Be grateful for MDMA

Sasha Shulgin is a legendary chemist and psychonaut and inventor of hundreds of psychedelics. In 1991, he and his wife, Ann, published a book. Part-novel and part-cookbook, PiHKAL—Phenethylamines I Have Known And Loved—told his story and the stories of the compounds he and his friends had ingested, a process he ironically termed ‘LAB’, or Large Animal Bioassay.

It’s a gorgeous book, and a work that is still unmatched in its candour and novelty (and notoriety).

Flip to the back, and there are 179 entries on various substituted phenethylamines, each with intricate synthesis notes and experience reports detailing the effects each compound had on him and his close friends.

My favourite is #109.

MDMA (MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE)

As the material came on I felt that I was being enveloped, and my attention had to be directed to it. I became quite fearful, and my face felt cold and ashen. I felt that I wanted to go back, but I knew there was no turning back. Then the fear started to leave me, and I could try taking little baby steps, like taking first steps after being reborn. The woodpile is so beautiful, about all the joy and beauty that I can stand. I am afraid to turn around and face the mountains, for fear they will overpower me. But I did look, and I am astounded. …

I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great, or believed this to be possible. The cleanliness, clarity, and marvelous feeling of solid inner strength continued throughout the rest of the day, and evening, and through the next day. I am overcome by the profundity of the experience … All the next day I felt like ‘a citizen of the universe’ rather than a citizen of the planet…

Everyone must get to experience a profound state like this. I feel totally peaceful. I have lived all my life to get here, and I feel I have come home.

I am complete.

Shulgin saw that MDMA had huge potential. A gentle empathogen and entactogen (meaning literally “to touch within”), it allows deep but unthreatening introspection. He was certain it would be of use in therapy, and only now are its medicinal properties being scientifically evaluated. He also knew that if it became a street drug, its use in psychotherapy would be drastically limited. He was right.

The MDMA experience tells us something important about being human. It shows that states of transcendence and emotional bliss beyond our normal capacity are possible. It proves that our brains are capable of amazing things, and that the substrates of superhappiness exist within our current wetware, even if such states are not normally available to us.

Shulgin was struck when he realised that the psychedelic experiences he had were not contained within the few hundred milligrams of white powder at the bottom of the glass, but were contained within him. The drug was merely a catalyst for revealing what was already there.

We should be grateful that we are already so rich, and that there is so much inside for us to discover.

Don’t confuse consuming and producing

I’m trying to figure out what to do with my life. Give me your thoughts.

Michael Idov writes in his piece Bitter Brew in Slate:

I never realized how ubiquitous the dream of opening a small coffeehouse was until I fell under its spell myself. It seemed that just about every boho-professional couple had indulged in this fantasy at some point or another.

The dream of running a small cafe has nothing to do with the excitement of entrepreneurship or the joys of being one’s own boss—none of us would ever consider opening a Laundromat or a stationery store… The small cafe connects to the fantasy of throwing a perpetual dinner party… To a couple in the throes of the cafe dream, money is almost an afterthought. Which is good, because they’re going to lose a lot of it.

This article is the story of a young married couple who decide to run a cute little coffee shop (in New York, but any big city’ll do). They’re enamoured with the idea of it, not because they want financial independence, to set their own hours or to be their own boss(es), but because they’ve fallen in love with the notion that providing that service will be just as fun as consuming it.

The thing is, running a coffee shop is nothing like drinking lattes in a coffee shop. It’s gruelling, expensive and hugely risky. That’s why so many people fail—because they were in love with an aspect of the job that doesn’t exist.

My love of science, of biology and biogerontology and finding practical ways of slowing ageing can be subjected to a similar analysis. I’ve made the mistake of thinking that reading about/talking about/enjoying the fruits of scientific advance will be just as fun as actually doing the benchwork myself.

It’s the distinction between what you do day-to-day and the narrative you invent to describe your job—a distinction I’ve been deliberately (if unconsciously) blurring by describing my work in a biogerontology lab as making a grand contribution to understanding and ending ageing. It’s a great story but it’s not the truth, and wouldn’t be even if I had some scintillating project analysing rat brain ageing or dietary restriction in flies. I would still be a technician, just like the coffee shop owner is still a vendor and not a coffee connoisseur.

I could just as easily enjoy science from afar, and that way, I might be able to stay a consumer.

What’s the point of OpenPCR?

For those not in the know, PCR is a standard biological technique that lets you make lots of copies of a piece of template DNA. It’s crucial because a lot of molecular biology relies on having a large amount of a particular DNA, so it makes possible everything from DNA fingerprinting to genomics to forensics to getting bacteria to express a gene of interest. Its invention changed the face of modern biology.

Thermocyclers, the machines which do PCR, are expensive. Thousands of dollars expensive. And there’s no good reason for it because they’re pretty simple: they just need to reliably heat up and cool down sample tubes to allow the chemicals inside to do their job. In fact, early PCR machines were just three water baths, each at a specific temperature, between which a technician would move their samples.

OpenPCR is an open-source PCR machine. From Why we built OpenPCR:

There are really two core benefits I see to a machine like OpenPCR. The first is a drastically lower price point. … The second … was to create a substrate for further hacking.

I love it. I want one. It’s a really gorgeous machine, too, made of laser-etched wood panels with black rivets. And it’s cheap, with kits costing $599 and taking around three hours to assemble.

But who’s it for?

Hobbyists will certainly be attracted by the low price, but molecular biology requires a lot of kit. Thermocycler aside, you need primers for each reaction you want to carry out which often have to be custom-made, all the enzymes and reagents for the PCR itself, plus restriction enzymes and the equipment to run a gel to visualise the DNA you’ve amplified (so that’s agarose, buffer, DNA dye, an electrophoresis tank and a UV visualiser). Most of which has to be shipped refrigerated by companies which probably won’t sell to individuals.

I want to see home-brew biology flourish. I love the idea that you can analyse your own DNA to see if you have a particular polymorphism, or identify unlisted plant ingredients in commercial teas. But molecular biology has always been capital-intensive and as long as that’s the case, the kind of “garage biology” that OpenPCR’s inventors want to encourage will be out of reach for most.

Shortcuts for supercentenarians

First posted on Nature Student Voices. It’s a long and relatively technical piece on ageing and how there might be shortcuts to slowing it down without knowing much about its molecular mechanism.

The aging process is complex and multifaceted, but slowing it may be easier than we thought—and in biogerontology, there might be such a thing as a free lunch.

In the 1930s, biogerontologist Clive McKay found that rats whose diets were reduced to sixty per cent of what they would eat normally were living healthily, with glossy fur and eyes unclouded by cataracts, at ages where their normally-fed compatriots were dying[1]. McKay thought wrongly that it was stunting development that extended lifespan; Ed Masoro would later find that caloric restriction could be started during adulthood and cause a similarly profound drop in mortality[2]. Calorie restriction (or CR) has been found to work in mice, rats, worms, fruit flies and yeast, and probably works in higher organisms as well[3]. A trial at the University of Wisconsin–Madison is attempting to determine the effects of CR in rhesus macaques, the most humanlike animals yet used in such experiments. While the final results of the trial are many years away—these monkeys do live for 25 years on average, after all—already the animals on CR show signs of increased lifespan and ‘youthspan’, with normally-fed monkeys dying at three times the rate of calorie restricted ones[4].

Biogerontology’s grand claim—that we can control and slow aging—is thus made credible. If simple interventions can reliably increase lifespan in animals, they almost certainly work in humans, too. The island of Okinawa off the southernmost point of Japan harbours the world’s largest population of supercentenarians (those lucky few who live for a century or longer), and it is likely no coincidence that the Okinawan Japanese have a culture of leaving the stomach part empty at the end of every meal.

Of course, calorie restriction is hardly fun. The regimen has side-effects and few would be able to stomach a one-third reduction in their calorie intake. But as proof-of-principle, CR shows that there are low-hanging fruit in life extension: simple biological switches that can increase longevity. Finding a simple way of flicking those switches is a major goal of modern biogerontology.

As a phenomenon, CR is intriguing: if we have genes that specifically lengthen animal lifespan, as xenometabolic enzymes, heat stock proteins and protein chaperones seem to[5], why aren’t those genes switched on all the time? Certainly if living longer was evolutionarily favourable, they would be. But the opportunity cost of expending energy on cellular maintenance is investing less in reproduction. In species where early and prolific reproduction is evolutionarily favored, faster aging is promoted at the expense of extended lifespans and long reproductive careers. The battery of life-extending genes that lie dormant within so many species are only activated in times when food is scarce and conditions harsh, delaying reproduction to concentrate on surviving the drought before returning to full reproductive capacity. Simply, CR probably switches on a form of reproductive diapause—a way of adjusting the balance between reproduction and longevity.

Sirtuins are a major candidate in the search for ‘CR mimetics’, or drugs that trick the body into thinking calories are few and far between, so simulating CR. Notable among them is resveratrol, a compound found in grape skins and present in red wine, which stirred much enthusiasm in the field (and not a few high-profile headlines). If these chemicals could trick our bodies into thinking their calorie intake was being drastically reduced—if they could switch on longevity genes—we could enjoy longer lifespans and healthspans. With most people having few children late in life, the cost of reduced fertility would not be a hard one to bear.

David Sinclair was formerly a postdoctoral researcher working for Leonard Guarente in MIT where he discovered that the protein Sir2 prevents the formation of ERCs (extrachromosomal rDNA circles, a key biomarker of aging in yeast). Another postdoc in that lab, Matthew Kaeberlein, found that overexpressing the Sir2 gene extended yeast lifespan. The gold rush for CR mimetics began, with Sinclair founding Sirtris, a company trying to develop and commercialise sirtuin-based anti-aging compounds[6]. His firm was later acquired by pharmaceutical giant GlaxoSmithKline for a staggering $720million, symbolic of the commercial significance a drug that could slow aging would have.

But the effectiveness and pututative mechanism of resveratrol has been called into question. It extends the lifespan of mice, but only those fed a high-fat diet. Later work by Kaeberlein failed to find any life-extending effect of resveratrol on several strains of yeast[7]. The compound was found to increase the lifespan of the humble nematode C. elegans, but its activity may be unique to that species alone (a ‘private’ rather than ‘public’ mechanism of aging). More worryingly, a 2010 study by David Gems and Linda Partridge at UCL’s Institute for Healthy Ageing found that sirtuin overexpression left fly lifespans unchanged and caused only minimal life extension in worms, casting doubt over the entire premise that firms like Sirtris are counting on[8].

Gems recently made newspaper headlines when his laboratory published a paper claiming poor-quality research was to blame for the conflicting results[9]. Specifically, poorly-controlled genetics (such as sirtuin overexpressing animals picking up other life-extending mutations) seem to account for the life-extending properties described by previous researchers, and Gems showed this by demonstrating that sirtuin overexpression and lifespan extension were separable genetically. Guarente challenges this in the same issue of Nature, claiming that he used the best techniques available at the time, and that carefully-controlled followup work confirms a (somewhat smaller) life-extending effect[10].

It might be years before sirtuins’ mysteries are properly described. Some think that these compounds don’t activate the sirtuin pathway at all, perhaps acting via TOR (target of rapamycin) signalling. Other sirtuin activators with potencies orders of magnitude greater than resveratrol are under development and may work where resveratrol failed. But even if Sirtris fails to be the jewel in GlaxoSmithKline’s crown and sirtuins act by entirely different pathways, CR mimetics might be a quick and dirty way to extend lifespan without needing to know much at all about the underlying processes of aging.

References

1. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr. 1935;10:63–79.

2. Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms, Biochimica et Biophysica Acta 2009, 10:1040–1048. doi:10.1016/j.bbagen.2009.02.011. PMID: 19250959

3. McDonald RB, Ramsey JJ. Honoring Clive McCay and 75 Years of Calorie Restriction. J Nutr. 2010;7:1205–1210. PMID: 20484554.

4. Colman RJ et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009 Jul 10;325(5937):201-4. PMID: 19590001

5. Gems D, McElwee JJ. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech Ageing Dev. 2005 Mar;126(3):381-7. PMID: 15664624

6. Garber, K. A mid-life crisis for aging theory. Nature Biotechnology 26, 371 - 374 (2008) doi:10.1038/nbt0408-371

7. Kaeberlein M et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17038-45. PMID: 15684413

8. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev. 2007 Oct;128(10):546-52. PMID: 17875315

9. Burnett, C et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011 Sep 21;477(7365):482-5. doi: 10.1038/nature10296. PMID: 21938067

10. Viswanathan M and Guarente L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 2011 Sep 21;477, E1–E2. doi: 10.1038/nature10440.

Ambitious psychology

This month’s Lates night at the Science Museum—described as an evening of ‘free adults-only entertainment’—put the spotlight on the study of happiness. One event, a talk by Glenn Wilson, touched on a number of aspects of happiness research. In its modern form, positive psychology is a relatively young field, and it focuses specifically on evidence-based methods for improving happiness.

Positive psychology has a few perhaps obvious things to tell us: being employed (or better, self-employed) and having big, external life goals are all sources of happiness. People with a small group of intimate friends are happier than those with large groups of superficial friends. Commuting is miserable, but being jobless is worse. Negative self-talk is poisonous to happiness, which is why so many treatments for depression focus on quashing it.

There were some strange ones, too: the anticipation of a holiday is more enjoyable than the holiday itself, so perhaps several short breaks are advisable to maximise pre-vacation euphoria. Churchgoing rather than theological belief brings happiness to the religious. And women, in spite of increased equality and opportunity, have been becoming more unhappy for years. This is the counterintuitive dark side of the study of happiness.

But the talk felt trite. Drugs, for example, were quickly dismissed as reducing happiness long-term. Of course, highly addictive drugs like heroin likely produce net unhappiness. But volunteers given psilocybin, the active ingredient of magic mushrooms, overwhelmingly enjoyed the experience—and the majority said it had a lasting positive effect on their lives when asked 18 months later. Few would debate that, while it can be harmful, alcohol’s societal role could be a net good if it encourages people to make friends and enjoy rich social experiences. Yet an honest, evidence-based appraisal of different drugs’ harms and benefits—one that considers the enjoyment they bring as a benefit—is presumably too unpalatable to ever get funding at a time when every nation on the planet has drug prohibition laws of one sort or another.

What of the role of personality in happiness? In a culture where connections and networking are emphasised as crucial to building a career, do extroverts fare better than introverts? Malcolm Gladwell writes extensively about the role of ‘soft skills’ in people’s success—skills which he believes middle-class parents pass onto their children but working-class parents do not—like assertiveness, social graces and other learned behaviours which aren’t formally taught but can drastically alter life outcomes and signal membership of a particular social group, for better or for worse.

Wilson also mentioned the ‘hedonic treadmill’, the notion that people return to a particular happiness set-point over time. Positive life events don’t affect long-term happiness—but nor do negative ones. (That paraplegics are no less happy than the able-bodied in spite of their loss is proof of this.) The hedonic treadmill guarantees that the we have much less control over our happiness than we would like, and that, in the end, it might be impossible to move our happiness significantly away from some immutable mean.

Later in the evening came a brief talk in a tiny, packed room from a curator at the Museum seeking to expand their collections. The resident Historian of Psychology reviewed the history of animal models of addiction. It was a useful lesson in experimental bias: the first animal models of addiction used rats placed in a Skinner box (a metal box with an assortment of levers) to see whether they would prefer to self-administer morphine delivered straight into the brain to to press a lever to get a food pellet. The mice preferred the morphine over food and water, even when they were dying of starvation. Ever since, this has been the prevailing model of addictive drugs - that the sheer force of the desire to consume them is overwhelming.

But a protégée of Skinner’s, Bruce K. Alexander, wasn’t convinced. He worried that by moving caged rats around when they were experimented on, the rats were responding more to the attention they were getting than to the drug, and that the results Skinner had seen were just an artefact of this. He set up Rat Park—an open space with toys, other rats and faux greenery—which he thought more accurately emulated rats’ natural environment. In Rat Park, he found that rats actually preferred water to morphine water, perhaps because the morphine made them asocial and unable to play with other rats. Adding naloxone to the drugged water neutralised the effect of the morphine, and the rats were then happy to drink it.

The outcome probably wasn’t as stark as was presented in the talk—other researchers succeeded only partially in reproducing the experiment—but the result is striking enough. Alexander’s experiments failed to have the intended effect on his peers, though, and the models of addiction he purported to have rubbished live on in contemporary academia. He now spends his days studying human drug addiction through history and anthropology, and his latest book is based on the premise that addiction is a social phenomenon, not a pharmacological one. He wants to ‘reshape society with enough force and imagination’ that people would be able to find meaning in their lives—meaning that he thinks would take the place of addiction in many cases.

Positive psychology is increasingly seen as a highly respected discipline. Studying mood and developing the tools to improve people’s happiness is a noble and ambitious goal. So is Bruce Alexander’s attempt to reframe addiction as a social disease—and to build a new society whose properties don’t allow it to exist. Both require an unflinching devotion to empiricism. But at their core, they are fields driven by a desire to understand what makes people tick, and an ambition to improve the human condition.