Finally, an article in the press that’s not a hit piece on Cassava

Cassava Biosciences has had the worst press imaginable with hit pieces in the Wall Street Journal, Science magazine, the New Yorker and the New York Times.  Finally Nature News has a balanced article showing how the shorts have been attacking the company and its drug — https://www.nature.com/articles/d41586-023-00050-z.

I’d written about this before and that post can be found after the ***

The Nature article discusses concerns by Elizabeth McNally editor of the Journal of Clinical Investigation, that journals are being manipulated by short sellers claiming that an article is fraudulent.

“Typically, when a whistle-blower contacts a journal about concerns over manipulated images or otherwise questionable data, the allegations are taken on good faith, McNally told Nature. The idea that whistle-blowers could be doing this for their own financial gain “was very eye-opening to me”, she says.”

One particular criticism of Cassava found in the Nature article is rather amusing. “Amid the allegations about Cassava’s data, researchers have expressed concern over how Simufilam works. Aside from the preliminary studies by Cassava and its collaborators, the strategy of stablilizing filamin-A to tackle Alzheimer’s hasn’t been on anyone’s radar, says George Perry, an Alzheimer’s researcher at the University of Texas at San Antonio. “The fact that it hasn’t been widely studied means that it hasn’t been confirmed.”

The fact that filamin-A hasn’t been on anyone’s radar is actually in its favor, since aBeta, the great white whale of Alzheimer’s research has been impaled with multiple expensive harpoons, with minimal benefit to patients.

The Nature article notes that some of the FDA petitioners wanted the Simulfilam studies stopped, something any drug company with a competing product for Alzheimer’s might wish, but should never ask for.

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The copy of this post was changed to respond to the valid criticisms of Dr. Elizabeth Bik.

 

Cassava shorts should be worried

Yesterday, 1 November ’22, a blockbuster  article was published in the Journal of Clinical Investigation (JCI) written by its editor Elizabeth McNally — https://www.jci.org/articles/view/166176.

It is just over a year ago since the first of the articles attacking Cassava Sciences appeared.  The first was in the New Yorker which profiled Jordan Thomas as the second coming of Christ for exposing supposed fraudulent data published by Cassava principals —

Radden Keefe P. The Bounty Hunter. The New Yorker. Updated January 17, 2022. Accessed October 11, 2022. https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers.

There were similar articles in Science — 2022;377(6604):358–363

and the New York Times https://www.nytimes.com/2022/04/18/health/alzheimers-cassava-simufilam.html.

They relied on the same assertions given to the FDA asking that the clinical trials be stopped because of ‘danger’ to the patients.

It’s worth reading McNally’s article completely.  It isn’t very long.

A few highlights (“the Journal” refers to the JCI)

“Throughout 2022, the Journal has been repeatedly contacted to comment on the 2012 JCI paper. Although we cannot be certain, there now appear to be new “short and distorters.” A recent round of emails was sent simultaneously to multiple journals and editors, identifying 25 articles with potential problems and providing recommendations on how the journals should respond. Importantly, these accusatory emails do not identify any financial conflicts of interest on the part of the whistleblowers. The emails insist that an investigation begin within 24 hours and request that the journals update them on investigative progress. As an editor, I am expressing concern because this represents a new means of manipulating the scientific publishing industry.”

So journal editors are like docs. They talk to each other to find out what’s really going on.  It is likely that McNally called up other journal editors to find out if her experience was common.

Here is why those sending the eMails should not sleep well of a night.

“Last, if the Journal uncovers allegations made for the purposes of stock manipulation, with evidence of misinformation, the JCI may elect to express its concern to the US Securities and Exchange Commission or the Department of Justice.”

It’s about time.

Whether the ‘whistle-blowers’ are guilty of anything will be determined by the suits (from investors losing money on Cassava, or perhaps Cassava itself) which are almost sure to follow.

As some of you know, I think Cassava’s data is even better than they realize. Be warned the following link is long, detailed and will require your concentration  — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

One good thing about Trump’s election (maybe two)

Two comments on the election then back to some neuropharmacology and neuropsychiatry which will likely affect many of you (because of some state ballot initiatives).

First: Over the years I’ve thought the mainstream press has become increasingly biased toward the left (not on the editorial page which is fine) but in supposedly objective reporting. Here are just two post election examples

#1 Front page of the New York Times 9 Nov — the first sentence from something they characterize as ‘News Analysis’

““Donald John Trump was elected the 45th president of the United States on Tuesday in a stunning culmination of an explosive, populist and polarizing campaign that took relentless aim at the institutions and long-held ideals of American democracy.”

#2 Front page of the New York Times 10 Nov — more ‘News Analysis’ — Here’s the lead “Populist Fury may Backfire”. Don’t they wish.

I’ll never complain about this sort of thing again (well at least not for four years). Why? Because I’ve been reading the Wall Street Journal, The New York Times, The Nation and the National Review for probably 50 years, and Trump as the antiChrist is the first thing I’ve ever seen all four agree on. This biased coverage simply no longer matters. If it did, Trump would have lost and lost big. This just confirms the marked loss of credibility that the mainstream media has suffered.  People aren’t as dumb as the elites think they are.

Second: Political correctness and attempts to control speech so as not to offend lost big. That’s very good for us all right and left (although the impetus for speech control has switched to the left from the right over the past 56 years) — see https://luysii.wordpress.com/2015/11/22/from-banned-in-boston-to-banned-in-berkeley-in-55-years/

What do the state ballot initiatives have to do with neuropharmacology? Just this. Voters in California, Massachusetts and Nevada approved recreational marijuana initiatives Tuesday night, and several other states passed medical marijuana provisions.

I don’t think this is good. One of the arguments in its favor is that marihuana isn’t as bad as alcohol, which may be true, but if marihuana isn’t all good why add it to the mix? We don’t have a good handle on marihuana use, but it is likely to increase if it’s legal.

Why do I think this is bad (particularly for adolescents)? It is likely that inhibiting synaptic feedback isn’t a good thing for a brain which is pruning a lot of them (which happens in normal adolescence as the thickness of the cerebral cortex shrinks).

There have been many explanations for the decline in College Board Scores over the years. This has led to their normalization (so all our children are above average). If you’re a correlation equals causation fan, plot the decline vs. time of atmospheric lead. It is similar to the board scores decline. Or you can plot 1/adolescent marihuana use vs. time and get a similar curve. The problem, of course, is that we have no accurate figures for use.

Here’s the science — it’s an old post, but little has happened since it was written to change the science behind it

Why marihuana scares me

There’s an editorial in the current Science concerning how very little we know about the effects of marihuana on the developing adolescent brain [ Science vol. 344 p. 557 ’14 ]. We know all sorts of wonderful neuropharmacology and neurophysiology about delta-9 tetrahydrocannabinol (d9-THC) — http://en.wikipedia.org/wiki/Tetrahydrocannabinol The point of the authors (the current head of the Amnerican Psychiatric Association, and the first director of the National (US) Institute of Drug Abuse), is that there are no significant studies of what happens to adolescent humans (as opposed to rodents) taking the stuff.

Marihuana would the first mind-alteraing substance NOT to have serious side effects in a subpopulation of people using the drug — or just about any drug in medical use for that matter.

Any organic chemist looking at the structure of d9-THC (see the link) has to be impressed with what a lipid it is — 21 carbons, only 1 hydroxyl group, and an ether moiety. Everything else is hydrogen. Like most neuroactive drugs produced by plants, it is quite potent. A joint has only 9 milliGrams, and smoking undoubtedly destroys some of it. Consider alcohol, another lipid soluble drug. A 12 ounce beer with 3.2% alcohol content has 12 * 28.3 *.032 10.8 grams of alcohol — molecular mass 62 grams — so the dose is 11/62 moles. To get drunk you need more than one beer. Compare that to a dose of .009/300 moles of d9-THC.

As we’ve found out — d9-THC is so potent because it binds to receptors for it. Unlike ethanol which can be a product of intermediary metabolism, there aren’t enzymes specifically devoted to breaking down d9-THC. In contrast, fatty acid amide hydrolase (FAAH) is devoted to breaking down anandamide, one of the endogenous compounds d9-THC is mimicking.

What really concerns me about this class of drugs, is how long they must hang around. Teaching neuropharmacology in the 70s and 80s was great fun. Every year a new receptor for neurotransmitters seemed to be found. In some cases mind benders bound to them (e.g. LSD and a serotonin receptor). In other cases the endogenous transmitters being mimicked by a plant substance were found (the endogenous opiates and their receptors). Years passed, but the receptor for d9-thc wasn’t found. The reason it wasn’t is exactly why I’m scared of the drug.

How were the various receptors for mind benders found? You throw a radioactively labelled drug (say morphine) at a brain homogenate, and purify what it is binding to. That’s how the opiate receptors etc. etc. were found. Why did it take so long to find the cannabinoid receptors? Because they bind strongly to all the fats in the brain being so incredibly lipid soluble. So the vast majority of stuff bound wasn’t protein at all, but fat. The brain has the highest percentage of fat of any organ in the body — 60%, unless you considered dispersed fatty tissue an organ (which it actually is from an endocrine point of view).

This has to mean that the stuff hangs around for a long time, without any specific enzymes to clear it.

It’s obvious to all that cognitive capacity changes from childhood to adult life. All sorts of studies with large numbers of people have done serial MRIs children and adolescents as the develop and age. Here are a few references to get you started [ Neuron vol. 72 pp. 873 – 884, 11, Proc. Natl. Acad. Sci. vol. 107 pp. 16988 – 16993 ’10, vol. 111 pp. 6774 -= 6779 ’14 ]. If you don’t know the answer, think about the change thickness of the cerebral cortex from age 9 to 20. Surprisingly, it get thinner, not thicker. The effect happens later in the association areas thought to be important in higher cognitive function, than the primary motor or sensory areas. Paradoxical isn’t it? Based on animal work this is thought to be due pruning of synapses.

So throw a long-lasting retrograde neurotransmitter mimic like d9-THC at the dynamically changing adolescent brain and hope for the best. That’s what the cited editorialists are concerned about. We simply don’t know and we should.

Addendum 11 Nov ’16:  From an emerita nonscientific professor friend of my wife. “Much of the chemistry/pharmacology etc. is way beyond me, but I did get the drift of the conversation about marihuana and am glad to now have even a simplified concept of what it does to the brain. Having spent the last 20 years working with undergraduate and graduate students, I’ve seen first hand the decline in cognitive ability.” 

Scary ! ! ! !

Having been in Cambridge when Leary was just getting started in the early 60’s, I must say that the idea of tune in turn on and drop out never appealed to me. Most of the heavy marihuana users I’ve known (and treated for other things) were happy, but rather vague and frankly rather dull.

Unfortunately as a neurologist, I had to evaluate physician colleagues who got in trouble with drugs (mostly with alcohol). One very intelligent polydrug user MD, put it to me this way — “The problem is that you like reality, and I don’t”.