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.”

Qual­i­ty Con­trol in Cell and Gene Ther­a­py – What’s Re­al­ly at Stake?

In early 2021, Bluebird Bio was forced to suspend clinical trials of its gene therapy for sickle cell disease after two patients in the trial developed cancer. As company scientists rushed to assess whether there was any causal link between the therapy and the cancer cases, Bluebird’s stock value plummeted – as did those of multiple other biopharma companies developing similar therapies.

While investigations concluded that the gene therapy was unlikely to have caused cancer, investors and the public may be more skittish regarding the safety of gene and cell therapies after this episode. This recent example highlights how delicate the fields of cell and gene therapy remain today, even as they show great promise.

Law pro­fes­sors call for FDA to dis­close all safe­ty and ef­fi­ca­cy da­ta for drugs

Back in early 2018 when Scott Gottlieb led the FDA, there was a moment when the agency seemed poised to release redacted complete response letters and other previously undisclosed data. But that initiative never gained steam.

Now, a growing chorus of researchers are finding that a dearth of public data on clinical trials and pharmaceuticals means industry and the FDA cannot be held accountable, two law professors from Yale and New York University write in an article published Wednesday in the California Law Review.

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

As fears mount over J&J and As­traZeneca, No­vavax en­ters a shaky spot­light

As concerns rise around the J&J and AstraZeneca vaccines, global attention is increasingly turning to the little, 33-year-old, productless, bankruptcy-flirting biotech that could: Novavax.

In the now 16-month race to develop and deploy Covid-19 vaccines, Novavax has at times seemed like the pandemic’s most unsuspecting frontrunner and at times like an overhyped also-ran. Although they started the pandemic with only enough cash to last 6 months, they leveraged old connections and believers into $2 billion and emerged last summer with data experts said surpassed Pfizer and Moderna. They unveiled plans to quickly scale to 2 billion doses. Then they couldn’t even make enough material to run their US trial and watched four other companies beat them to the finish line.

FDA of­fers scathing re­view of Emer­gent plan­t's san­i­tary con­di­tions, em­ploy­ee train­ing af­ter halt­ing pro­duc­tion

The FDA wrapped up its inspection of Emergent’s troubled vaccine manufacturing plant in Baltimore on Tuesday, after halting production there on Monday. By Wednesday morning, the agency already released a series of scathing observations on the cross contamination, sanitary issues and lack of staff training that caused the contract manufacturer to dispose of millions of AstraZeneca and J&J vaccine doses.

Brad Bolzon (Versant)

Ver­sant pulls the wraps off of near­ly $1B in 3 new funds out to build the next fleet of biotech star­tups. And this new gen­er­a­tion is built for speed

Brad Bolzon has an apology to offer by way of introducing a set of 3 new funds that together pack a $950 million wallop in new biotech creation and growth.

“I want to apologize,” says the Versant chairman and managing partner, laughing a little in the intro, “that we don’t have anything fancy or flashy to tell you about our new fund. Same team, around the same amount of capital, same investment strategy. If it ain’t broke, don’t fix it.”

But then there’s the flip side, where everything has changed. Or at least speeded into a relative blur. Here’s Bolzon:

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Bay­er plots a ma­jor facelift at Berke­ley cam­pus, un­cork­ing a 30-year, $1.2B plan to dri­ve cell and gene ther­a­pies

Bayer first set roots in Berkeley back in 1974, when it was still operating as Miles Labs. The site has pumped out three hemophilia A treatments for distribution worldwide; but now, as the pharma continues its cell and gene therapy push, it has something bigger in mind.

Bayer is planning a 30-year revamp at the campus, which includes 918,000 square feet in new buildings and double the jobs, according to a report by the Bay Area Council Economic Institute.

LLS backs 5 new can­cer drug projects with up to $50M; Trodelvy con­tin­ues to im­press with more TNBC da­ta

The Leukemia and Lymphoma Society has tapped 5 new early-stage projects to back with up to $10 million each in fresh investments. The 5 biotechs are:

— Caribou, headed by Rachel Haurwitz and co-founded by Jennifer Doudna, is working on next-gen, off-the-shelf CAR-Ts to replace the patient-derived cells now in use.

— The LLS supported NexImmune’s IPO, helping fund its work on nanoparticles that can gin up an immune response directed at cancer cells. The biotech has 2 projects now in Phase I trials.

Steffen Schuster, ITM CEO

Ra­dio­phar­ma re­mains hot as Ger­many's ITM rais­es $109M to ad­vance neu­roen­docrine can­cer pro­gram

The world of radiopharmaceuticals has been heating up over the last few years, and Thursday saw another company focused on the field pull in a new nine-figure raise.

Germany’s ITM, or Isotopen Technologien München, scored a $109 million round of loan financing to push forward its precision oncology pipeline and fund late-stage development for its lead program. As part of the agreement, the loan will convert to shares in the event of future financial or corporate transactions, ITM said.

Jenny Rooke (Genoa Ventures)

Ear­ly Zymer­gen in­vestor Jen­ny Rooke re­flects on 'chimeras' in biotech, what it takes to spot a $500M gem

When Jenny Rooke first heard of Zymergen back in 2014, she knew she was looking at something different and exciting. The Emeryville, CA biotech held the promise of blending biology and technology to solve a huge unmet need for cost-effective chemicals — of all things — and a stellar founding team to boot.

But back then, West Coast venture capitalists didn’t see in Zymergen the one thing they were looking for in a winning biotech: therapeutic potential. Rooke, however, saw an opportunity and made her bets. Seven years later, that bet is paying off in a big way.

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