Raz

How do de­pressed rats re­spond to psy­che­delics? New da­ta of­fer in­sight in­to the hu­man ex­pe­ri­ence

De­spite tricky reg­u­la­tions, re­search eval­u­at­ing the an­ti­de­pres­sant po­ten­tial of psy­che­delics in hu­mans is mush­room­ing — and the FDA has al­ready ap­proved a nasal spray con­coc­tion of the cat tran­quil­iz­er ke­t­a­mine for pa­tients whose de­pres­sion per­sists de­spite con­ven­tion­al ther­a­py.

But sci­en­tists still don’t quite ful­ly un­der­stand the an­ti­de­pres­sant im­pact of psy­che­delics on the brain — are the ef­fects pure­ly bi­o­log­i­cal or psy­cho­log­i­cal? A new study looks in­to the de­gree and du­ra­tion of an­ti­de­pres­sant ef­fects in­duced by these drugs — large­ly brand­ed by gov­ern­ments as il­le­gal he­do­nis­tic com­pounds with no ther­a­peu­tic po­ten­tial — in an an­i­mal mod­el.

“You re­al­ly can’t take the brain of a pa­tient and grind it up and ex­tract the genes and look at gene ex­pres­sion and see what’s changed in that brain — the best we have right now is imag­ing. But that’s still just a win­dow in­to the black box — to get in­to the black box, we ac­tu­al­ly need the brain tis­sue to be able to an­a­lyze,” said Charles Nichols, the di­rec­tor of the study and pro­fes­sor of phar­ma­col­o­gy at Louisiana State Uni­ver­si­ty (LSU).

“But to get that we have to have a mod­el where the drug works and no­body had yet been able to re­ca­pit­u­late the long term ef­fects or even an­ti­de­pres­sants ef­fects to a re­al­ly con­vinc­ing lev­el in an an­i­mal mod­el.”

Nichols, the son of long­time psy­che­del­ic re­search pro­po­nent David Nichols, has been study­ing the ef­fects of psy­che­delics in the brain for near­ly 25 years. In this study, Nichols and his team com­pared the im­pact of a one-time dose of psilo­cy­bin (the psy­choac­tive in­gre­di­ent in mag­ic mush­rooms), ly­ser­gic acid di­ethy­lamide (LSD, or acid as it is fond­ly known), and ke­t­a­mine in a rat mod­el for de­pres­sion.

There are al­ready emerg­ing da­ta sug­gest­ing the ben­e­fi­cial ef­fects of psy­che­delics in hu­mans — apart from the FDA-ap­proved ke­t­a­mine prod­uct, psilo­cy­bin is be­ing test­ed as an an­ti­de­pres­sant in a range of tri­als. Re­cent­ly, a psy­che­del­ic re­search cen­ter was opened at Johns Hop­kins.

Da­ta from Nichols’ study — the first di­rect pre­clin­i­cal com­par­i­son of the an­ti­de­pres­sant ef­fi­ca­cy of ke­t­a­mine and oth­er psy­che­delics — showed that both psilo­cy­bin and LSD sig­nif­i­cant­ly re­duces de­pres­sive-like be­hav­iors five weeks af­ter a sin­gle ad­min­is­tra­tion in rats, while on­ly the low­est dose of ke­t­a­mine eval­u­at­ed (5 mg/kg) was ef­fi­ca­cious in de­creas­ing de­pres­sive-like be­hav­iors. In ad­di­tion, the as­so­ci­at­ed an­ti­de­pres­sant-like ef­fects of ke­t­a­mine were tran­sient com­pared to psilo­cy­bin and LSD-treat­ed rats — and last­ed less than two weeks.

“Be­cause there’s so much po­lit­i­cal dis­cus­sion tied up in­to the re­search, it’s great…this can be a much more da­ta, ev­i­dence-based progress to­wards psy­che­del­ic ther­a­pies as op­posed to a more po­lit­i­cal grass­roots piece,” said Ro­nan Levy, ex­ec­u­tive chair­man of Toron­to-based com­pa­ny Field Trip Psy­che­delics that is open­ing up clin­ics to de­liv­er psy­che­del­ic-based psy­chother­a­py.

A WIN­DOW TO NEW COP­ING STRATE­GIES

In or­der to see how the “de­pressed’ rats re­act­ed to the psy­che­del­ic com­pounds, the an­i­mals were first put through what is com­mon­ly known as a ‘forced swim test’ to mea­sure if they were de­pressed.

“The short sto­ry is you throw them in a buck­et of wa­ter,” said Meghan Hi­bicke, the study’s lead au­thor and post­doc­tor­al re­searcher at LSU Health Sci­ences Cen­ter, Phar­ma­col­o­gy and Ex­per­i­men­tal Ther­a­peu­tics.

“You see how much they swim ver­sus how much they float. And then you can mea­sure that be­hav­ior — so that’s the plan­ning and the pas­sive cop­ing strat­e­gy that can be kind of com­pa­ra­ble to a de­pressed per­son in bed.”

De­pressed peo­ple find it dif­fi­cult to get up and brush their teeth — dai­ly func­tion­ing is re­al­ly hard and ac­tive, prob­lem-solv­ing is ar­du­ous, she said.

“So ba­si­cal­ly, what makes hu­mans feel bad, makes a rat float, and what makes a hu­man feel bet­ter, makes a rat swim … they are just dif­fer­ent mea­sures of pas­sive ver­sus ac­tive cop­ing strate­gies — like get­ting shocked and freez­ing when you’re hu­man would be a pas­sive cop­ing strat­e­gy ver­sus run­ning around and try­ing to get away.”

Con­verse­ly, if you give rats an­ti­de­pres­sant med­ica­tions that have been shown to be ef­fec­tive in hu­mans, the same rats will start to be­have more nor­mal­ly. They’ll start swim­ming in the wa­ter and ex­hib­it food-seek­ing be­hav­iors, Nichols added.

While con­duct­ing the study, Nichols and Hi­bicke were cau­tious in choos­ing the dos­es of the tri­fec­ta of psy­che­del­ic com­pounds, re­ly­ing on lit­er­a­ture re­views and con­sul­ta­tions with David Nichols to hone in on op­ti­mal dos­es. “If you use too much, the rat is go­ing to be ba­si­cal­ly su­per-stoned and it’s not go­ing to be able to per­form. And if you don’t use enough, you might not hit a ther­a­peu­tic lev­el,” Nichols said.

The study find­ings were sig­nif­i­cant on two lev­els. The re­searchers first ac­com­plished their pri­ma­ry goal of gen­er­at­ing a ro­dent ex­per­i­men­tal sys­tem that could be used to study the mol­e­c­u­lar, cel­lu­lar ef­fects with psilo­cy­bin as an an­ti­de­pres­sant.

“So we now have an an­i­mal mod­el, where psilo­cy­bin has long-last­ing ef­fects af­ter a sin­gle dose and we can go and take the (rat) brains out and be­gin to ask ques­tions on how is it (the drug) chang­ing the brain to do this,” Nichols said.

The sec­ond goal was broad­er — gath­er­ing in­sight in­to whether the ther­a­peu­tic ben­e­fit is pure­ly psy­cho­log­i­cal or bi­o­log­i­cal.

“What our re­sults have shown is that it’s re­al­ly kind of nei­ther — that at its core the an­ti­de­pres­sant ef­fects are bi­o­log­i­cal be­cause the rat doesn’t re­al­ly have the ex­is­ten­tial angst — the same rea­sons for de­pres­sion that a hu­man would have. But what we did find was that we could shape the an­ti­de­pres­sant ef­fect by the en­vi­ron­ment that the rat was placed in af­ter the treat­ment,” Nichols said.

What the rats en­coun­tered dur­ing their first week af­ter their psy­che­del­ic ex­pe­ri­ence ei­ther re­in­forces a cop­ing strat­e­gy that was al­ready there, or it taught them a new cop­ing strat­e­gy.

“So it seems like psilo­cy­bin at least is open­ing this kind of win­dow where a new cop­ing strat­e­gy is learn­able which would be re­al­ly re­al­ly help­ful for peo­ple who are suf­fer­ing from chron­ic life prob­lems like de­pres­sion and anx­i­ety and stress and drug ad­dic­tion or gam­bling ad­dic­tion — where there’s a pe­ri­od of time in which, af­ter their psy­che­del­ic ex­pe­ri­ence, they can learn a new way to be­have un­der old cir­cum­stances or un­der chal­leng­ing cir­cum­stances,” Hi­bicke said.

IM­PLI­CA­TIONS FOR IN­DUS­TRY 

What does this mean for the ex­plo­sion of com­pa­nies and re­searchers look­ing in­to the ther­a­peu­tic po­ten­tial of dif­fer­ent psy­che­del­ic com­pounds for a range of con­di­tions?

“Be­ing able to com­bine our dig­i­tal health ca­pa­bil­i­ties with the new in­sights in­to the bi­o­log­i­cal mech­a­nisms, giv­ing rise to an­ti­de­pres­sant-like ef­fects will en­hance our abil­i­ty to iden­ti­fy why some pa­tients may re­spond bet­ter to psilo­cy­bin or LSD ver­sus ke­t­a­mine…fur­ther jus­ti­fy­ing re­im­burse­ment for care,” said Shlo­mi Raz, the chief of Eleu­sis Ben­e­fit Cor­po­ra­tion, which spon­sored Nichols’ study.

“When you can make pre­dic­tions that have a high de­gree of ac­cu­ra­cy, the whole per­spec­tive on the use of these oth­er­wise cost­ly ther­a­pies will be­gin to change.”

For ATAI Life Sci­ences — an um­brel­la en­ti­ty that is be­hind com­pa­nies such as Com­pass Path­ways (which cur­rent­ly has a mid-stage treat­ment-re­sis­tant de­pres­sion study test­ing a psilo­cy­bin com­pound) and Per­cep­tion Neu­ro­science (which took its ke­t­a­mine de­riv­a­tive in­to clin­i­cal tri­als last year) — the study adds more ro­bust ev­i­dence sup­port­ing the ther­a­peu­tic use of psy­che­delics.

Pre­vi­ous­ly, the an­i­mal mod­els were large­ly in mice, Srini­vas Rao, ATAI’s chief sci­en­tif­ic of­fi­cer not­ed. “With rats, you’re just go­ing up the evo­lu­tion­ary lad­der a lit­tle bit,” he said. “Rats have much more com­plex be­hav­ior than mice — it’s just more brain there.”

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