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.”

How one start­up fore­told the neu­ro­science re­nais­sance af­ter '50 years of shit­show'

In the past couple of years, something curious has happened: Pharma and VC dollars started gushing into neuroscience research.

Biogen’s controversial new Alzheimer’s drug Aduhelm has been approved on the basis of removing amyloid plaque from the brain, but the new neuro-focused pharma and biotechs have much loftier aims. Significantly curbing or even curing the most notorious disorders would prove the Holy Grail for a complex system that has tied the world’s best drug developers in knots for decades.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Bob Bradway, Amgen CEO (Scott Eisen/Bloomberg via Getty Images)

Am­gen bel­lies back up to the M&A ta­ble for an­oth­er biotech buy­out, this time with a $2.5B deal for an­ti­body play­er

Five months after Amgen CEO Bob Bradway stepped up to the M&A table and acquired Five Prime for $1.9 billion, following up with the smaller Rodeo acquisition, he’s gone back in for another biotech buyout.

This time around, Amgen is paying $900 million cash while committing up to $1.6 billion in milestones to bag the privately held Teneobio, an antibody drug developer that has expertise in developing new bispecifics and multispecifics. In addition, Amgen cited Teneobio’s “T-cell engager platform, which expands on Amgen’s existing leadership position in bispecific T-cell engagers by providing a differentiated, but complementary, approach to Amgen’s current BiTE platform.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.

Ryan Watts, Denali CEO

De­nali slips as a snap­shot of ear­ly da­ta rais­es some trou­bling ques­tions on its pi­o­neer­ing blood-brain bar­ri­er neu­ro work

Denali Therapeutics had drummed up considerable hype for their blood-brain barrier technology since launching over six years ago, hype that’s only intensified in the last 14 months following the publications of a pair of papers last spring and proof of concept data earlier this year. On Sunday, the South San Francisco-based biotech gave the biopharma world the next look at in-human data for its lead candidate in Hunter syndrome.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.

Art Levinson (Calico)

Google-backed Cal­i­co dou­bles down on an­ti-ag­ing R&D pact with Ab­b­Vie as part­ners ante up $1B, start to de­tail drug tar­gets

Seven years after striking up a major R&D alliance, AbbVie and Google-backed anti-aging specialist Calico are doubling down on their work with a joint, $1 billion commitment to continuing their work together. And they’re also beginning to offer some details on where this project is taking them in the clinic.

According to their statement, each of the two players is putting up $500 million more to keep the labs humming.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.

Ugur Sahin, BioNTech CEO (Bernd von Jutrczenka/dpa via AP Images)

BioN­Tech is spear­head­ing an mR­NA vac­cine de­vel­op­ment pro­gram for malar­ia, with a tech trans­fer planned for Africa

Flush with the success of its mRNA Covid-19 vaccine, BioNTech is now gearing up for one of the biggest challenges in vaccine development — which comes without potential profit.

The German mRNA pioneer says it plans to work on a jab for malaria, then transfer the tech to the African continent, where it will work with partners on developing the manufacturing ops needed to make this and other vaccines.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.

Why is On­col­o­gy Drug De­vel­op­ment Re­search Late to the Dig­i­tal Bio­mark­ers Game?

During the recent Annual ASCO Meeting, thousands of cancer researchers and clinicians from across the globe joined together virtually to present and discuss the latest findings and breakthroughs in cancer research and care. There were more than 5000+ scientific abstracts presented during this event, yet only a handful involved the use of motion-tracking wearables to collect digital measures relating to activity, sleep, mobility, functional status, and/or quality of life. Although these results were a bit disappointing, they should come as no surprise to those of us in the wearable technology field.

UP­DAT­ED: Pan­el of neu­ro­science ex­perts lays out the com­pli­ca­tions with us­ing Bio­gen's new Alzheimer's drug

Treatment of early Alzheimer’s patients with Biogen’s new drug Aduhelm should closely resemble how the drug was studied in its pivotal clinical trials, according to new recommendations from a panel of neuroscience experts led by UNLV’s Jeffrey Cummings.

“Those considering aducanumab therapy should understand that the expected benefit is slowing of cognitive and functional decline; improvement of the current clinical state is not anticipated,” they wrote Tuesday in The Journal of Prevention of Alzheimer’s Disease, noting that some of their recommendations are more specific or more restrictive than the information provided in the FDA’s prescribing information.

Christophe Weber, Takeda CEO (Kyodo via AP Images)

Take­da flesh­es out CNS pact with pep­tide drug­mak­er, set­ting aside $3.5B in fu­ture mile­stones

One of a suite of drugmakers looking to reinvest in the neuroscience space, Takeda has been aggressive in signing on new partners to help build up its pipeline in that space. But sometimes the best partner is the one you already have.

Takeda will set aside $3.5 billion in future milestones and an undisclosed upfront payment to build out its drug discovery deal with Japanese peptide conjugate maker PeptiDream, adding neurodegeneration to the partnership’s list of CNS targets, the companies said Tuesday.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.

George Yancopoulos, Regeneron

Re­gen­eron's lat­est ge­net­ics dis­cov­ery hooks As­traZeneca — now all-in on de­vel­op­ing small mol­e­cules for obe­si­ty

Just weeks after its widely lauded genetics research arm tagged a promising new target for obesity, Regeneron has signed up an industry heavyweight to collaborate with on developing new drugs that can potentially act as a game-changer in what has proven to be a tough field for developers.

The Regeneron Genetics Center published a paper in Science at the beginning of this month highlighting how their work sequencing the genomes of 650,000 people highlighted how people with at least 1 inactive copy of the GPR75 gene weighed on average 12 pounds less than the rest of the population with a 54% reduction in risk of obesity.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 112,800+ biopharma pros reading Endpoints daily — and it's free.