Researchers unravel the biosynthesis of psilocybin | Hacker News Reader

Researchers unravel the biosynthesis of psilocybin

cen.acs.org

277 pointsrobin_reala88 comments

Always wondered what will happen to drug use and trade when at some point not too far in the future we start to have GM yeast that can produce opioids, cannabinoids, and psychedelics easily at anyone's home.

YC SS 18 anyone, disrupting the $435 billion global drugs trade? :D

To be fair, I can't speak to opioids but cannabis and natural psychedelics are already very simple to produce. The main reason not to try them isn't because they're hard it's because of not wanting to fail a drug test for work or not wanting to be arrested for possession.

It's much more difficult than biosynthesis of alcohol, which is so easy you can do it by accident. Leave a container of fruit juice uncovered and wild yeast will most likely ferment it. If you add dried yeast and cover it with an airlock (which can be as simple as a lose snap-fit lid (snap-fit so it won't get stuck and explode)) and it will most likely taste acceptable too.

Fermenting alcohol is so easy that there's no practical way to enforce alcohol prohibition. It takes no specialized equipment (lights etc.), it's easy to hide, and you might be able to pass it off as an accident if you get caught. If you could make other drugs in the same way it would become very hard to enforce their prohibition.

Many drugs are within that general level of simplicity to produce. They're plants and fungi, and growing them is as simple as regular plants and fungi. Psilocybin, mescaline, cannabis, even opium is pretty simple.

The details difficulties are related to regulations, or stealth (for illegal producers).

I grow regular food plants (chiles), and it's not that simple. You have germination, irrigation, fertilization, repotting, pest control, weeding, etc. If you just carelessly throw some seeds on the ground then they probably won't germinate or they'll get eaten by animals and you'll get nothing. If you forget to water them they'll die. You have to check them every day if you want them to grow reliably.

Making wine is as easy as buying a carton of grape juice, adding some dried yeast, and covering the top with some aluminum foil. It won't be good wine, but it will be recognizably wine. People living under prohibition would be happy with it. If you try growing chiles with that level of effort you'll get nothing edible.

Weed is often grown by people tossing seeds on federal or someone else's land then coming back to collect when grown and doing nothing else. For a while it was in WV's top 3 crops because there was so much unused land for people to do this.

Like all crops they benifit from care, but the trade off of ~zero time, effort, and risk for some value is the appeal.

Eh, peppers are harder than lots of other vegetables. If you have good results with them, you'd have no problem with tomatoes, turnips, onions, radishes, lettuce, etc. I've never grown an "illegal" plant, but you may not be able to generalize from chili peppers to e.g. pot.

Eh, mescaline, weed and (sort of) Psilocybin) is fairly easy. I guess the difference is it takes a lot longer to grow these things rather over fermenting alcohol.

These are the two I was thinking of. If you're trying to optimize for quality then there's difficulty. But simply hiding a weed plant and getting a yield isn't difficult unless you live in a colder climate. Shrooms are so easy people grow them in shoeboxes.

Edit: When I said two I failed to notice mescaline. I haven't done much reading on mescaline.

People in California grow huge San Pedro cacti in their garden, but that doesn't work so well when you are living in a colder climate.

Ever grown mushrooms? I wouldn't call it easy. It takes a few months and a lot of preparation, plus you need a pressure cooker and some other equipment.

A lot of that is just time though. A pressure cooker isn't a difficult item to acquire and it's hardly suspicious. Even in America, it's mainly difficult in states like California and that's only because of the increased challenge to acquire spores. Most states in the USA have a weird loophole where you can purchase spores but the shrooms themselves are an illegal good. There are people who grow them in shoeboxes from kits. As long as you're willing to compromise quality in exchange for simply producing some amount of quantity you can get mushrooms with relatively little risk.

Depends what you're comparing it to I guess. It's still very much hobby-grade though and with some techniques (like the famous PF tek) you don't even need a pressure cooker.

It still requires some time and dedication but it's really simple compared to, say, the synthesis of LSD.

i believe a pressure cooker is optional for sterlization, and by all accounts it is easy, much easier than growing cannabis, which can be a bit more labor intensive

I've collected them growing in the wild... yes I mean psilocybin as well as morels, etc.

That also takes a decent amount of training (especially with the morels as they have poisonous lookalikes I've heard) and you need to be in the right environment. The PF Tek that another person mentioned is also not going to be so easy for the average person. I got 3-4 ounces my first try growing in mason jars and big plastic tubs, but it could have yielded a lot more if the tub hadn't gotten infected after one or two rehydrations. Initially I remember not knowing where to start as I read through the assortment of information and techniques out there, so that too adds to the difficulty of learning.

Selection bias. You found the lucky plants that managed to live. I had a friend try to grow shrooms, and despite managing the humidity, temperature and light exposure, disinfecting the container, and carefully controlling just about every aspect of the process he couldn't get shit to grow.

Likewise when I was strapped for cash in college I briefly considered growing a few cannabis plants and decided against it after it seemed to be a lot harder to grow anything sell-able than expected.

Counter anecdote: I did it about 15 years ago and got several pounds of good quality shrooms with no special knowledge or effort. Got lucky I guess.

I've always considered the main reason we don't have a larger home grown drug problem is the same reason high-end crime is relatively rare: you're selecting a technically capable subset that our society already rewards fairly well.

Such is the setup of Breaking Bad: were Walter White not terminal, would he still take the risk?

That and the fact that police techniques for locating this kind of thing is pretty advanced. Until recently (LED grow lamps) the power consumption from grow lamps was so high that the power company would notice and the police would take interest. Cops can also drive around with infrared cameras looking for hot exhaust air/lamps, visible even if windows are blocked. Helicopters with infrared cameras can see hidden grow plots outside.

Even when I was looking at it people were still split over LED vs conventional lights for growing, so it's only gotten easier to evade detection as the legality of growing has relaxed (literal definition: become less strict again).

I don't know about shrooms, but they're peanuts compared to weed anyway. Obviously it's infeasible to grow coca anywhere in the US- you need a huge amount to produce any drug. Likewise creating LSD/MDMA/meth without synthetic, highly controlled precursors is pretty much completely infeasible. You could grow morning glories for ergot... if you wanted to harvest an entire field of them.

But yeah, any decent chemist could figure out how to make any of the big drugs very easily. The precursor restrictions only keep out the non-experts. Even a penniless chemist knows that going to jail for that will make him totally radioactive for the rest of his life.

That's not a counter, it's more selection bias. Nature is a good place for mushrooms to grow, but that doesn't mean it's easy to grow them yourself. Cannabis is a very successful plant but it still isn't as easy to grow in your home. You can go outside and find a fern almost anywhere in the world- they're one of the oldest, most successful, and most widespread plants, but they are a pain in the ass to grow yourself: http://articles.latimes.com/1991-10-27/realestate/re-649_1_m...

Sorry, I may have been too vague. I grew them in a large plastic bin in my bathtub. I got the spores and was able to start the mycelium without any bacteria problems, somehow (My kitchen was no more sanitary than you would expect from a 21 year old bachelor). I really had no idea what I was doing so, based on the stories I hear of other people trying and failing several times before giving up, I assume I was just exceptionally lucky. :)

Edit: Ah, I get your point about selection bias now. Yes, based on self-reporting on drug forums I am surely in a small minority of clueless yet successful psychedelic mushroom farmers. I suppose if I ran through a minefield once and didn't lose any limbs, I would think that was easy too: "just run in a straight line as fast as you can, no problem!"

I also had success growing mushrooms at around that age. I just followed the instructions and did try to take extra care with cleanliness, my guess is that as we're both here on HN we're probably predisposed to be better at following a process.

There are kits available with the sterilization part done for you.

Or just move to pasteurized hay, which is much more lenient

My friend said that pressure cooking popcorn kernels as an incubation medium allowed fast mycillial colonization. He could shake the jars every couple days to speed up the process. He also claimed pasteurized hay made an excellent growth substrate.

the hard part is keeping everything clean once youve inoculated

LSD is not trivial to make but once you can, you can produce an entire country's supply in no time, given the minuscule dosage.

The United States is estimated to have very few acid makers, with roughly a half-dozen accountable for most of the country's supply.

1P-LSD is currently legal and mass produced for cheap online. Much what we see is this.

Since 1P-LSD is theorized to be a prodrug of LSD, it would likely be illegal in the United States under the Federal Analogue Act. https://en.wikipedia.org/wiki/Federal_Analogue_Act

> likely be illegal

It's not illegal.

I always had the impression that psilocybin in particular either was not tested for or does not stay in your body long enough to be tested for. My only concern with psilocybin mushrooms would be their legality, but IIRC, it is not illegal to possess spores for them.

Better yet, the ability to integrate synthesis in your body. So you can trip whenever you like. Burroughs predicted that decades ago.

This is less good in practice than in theory:

https://en.wikipedia.org/wiki/Auto-brewery_syndrome

Woah. But I was imagining more conscious control.

Yeah, made me think of "glanding" in the culture novels (iain m banks scifi)

Our body already has this ability but does not use it often.

I'm sure that our bodies produce molecules that interact with the same receptors that psilocybin does. But that doesn't mean that our bodies produce psilocybin.

Psilocin is 4-hydroxy-DMT, and psilocybin is just phosphorylated psilocin. DMT is itself just dimethyl tryptamine, which is a modified serotonin. Serotonin itself is itself just modified tryptophan (without the hydroxyl group). The body produces small amounts of DMT naturally, I wouldn't be surprised if that is also the case for Psilocybin. Biochemistry is messy and small amounts of many "unintended" products are created.

Of course... serotonin.

can you elaborate on that?

I'm guessing it's the production of DMT (similar to psilocybin and LSD) by the pineal gland that is being referred to. IIRC there's still a debate about whether it can cross the blood-brain barrier, but it seems quite likely. Ostensibly it's produced at birth and at death.

Please excuse the lack of sources, but the book The Spirit Molecule kickstarted this line of thought if you're interested in learning more.

Cannabinoid GM yeast has already been created

https://mobile.nytimes.com/2015/09/15/science/newly-risen-fr...

It's already possible and easy to grow psychedelic mushrooms at home from growkits.

the best way to save the rainforest is to make more efficient drug crops.

Probably about the same.

There are already tons of similar psychedelics available that are produced synthetically, including the extremely similar (if not identical, in terms of active metabolites and subjective experience) 4-AcO-DMT.

Still, it's always good to see progress in this area, and for medical research I guess it's not acceptable to use analogues because "it should be similar!" isn't a medically sound reason to use an analog instead of the better researched psylocibin.

4-AcO-DMT is psilacetin, which is an acetylated form of 4-HO-DMT, or psilocin. Acetylization seems to result in an easier time crossing the blood-brain barrier, resulting in a quicker onset of effects, with a matched quicker comedown. You're still looking at a couple hours.

Even without the psilocybin (or other alkaloids present), the experience appears mostly identical to P. cubensis mushrooms, but without the nausea, and seemingly a higher disposition toward producing negative experiences. It's incredibly easy to be overwhelmed by the euphoria being too intense, and dysphoria over negative effects such as akathisia. This can very easily spiral into mild panic attacks, knowing full well that things aren't going to wear off for a few more hours.

The milder variants 4-AcO-MET and 4-AcO-DET seem to reduce negative experiences, but overall they're still far too unpredictable whether the experience will end up enjoyable or not.

Whether natural or synthetic -- regrettably, the efficacy in treating depression and obsessive compulsive disorder appear to be overly optimistic.

>(if not identical, in terms of active metabolites and subjective experience)

I suppose the limits of 'subjective experience' have way more fluctuation than the 'active metabolites' category they were able to test for.

For synthesis, you don't need to know the exact pathway, but phosphorylation is very awkward synthetically, so you do need the enzyme for that (usually doesn't have to be the exact one, though). Synthetic psilocin is already a thing, it's just not sold because it's illegal and rapidly oxidized by air. Understanding the biosynthesis of stuff is more of a gateway to messing with it where it is or transplanting it into bacteria (which can be cheaper than synthesis).

Aren't there a number of pharmaceutical drugs that are exactly "it should be similar"?

The benzodiazepines spring to mind, as do many of the SSRI drugs. Amphetamine is chemically rated to that from which it is derived: ephedrine.

no. drugs that act on GABAA, serotonin, norepinephrine, and dopamine receptors individually don't seem to affect the whole of the brain the way psychedelics do,[0] which we didn't really know about until 2016. from the available literature, which is scarce, it seems like psychedelics are more analogous to something like transcranial magnetic stimulation, which also "wakes up" and potentially even heals the prefrontal cortex. it's too bad it's so hard to study medical applications of these drugs.

0. http://www.pnas.org/content/113/17/4853.full

I'm confused as to what you are disagreeing with here.

I was responding, in the general sense, to the claim that for medical research I guess it's not acceptable to use analogues because "it should be similar!" isn't a medically sound reason to use an analogue. This statement, evidently, doesn't map well to the field of pharmacology.

The benzodiazepines comprise at least twenty different chemicals in five classes.[1] Structural analogues[2] are as common as horse shit in medicine and medical research. Structural analogues are also present in the SSRI class of drugs[3].

Psilocybin and dimethyltryptamine are structural analogues. It's unsurprising that their effects are broadly similar when ingested orally.

With regards to your comment "... don't seem to affect the whole of the brain the way psychedelics do which we didn't really know about until 2016"... Surely that was evident to anyone who'd tried amphetamine at least once and mushrooms or LSD or DMT at least once. Amphetamine can be compared to caffeine, and even at high doses it doesn't really alter your way of perceiving the world. Where as the psychedelics, at sufficiently large doses, can be likened to being fucked open to God by Jesus, while riding a fluorescent unicorn and as you watch the universe unfold.

1. https://en.wikipedia.org/wiki/Benzodiazepine#Common_types

2. https://en.wikipedia.org/wiki/Structural_analog

3. https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_i...

sorry, after re-reading the op I can see I misinterpreted your comment to mean SSRIs, benzodiazepines, and psilocybin had a similar effect on the brain. we don't disagree.

I take gabapentin for nerve damage, no euphoria but I do get a detached feeling of general wellness.

Its not all good though, it also makes my head fuzzy, enough that it impacts work so I keep the doses to the minimum during the day and take some pain in return for clarity, it's a devils choice either way though.

We actually do know that drugs that are considered "psychedelic" tend to have a dominant 5-HT2A agonist effect (serotonin targetting), actually. Chemical compounds are often not terribly specific, so other receptors get tickled as well... and there are other hallucinogen classifications that do not target serotonin receptors. But pretty much all of the "classic" psychedelics (ergolines and tryptamines) target 5-HT2A quite heavily; many phenethylamines also target 5-HT2A as well (although there is more receptor variety in that class of compounds).

I believe you are right that much of the overall effect on the brain of these compounds is poorly understood.

For those interested, YC has invested in a few synthetic organism companies. Ginkgo Bioworks (YC) is probably the most notable, they've raised a good amount of money on this platform. Teewinot is also working on biosythentic cannibis.

I wouldn't get your hopes up, biosythensis is a much messier and less defined process than chemical synthesis, meaning the route to market is much more rugged. There are some cool use cases that may arise - such as rust eating bacteria - but in general I'd expect an experienced synthetic chemist to be a more economy favorable route to most chemicals. Partial synthesis, where a chemist works with a partial product produced in yeast, might yield good results in some edge cases.

I am glad to see research like this is moving forward. The potential benefits really are huge.

Biosynthesis. Ah. Here's a sythensis from 2003:

Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of “Magic Mushroom”

http://pubs.acs.org/doi/abs/10.1021/np030059u

Synthetic cannabinoids like JWH018 are a failure , I've tried it. Nothing like the real thing. And it's reported to cause psychotic episodes. I don't think I would trust synthetic mushrooms. Regular mushrooms can already be very nerve wracking

There are already psilocybin prodrugs that are legal on the market that are qualitatively identical after metabolizing. Pre-metabolism there may be distinct phenomena and concerns, but it degrades quickly.

Cannabinoids are different entirely; i can't speak to the dangers there, particularly when combustion is involved.

Is there any further research in this space that you could recommend worth reading? It's very interesting.

Hopefully they can make it taste better?

Many years ago, we grew ours on white rice. Eaten fresh, they were quite tasty. Also OK after freeze drying. But commercial Psilocybe do have an unpleasant taste, even fresh. Maybe they grow them on manure.

Well you effectively have 3 common ways of consuming them: fresh, dried and truffles. In my opinion dried is very easy to consume, they don't have most of their taste (nor mass); truffles come second because they don't taste too bad (kinda like nuts but tartier) and finally the worst to consume because of volume and taste is regular fresh caps and stalks but even then they don't taste that bad.

Eating them in something like a ham sandwich makes it OK in my opinion.

I've only ever ordered them from legal producers so I don't know how much extra work they put into making them not taste bad versus illegal growers.

4th: brew them in a cup of tea.

Yeah, this is the best way to consume the shroom. Mix with a little loose leaf green tea and it actually tastes pretty good, with a tingly after-feeling on your tongue.

For anyone that's interested, basically just roughly dice 1/8 oz. of dried mushrooms and add a scoop of your favorite tea. Put the mix in a large teaball (or multiple small ones). Boil 2-3 cups of water. Let the water cool for 20-30 seconds on a cold burner before pouring into your teapot. Steep and drink!

Where / how is it legal?

At least in the United States, it's legal to buy and ship the spores in almost every state (one notable exception being California).

I grind mine to ~dust and pack them in 0.3 g gelatine capsules - no taste and 1 is just enough for microdosing.

you microdose mushrooms?? Interesting. Just for recreation when you want to relax or do you ever do it during the day?

I'm on a break but I used to take them for the general enhancing effect and going deeper into meditation. Sometimes during day even in public places, which was a big mistake in the generally nervous/anxious place I was in life. Perhaps I got too arrogant.

edit: then again a capsule or two and a remote cabin could be just what I need to reset from the upheaval in my mind..

Do you get any meaningful work benefit from a single 0.3g capsule? That sounds low even for a microdose.

It is possible I'm more sensitive to its effects for various reasons but ime one capsule starts working in 30-45 minutes and I get a noticeable effect affecting mood and bodily sensations. 1 capsule certainly gets me more in touch with the internal world when meditating.

I don't know how much one should talk about this stuff on open forums but it certainly can be a shortcut to achieving or visiting some powerful states of experience, which may not be always be or seem positive at least during, so Ymmv and be safe.

I've microdosed mushrooms maybe a dozen times and generally the last thing I want to do is work. Would not recommend to anyone looking for a productivity boost.

With that said, they're a great stress reliever.

Tea with honey. Tastes wonderful.

Blue Honey, my friend... blue honey. Many years ago I was gifted a mason jar of it, made from fresh whole mushrooms, blue as can be, beautiful and very tasty. Started the day with one thin spread on a piece of buttered toast, then breeze through the day until after work, when a nice cup of blue honey tea got me through the night. Yeah, I miss that.

ah such a romantic feeling description and so dead on

Hopefully they make it trip better.

Bad trips are a ...doozy, to say the least.

this discovery will likely have little impact on the taste of what's being consumed, or the subjective quality of the trip.

the bad taste is the result of either a) the flesh of the mushrooms, or b) (in the case of isolated psilocybin) the alkaloid being a bitter "chemical" tasting chemical. in either case, the problem can be mitigated without understanding the mushroom's psilocybin synthesis pathway.

the bad trip has to do with the alkaloid itself, and a the reaction of particular brain that's been dosed with it at a particular time. again, understanding the mushroom's synthesis path isn't going to change the end result. it might help chemists discover new and worthwhile paths to synthesizing other tryptamines with a lower potential for bad trips, but it's not like there's a shortage of viable methods for producing novel tryptamines at the moment.

still, really really cool discovery. not trying to downplay that. just saying the parent and GP i'm replying to are talking about things that are pretty much orthogonal to this discovery.

EDIT: ok, i can imagine one situation where this could impact flavor: in a world where psilocybin is legal, one might imagine boutique engineered mushroom strains that have desirable flavor characteristics, and which produce psilocybin. this discovery could help with engineering that sort of thing. i don't actually think that's a worthwhile use of anyone's time (again, there are ways to mitigate the taste issue, and determining the amount of mushrooms you eat by anything other than the desired intensity of the trip seems like a flat out bad idea). but still, i stand partially corrected.

You are right, I'm sure. Just a cheeky response to a cheeky response. (Though, with the hopeful side-effect of luring more learned answers, like yours :))

> the subjective quality of the trip

I dunno. I mean, anecdotally, I get a a different kind of drunk on regular beer, fancy beer, and different kinds of liquors. People seem to swear by the different weed strains. I wouldn't be surprised if the rest of the composition of the mushroom has a noticeable effect on the trip.

To me, this just means it'll be easier to try blending substances together; I can totally imagine designer packs that use time-release and a collection of substances to create particular experiences.

Alcohol is alcohol. The differences you are noticing are probably due to the amount of water you're consuming with your alcohol (two pints of 5% beer contains a lot more water than one pint of 10% beer), how fast you're drinking (some liquors you shot, some you sip for example, sweeter drinks get drunk faster than bitter drinks), and possibly also related to the amount of sugar you consume (as is common in sweeter mixed drinks).

That's not entirely true, the other substances in the drink also effect the intoxication.

[1] https://en.wikipedia.org/wiki/Congener_(alcohol)

[2] https://en.wikipedia.org/wiki/Tryptophol

I could go on listing other substances in alcoholic drinks, but ethanol is far from the only substance in alcoholic beverages with biological and psycholical impact.

don't forget placebo

Cannabis has multiple psychoactive compounds, mainly THC and CBD. That's the reason different strains can have very different effects.

On the other hand, there seems to be a lot of arguing about different experiences with the same compound, not just with alcohol, but also with other drugs like LSD, MDMA, etc., if you look at forums... I'm skeptical and think most underrate the effect of previous mood and dosage in the effects of drugs.

Is it at all possible there are other psychoactive components to shrooms? I suspect not, but that might differentiate strains.

Pro-tip: blend your mushrooms into a drink with milk and a little sugar. You can pound this drink easily, and the onset is faster and more predictable.

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