The Drug Report: Life Extension, LSD, Oddities, Sundries

I didn't do a drug report last month, so you might say I've been "clean" for at least a month. Add to that: I haven't smoked any pot for at least 20 minutes, as of this writing. Sooo: two and a half cheers for moi?

On with it...

Possible Life Extension Drug: Metformin
If you're the sorta dreamer I am, you long for the day when you swallow one or what the hell: a handful of pills and they:

1. Stop your telomeres from fraying while continuing to do what they did when you were 15
2. Wipe out any and all cancers forming while not throwing your hardy-yet-delicate immunological systems out of orbit
3. Erase all plaques that gum up your aorta and arteries and that crap that leads to Alzheimer's
4. Level the playing fields of life by making you really pretty and attractive to possible sex partners
5. Laughs: life will be full of 'em with this/these new drugs

Those of you trained in cryptanalysis and steganography might notice the first letters of my five here spell out SWELL. Yea, it would be real swell if we had drugs that did this stuff, but no matter how optimistic/hedonistic/giddy or just plain stoned we are, let's get real.

As I handicap a bevy of life extension drugs over the past three years, a diabetes drug called Metformin looks fairly promising. And I confess the older I get and the more I accumulate readings of articles about the Possible Miracle Drug For Everything, the less sanguine I've become. But Metformin has about 60 years of safety. For Type 2 diabetics it suppresses the liver's glucose production and increases sensitivity to insulin. It's increased the lifespan in worms and mice. Researchers think there's a physiological basis in this diabetes drug that delays the aging that gives rise to diseases. Ones even worse than diabetes, like dementia, cancer and heart disease.

Here's the crux: doctors and researchers need to convince regulators and research funding agencies to give 'em the money to test this. What are they gonna test? How long will it take? Will I be dead by the time it hits the market? Probably not: under the TAME (Targeting Aging With Metformin) clinical trial they'll take over 3000 70-80 year old folks who have one or two of these lovely maladies: cancer, heart disease, or cognitive impairment, give them Metformin, then see if it forestalls these septuagenarians and octogenarians from getting those other brutal disease they don't already have.

It'll take five to seven years and cost $50 million.

I know, I know: this is not what you wanted to read about. But you tell me what's out there that's more robust and promises more in the way of longevity.

The horrible truth is, if you have dementia but don't already have cancer or heart disease, you're gonna get one or both of those others before you kick off for the Big Dirt Nap. Talk about a reality sandwich!

Researchers caution: this is not an "immortality" drug! (As if they needed to tell us, after what you've just read.) The big deal here seems to be: Metformin is a well-accepted drug for Type 2 diabetes. But: the TAME study, if it pans out, will establish Metformin as a drug that delays aging. And aging is statistically linked with nasty-ass degenerative diseases, which have already been named in this article, no need to give them more press here. The Unistat FDA says they are open to the study. Researchers want merely to "extend a person's healthy years by slowing down processes that underlie common diseases of aging."

So, in closing I must confess what I know about myself. I read this stuff and one part of my brain - the part that I associate with non-magical thinking and statistics, knowledge of inherent human biases, and appreciation of ever-changing information about the complexity of systems - this part thinks "this seems pretty realistic and at least it's something." But I also know I will wake up tomorrow, and sometime after lunch, catch myself dreaming of the True Wonder Pills, the ones that will do the SWELL stuff. Am I the only one?

Instead of Exercise, Take a Pill? (Just: Not Yet)
I confess I love exercise, sweating, stretching, getting all breathless, even if it has nothing to do with sex. I do yoga and cycle, love hiking, but Cross-Fit seems vaguely fascistic to me, but I digress...

So, a welter of exercise physiologists have determined that, when we're exercising - not doggin' it, but really working up a sweat and approaching oxygen debt - we experience over 1000 molecular changes in our skeletal muscles. And who knew? What's going on at that level rarely crosses my mind as I approach a 1500 foot uphill climb on my bike. My thinking's more along the lines of, "If my heart explodes and they find me dead and my bike in the middle of the road here, after a cement truck and school bus run my body over, it's good I brought my ID with me so they can notify next-of-kin, but at least I can say I wore a helmet if I wasn't already dead" or "this ascent looks like a mutha; just think of the endorphin buzz I'll cop about 40 minutes after I summit." Stuff like that.

But: if we know the 1000 molecular changes that happen, maybe we can just mimic those in a pill! It's all just biochemistry, isn't it? Hey yea: they're working on it. For reals! (Or they're fucking with science writers and the public, hoping for more funding to do far less romantic research, but I don't want to be a bummer, especially after that take on Metformin.)

There are a lot of people who can't exercise, so this would really help them. It would be a godsend for the obese, for people with diabetes, heart disease, etc. One article I read on this research said it would be really great for people who already exercise. That sounded gluttonous to me.

The sobering news here: it's gonna be at least ten years, as one researcher said, "before a pill could conceivably be available." Let's hope the Metformin we'll be able to take will get us there at a young enough state that...oh hell: I need a drink.


Maurice Mikkers: Microscopy and Drugs = Art
If you have the time, check out the gorgeous colors and lines in drugs. This link begins with what Mikkers calls "party drugs" but I really only think of GHB and MDMA/Ecstasy and maybe amphetamine as drugs to "party" with. DMT, 2C-B, and LSD should be used in the proper set and setting, which often is NOT a "party" in the sense most of us think of parties. But aside from that, who knew these drugs were so beautiful, under the microscope, enlarged 40x-400x?

The MDMA/Ecstasy was breathtaking to me. Of course Ecstasy would do that.

Check out Mikkers's website for tonnes of astonishing photography, especially if you need a contact high.

Also, nota bene: it's officially been declared, by the International Moral Credit League ("Oh yea, the IMCL? Great buncha people...") that if you just "take a languid gander" at an "exhibit" - that's the way I see how Mikkers has laid out his wares online here - then you get "credit" for not going to the actual brick and marble Museum this month. I mean, what it'll cost you here? 12 minutes? Think about it. This offer only good through April of 2016; after that you must feel vaguely guilty again on May 1st until you go to the museum or talk or poetry reading. Just floatin' that out there. Hey, facts are facts.

                                            Robin Cahart-Harris, PhD

Recent LSD Research
Just in time for April 19th/AKA "Bicycle Day" and I'm no doubt writing yet another Epistle to the Converts, but what the hell, I just have to mention it. The Beckley Institute crowd-funded a study on LSD and got some stellar drug researchers from Imperial College in London to conduct it. The eminent Dr. David Nutt was the study's lead author, and Robin Cahart-Harris led the study. These are not lightweights. What did they find?

After giving 20 healthy volunteers injections of 75 micrograms of LSD (and others got a lousy placebo, but it was FOR SCIENCE!), the trippers had their brains imaged three ways: with fMRI, something called "arterial spin labelling" (don't ask), and magnetoencephalography. The study said the LSD users tripped for "six hours."

Aside: every LSD trip I've done was at minimum 200 mikes, but always on blotter. And it always lasted at least 10 hours. This Imperial College London stuff Nutt got must have been really righteous! Moving on...

So: there are numerous reports on this study, but the finding that most intrigued me: neural networks in the adult brain normally "talk" to closely-connected networks nearby. It's about specialized function. To rehash basic developmental neuroscience, we have way more neurons as babies, but they get pruned away with experience in the world, which we can call "learning." The stuff that's not pruned gets reinforced and the connections get stronger. We develop neural pathways that "know" how to do millions of things. Neurons are use-it or lose it: what's not recruited in learning/experience in the world gets flushed, literally. Eventually, we develop a sense of our "self" and some sort of "ego," hopefully a relatively healthy one.

What this study did was show how LSD gets the brain to "talk" and connect to other areas it usually doesn't, and therefore it was likened to a return to a "childhood" sense of wonder and imagination. It also reduced the "normal" connectivity we usually experience. What it taketh away it more than giveth backeth in spadeths.

In the past 30 years, neuroscience has continually found more fascinating aspects of how "plastic" the brain can be, even in adults, in the right circumstances. This is termed "neuroplasticity" and is the main reason why even stodgy old farts can still learn a thing or two.

As I read the articles about this study, certain lines jumped out. LSD and presumably other psychedelics "might help some users return to a childlike sense of wonder and imagination." (Most of these quotes are from Cahart-Harris or David Nutt.) When I read this, I think my first reaction was, "I wonder how many church-goers privately think, "This ain't working for me, but it's what's expected...I need to show up at least..." Well, what you REALLY want is a return to a childlike sense of awe and wonder, where parts of your brain get to know other parts for the first time, then you'll know what true religion is. But here of course I'm biased.

In a repetition of research with psilocybin over the past five years (or more), it was observed that the users experienced "improvements in well-being" after the effects of the drug wore off. Psilocybin research showed that one trip significantly changed people towards more openness for the rest of their lives. I know it's an olde riff, but if we could only get this stuff in the punchbowl at the Republican National Convention, amirite?

Cahart-Harris: "This experience is sometimes framed in a religious or spiritual way, and seems to be associated with improvements in well-being after the drug's effects have subsided." Yes, and it's once again suggested by people with actual PhDs from high-ranking universities - actual scientists, not assholes like Ted Cruz or some raging right wing pastor who thinks Jesus needs more nuclear missiles so we get to live out the book Revelation.

But Cahart-Harris also addresses a point I blogged on a few weeks ago: why must psychedelic experience use religious language? I recently read Dennis McKenna's book Brotherhood of the Screaming Abyss and here's a PhD psychonaut of impeccable credentials who has managed to develop a vocabulary to talk about psychedelic experience that's drawn from cosmology, phenomenological philosophy, science fiction, and the arcana of alchemy.

We have our work cut out for us, friends.

Once again, hard-core researchers are suggesting these drugs might or can or should be used for depression, addiction and - presumably if Metformin and the exercise pill never get here in time - for end-of-life anxiety.

I will close with a quote from the estimable British drug researcher, Dave Nutt, talking about this latest LSD research:

This is to neuroscience what the Higgs boson was to particle physics.

And with that, I bid you all a fondue.

The Drug Report: Crisis In Psychopharmacology

It's been at least 30 years since a truly new drug has hit the market that addresses the needs of patients suffering from depression, anxiety, manic depression (now rather bloodlessly called "bipolar disorder"), and schizophrenia. Any "new" drugs in the last 30 years have been basically some variation on an older, established drug (called "Me Too" drugs), in an effort of competing drug companies to keep up with the competition. These non-new "new" drugs are almost always marketed as "blockbuster" or "revolutionary" therapeutics, touting less side effects than older, competing drugs. They are not new and the side effects are just different, not less. 50 or so psychiatric drugs bring in $25 billion a year in Unistat alone. And they're pretty lousy.

(I know, I know: you'd be far worse off without the one that worked for you. Hey: they do some good. For some people. I want better drugs for you, is all. And we were promised them with the 2000 mapping of the human genome. So...where are they? Later.)

                                                        serotonin

The drugs people use - by every estimate I've seen between 20% to 25% of the Unistat population takes  at least one of these - were discovered by accident. By serendipity. In the 15 years after 1945. In 1952 a tuberculosis drug didn't work for TB, but iproniozid sure elicited euphoria when tested! Bingo: the first antidepressant. The drug that became Tofranil was supposed to work for schizophrenics, but it didn't help them, only make them run naked into town, laughing. Another antidepressant. In 1949 lithium was discovered, by accident, to treat manic depression. In 1957 Leo Sternbach was about ready to give up his research into a class of antihistamines, things were looking like a dead-end, when he stumbled onto the benzodiazepines: your Valium, Xanax, Lorazepam, Klonopin, etc: an empire of anti-anxiety drugs, and a huge influence on the tonality of culture in the West in the latter half of the 20th century.

With better technics, we learned much more about neurons and neurotransmitters. The SSRIs seemed to treat depression and anxiety. They were really the last big breakthrough. Ever since then, clinical trials that have made it to Stage III have been nothing but huge, sad, very expensive wastes. And so Novartis, Glaxo-Smith-Kline, Astra Zeneca, Pfizer, Sanofri and Merck have by and large quit trying. They've halted clinical trials, moved onto research that shows more promise. The pipeline for new psychopharmacological drugs is dry.

                                    psilocybin, very much like serotonin in structure

Wait a minute: with more neuroscientists than ever before, far better imaging devices, a tremendous acceleration of knowledge about the human brain over the past 30 years...why? And mental health takes an increasing toll on us. If not you, someone you know. Why is this so difficult? Is it because what R.D. Laing called "the medical model" finally showed its hand? (A pair of nines?)

Again: our technology to map with ever finer-grains our cells, genes, and organs is greater than ever. We now have a deeper understanding of the human genome, an explosive discovery of the complexity of the epigenome, increasing understanding of how our environment and microbes interact with us...why don't we have a drug that will cure depression by now? Are we simply too complex to understand? Were we destined to be granted a brief window of time in which a few "happy accidents" would yield up as good as it gets, and it all ended 30 years ago? What about our computing power and pharmacological knowledge? Isn't it also subject to Moore's Law: a doubling roughly every 18 months? Shouldn't we have had a bevy of breakthroughs by now?

What are we doing wrong?

In 2011 Eli Lilly thought they had a breakthrough for schizophrenia. They'd given PCP to mice, then their new drug and...the mice calmed down! Everything went well. They got to Stage III clinical trials (humans) and 18 months later the drug was dead. Placebos worked just as well. Lilly is another company that has all but given up now too.

                                    LSD: like psilocybin and serotonin, structurally

Some New Ways of Thinking and Genuine Promise 
Steven Hyman of Harvard and M.I.T. knows this field well. He was quoted in an article I read as admitting of his colleagues, "People are tired of curing mice."

Let's go back to the last breakthough: Prozac and all its cousins.

It had been assumed that, when those happy accidents occurred, there must be a theoretical basis. Pharmacologists have always acted like they were on top of what was going on, but the trade secret was they were faking it: when a drug worked, it went on the market, people used it and they "worked" well enough, but at first the chemists and psychiatrists had no idea why. With better understanding of the brain, they found the ancient model of the imbalance of humors as an explanatory scheme. Only they juiced it up: they found  these drugs altered neurotransmitters. Therefore, the lack of the neurotransmitter caused the disease! It seemed quite plausible, and very much like the hardcore finding that insulin works for diabetics.

Nassim Nicholas Taleb says this is a classic case of the "reverse-engineering problem": drop an ice cube on the floor and then go play cards with your friends in the other room. Can you visualize the cube breaking down into a tiny pool of water? Of course you can. You walk back into the kitchen and see a tiny pool of water where you had dropped the cube. It's pretty straight-forward. Now: imagine walking down the street and coming upon a tiny pool of water. A little spot of wet. How many ways can you dream up the cause of this spot?

A cop comes upon a drunken man looking for his keys, at night, under a streetlight. The cop asks the drunk why he keeps looking under the streetlight, and the drunk says it's because the light is so much better there.

Obviously, even our best researchers have been looking where the light was bright. And the reverse-engineered explanation of our not-all-that-great/we-can-do-better psychopharmacological drugs? Human. All-too human.

The neurotransmitters are not the cause of the mental illness. They merely point at the underlying cause; neurotransmitters (dopamine, serotonin, norepinephrine, etc) are tangential and partial. Reverse-engineering to allow more serotonin to remain in the synaptic gap between neurons was a genius move; too bad there are a handful of studies that show SSRIs work little better than placebos. (For some people they have worked well enough; I don't want to slight this!) All in all, there's a "truthiness" about depression drugs.

We treat everyone the same in studies, while knowing they have variable epigenomes. This is receiving some major research and seems quite promising, to my eyes. We have a semantic problem with experts dealing with a patient, making observations and tests, then naming the disease they "have," which is a major problem: people and diseases do not fall into our socially-constructed and convenient categories as well as we'd like. This problem is now far more acknowledged than ever, which seems promising to me. One example is the Research Domain criteria: we map behavioral abnormalities and symptoms and link them to specific causes in the brain, without the label of "schizophrenia" or "panic disorder." Why is this approach better? Because it's more targeted. Instead of looking at one or two neurotransmitters that "cause" schizophrenia, we try to find out specifically what causes people to hear voices, or become catatonic.

The idea that we must take 18 years from conception through clinical trials is being re-thought. Even more crucially for mental disease: non-human animal studies long ago reached diminished returns. Now the idea is small-scale, carefully controlled studies on humans will speed up the process and may yield breakthroughs in shorter periods.

Another area of promise: when a drug failed, it often worked for a few people. But our gold standard of drug testing: double-blind and placebo-controlled? The rules were that if the placebo worked as well as the drug, throw out the drug. But the people who were helped probably should have told us something.

Along those lines, there is a strong call to restore abandoned or "invisible" clinical trials to correct the scientific record. We may learn some very interesting things from "failed" trials.

The techniques surrounding stem cells have accelerated at an incredibly dizzying pace upward and for the better: now researchers can test cells and drugs in a a dish and make very good guesses as to whether a compound would have some efficacy.

With the mapping of human genome in 2000, hundreds of utopian promises were made that now seem embarrassing or outright quackery. But there was reason to be optimistic. We thought because we were very complex, we'd have the most genes, but instead of 100,000 we only had about 21,000. Grapes have more genes than us: this was nothing like what we'd expected. Worse: 13 years later we now know that a "bigger" system - in terms of complexity - governs the genome: the epigenome. It turns out that RNA plays a far, far bigger part than we'd thought. The complexity can seem overwhelming.

In 2002 researcher Andrew Hopkins came up with an eye-opening paper, the "druggable genome": Okay: we'd thought we had 100,000 genes. We have closer to 21,000. He estimated that only about 10% of those genes coded for proteins that could bind to small molecules, which is how drugs work, basically. So: about 2,100 genes. But he estimated that, of those, only about 20% would be likely to involve diseases. So now we're down to about 420 possibilities for targets. And then he guessed we'd already discovered 50% of those (probably accidentally?). We only had 210 targets left? For all diseases, not just mental illnesses? Not exactly a rosy scenario. But...

Cheminformatics! This is a burgeoning discipline using the aforementioned computational doubling: there are tens of thousands of compounds in digitized libraries. Do you test them all? Two guys wrote  an algorithm to teach a computer to sift through a welter of data on TB, which is becoming antibiotic-resistant. A Big Deal, quite threatening to all of us, potentially. Their algorithm said: find all compounds that are like the drugs that used to work on tuberculosis. So you get that data set. Then the algorithm says, throw out every compound known to be toxic to mammalian cells. You have a smaller set, but a safer one to work with. The algorithm discovered a 40-year old drug that was shown to have anti-TB properties but had been forgotten.

Even more interesting and promising: researchers in Cambridge, MA have taken messenger RNA (mRNA), an ultra fragile molecule which, when injected activates the body's immune response, tweaked a couple of "letters" in its nucleotide sequence, and made a non-fragile mRNA that does not turn on the immune system. What this could do is take the information from the DNA in a gene and make it "fix" missing or broken proteins in another cell, in effect causing a patient with a (probably inherited?) protein abnormality to make a drug inside their own cells!

Nessa Carey, a gifted explainer of how epigenetics works in our bodies, has urged us to be cautious about getting too excited over drugs based on DNA-RNA, because so far, "One of the major problems with this kind of approach therapeutically may sound rather mundane. Nucleic acids, such as RNA-DNA, are just difficult to turn into good drugs. Most good existing drugs - ibuprofen, Viagra, antihistamines - have certain characteristics in common. You can swallow them, they get across your gut wall, they get distributed around your body, they don't get destroyed too quickly by your liver, they get taken in by cells, and they work their effects on the molecules in or on the cells. Those all sound like really simple things, but they're often the most difficult things to get right when developing a new drug."

Finally, there is a very real call to combine all our new technologies with an active looking for happy accidents, like in the 1945-60 period. We find as many compounds that could possibly have efficacy, get people willing to be guinea pigs to try them (we have far better ways to guess at what's likely to have horrendous side effects or death-dealing qualities, but we're by no means "covered" here), and see what happens! Yes, the dark side is that the poor will probably be the ones to sign up...How do we find new things to try? "Scientists Map All Possible Drug-Like Chemical Compounds." It turns out the drunk looking for his keys was far more accurate an analogy than we might've guessed. Or wanted to guess. Check out all the unexplored chemical "space" yet to be charted! It reminds me of the incredible number of phenethylamines and tryptamines that Alexander Shulgin mapped: but a drop in the ocean? (Shulgin deserved the Nobel Prize for Chemistry: just read-up on his career! It's almost criminal he didn't get the Prize.) It's like looking for signs of life in the Milky Way! Or more prosaically: like geologists learning how to more profitably drill for oil. It's also about algorithms and possibilities and adventure and hellacious mistakes yet to be made.

To all of us looking for better living through chemistry: Bon appetite! I do think we may make it through this bottleneck to a whole new world of more sophisticated drugs that will make all the ones we've had since 1945 look primitive. Maybe?

Some Of The Works Consulted:
The Epigenetics Revolution by Nessa Carey
"No New Meds," by Laura Sanders:
http://www.sciencenews.org/view/feature/id/348115/description/No_New_Meds
Happy Accidents: Serendipity In Modern Medical Breakthroughs, by Morton A. Meyers
"The Psychiatric Drug Crisis" by Gary Greenberg:
http://www.newyorker.com/online/blogs/elements/2013/09/psychiatry-prozac-ssri-mental-health-theory-discredited.html
PIHKAL: A Chemical Love Story, by Alexander and Ann Shulgin
"Where Are All The Miracle Drugs?" by Brian Palmer:
http://www.slate.com/articles/health_and_science/human_genome/2013/09/human_genome_drugs_where_are_the_miracle_cures_from_genomics_did_the_genome.single.html
"Messenger RNAs Could Create a New Class of Drugs," by Susan Young:
http://www.technologyreview.com/news/512926/messenger-rnas-could-create-a-new-class-of-drugs/
"Faster, Smarter and Cheaper Drug Discovery":
http://www.sciencedaily.com/releases/2013/03/130321131920.htm
Serendipity: Accidental Discoveries In Science, by Royston Roberts
Hope or Hype: The Obsession With Medical Advances and the High Cost of False Promises, by Richard A. Deyo and Donald L. Patrick
"Experts Propose Restoring Invisible and Abandoned Trials to 'Correct the Scientific Record'":
http://www.sciencecodex.com/experts_propose_restoring_invisible_and_abandoned_trials_to_correct_the_scientific_record-114055
The Black Swan: The Impact of the Highly Improbable, by Nassim Nicholas Taleb