2026-01-02 06:30:24
Published on January 1, 2026 10:30 PM GMT
TL;DR: Most AI forecasts generally assume that if a conflict over Taiwan occurs, it will largely be about AI. I think there's a decent chance for a conflict before either side becomes substantially AGI-pilled.
Thanks to Aaron Scher for comments on a draft of this post.
I'm no China expert, but a lot of China experts seem pretty concerned about the possibility of a conflict over Taiwan. China is currently engaged in a massive military buildup and modernization effort, it's building specialized invasion barges like the Mulberry harbors used in the WWII Normandy landings, and it's conducting amphibious landing exercises with civilian roll-on/roll-off vehicle ferries, many of which China modifies for potential military use. Increasingly frequent military exercises around Taiwan could let China rapidly transition to a full blockade. Its internal propaganda suggests that Taiwanese "provocations" could justify military action, and its leadership continually talk about Taiwan's "return to China", with some even openly discussing "reeducation".
By some cosmic coincidence, 2027, the PLA's centennial, is sometimes identified as the year when the PLA hopes to be ready for a conflict over Taiwan. This doesn't mean China will immediately pull the trigger, but they might want to be prepared by then in case things do escalate. They may believe the next few years represent a window of opportunity before slower growth and a demographic crisis reduce China's power relative to the US. Plus, Xi is 72, and would probably love to cement his legacy by retaking Taiwan in his lifetime.[1]
Manifold currently puts the probability of an invasion of Taiwan by the end of 2027 at around 22%, and before 2030 at around 37%, although I don't think these markets count blockades and other actions that fall short of a full invasion:
Other markets put the chance of a more limited conflict higher:[2]
I'm not trying to make the case here that there will probably be a war. The point I want to make is that while most AI forecasts assume any conflict with China would largely be about AI, I think there's a decent chance a conflict occurs for other reasons before either side becomes AGI-pilled. This point has been made previously here and here, but I think the possibility of war is much more relevant now that people have somewhat longer timelines. Back when many expected takeoff in 2027 or so, it was pretty reasonable to assume that the probability of a conflict entirely unrelated to AI was low.[3] But the forecasters behind AI 2027 now expect takeoff in the 2030s. If that's the case, I think there's a good chance Xi decides to escalate over Taiwan before he (or his successor) starts paying serious attention to AI. At the very least, the timelines overlap considerably: developments in AI could shift China's calculus over whether and when to invade, but equally Chinese aggression unrelated to AI could drastically impact AI timelines.
It's perfectly reasonable to build a forecasting model that doesn't try to take these kinds of exogenous shocks into account. But I think forecasters should clearly flag when they do this, and ideally provide estimates for how likely they think such events are if the chances are significant. I haven't really seen this in the AI forecasting space: for instance, the AI Futures Project's all-things-considered forecasts don't mention the possibility of a conflict, and this scenario has China blockading Taiwan as late as 2034, and only in response to US cyberattacks on Chinese AI development.
I also think the chances of conflict are high enough that it would be very valuable to have forecasts specifically focused on understanding AI timelines in the event of a war. There's been some discussion of this here and here, but those are ancient history over two years old at this point, so something more up-to-date would be useful. I'll give a few of my thoughts below, but this is mostly just speculation -- I'd really like to see modeling work by more knowledgeable people on how a conflict would impact AI.
In general, a conflict over Taiwan would almost certainly slow down progress in AI by disrupting access to compute. This report estimates 20 months for other firms to catch up to TSMC; this discussion is more apocalyptic, predicting global microprocessor production falling to "early 2000s levels for perhaps 15 years." It's less clear to me who would come out ahead in relative terms, though. The US is very reliant on Taiwan, but I think in some cases it might actually be able to maintain a good portion of its compute advantage even if Taiwanese production is cut off, because China also depends on Taiwan for much of its compute. I'm pretty uncertain about this, though.
If things escalate to a shooting war, it's likely that much of Taiwan's manufacturing will be destroyed by one side or the other. If China manages to take over Taiwan, they might gain access to some of TSMC's expertise or technology even if the fabs are destroyed. A good part of TSMC's edge is reportedly in its engineering talent and in knowledge held by a small number of individuals. But I think China would probably have a lot of difficulty gaining the cooperation of TSMC employees or recreating the talent base after a war, so I don't expect China to benefit very much: the main effect would be everyone losing access to Taiwanese production.
Meanwhile, I don't think Chinese chip production would be disrupted as much by a war. A US blockade or other wartime supply-chain disruptions would certainly make things more difficult, but it seems much harder to cut off Chinese production without just bombing the fabs. The US might do that,[4] especially if TSMC's fabs get bombed, but if the conflict isn't centrally about AI I think there's a good chance they'll survive.
But Chinese chip production currently isn't very competitive and might not catch up for some time. If China is still reliant on foreign chips, the conflict could see the US maintain its compute advantage because it would almost certainly stop selling China chips and crack down on chip smuggling. While the US would likely lose access to Taiwan's production, at least for the duration of the conflict, it would still have TSMC's Arizona fab plus whatever production Intel can manage.[5] I think the relative compute balance here really depends on how quickly US domestic production ramps up compared to Chinese production -- modeling this properly would be very valuable!
A major risk, though, is that Taiwanese production might be used as a bargaining chip if it's not destroyed. This could be as part of a peace deal after a war, but it could also happen before a full-scale war starts. China might impose a blockade, take some outlying islands, or use other kinds of pressure to try to force a capitulation or extract concessions without having to invade. It seems unlikely that China would be able to take over completely without a fight, but it could gain better access to Taiwanese production: the US might agree to loosen export controls or even give China access to TSMC or ASML's tech as part of a settlement. If the US government isn't AGI-pilled at this point, it might not even value this particularly highly, or view it as opening up a market for American companies.
One other scenario worth considering is that US or Chinese leaders might start to wake up to AGI during the conflict. An intelligence explosion probably increases the risk of war in the best of times; if there's already a war going on, things could get very ugly. If AI gets securitized we'd likely see attacks on fabs and data centers, secret Manhattan Projects, assassinations, and little room for safety research, let alone any sort of coordination on AI. On the other hand, if the US and China sabotage each other hard enough this could end up delaying AGI significantly.[6]
Of course China might decide not to invade, or we might get AGI first, rendering all of this moot. But I think the chance of a conflict over Taiwan years before AGI is high enough that it should probably be factored into peoples' timelines. It's easy to forget, but people care about other things besides AGI! And the decisions they make could have big impacts on the AI race; we've seen this repeatedly with chip sales to China, and we could very well see it again.
And despite recent talk, I don't think he genuinely expects to live to 150, although I suppose it would explain his apparent lack of succession planning.
I don't think you should pay much attention to my probabilities because I'm neither a China expert nor an experienced forecaster, but for the record, I think 22% for invasion by the end of 2027 is maybe a bit high (and I've bet on this), while the other markets roughly match my estimates.
In the original AI 2027 timeline the CCP contemplates an invasion or blockade of Taiwan, but only in response to the US advantage in compute.
Can the US bomb the Chinese mainland without triggering a nuclear war? I don't know! China maintains a no first use policy, but who knows how that will hold up during a war.
China could try to disable the US fabs (e.g. with cyberattacks), but the US would likely retaliate against Chinese fabs, at which point I'm not sure anyone's left making chips. I guess in that case the US's larger preexisting stock of compute might give it an advantage.
I'm not sure I'd want to stay in the Bay Area for this, though -- I don't want to get "sabotaged."
2026-01-02 06:29:43
Published on January 1, 2026 10:29 PM GMT
Hi, I’m a baby fiction-writer. If you like this first chapter, please like, share, or comment. It will increase the chance of me writing additional chapters. Enjoy! <3
Imagine you woke up and went about your day and hurt yourself, horrifically, in a perfectly mundane way. Maybe you sliced your wrist with a box cutter cause you are unfathomably clumsy, or you tripped and tumbled off the top of your surprisingly high stairs.
Whatever agony you are feeling, your mind is rejecting the reality of what just happened. It’s screaming itself inside out that this can’t be happening and you were fine just moments before but now you are dying.
Instead of calling 911 like any sane person would do, you just lay there in shock, your mind raging against the dying of your light. It’s seeping out of you where the blood gushes out of your wrist or the pressure in your skull crushes your brain.
You imagine instead your healthy body, the way it was before. Far more real than whatever this current horror is. Your normal body, without any additional apertures for blood to escape or dents crushing bone shards into your brain.
Till the pain fades away in a haze and you feel yourself splitting away from yourself. Is this what dying is like? you manage to wonder before you come to, on the floor, naked, someone hugging you from behind.
Nothing makes sense for a moment, and you wonder if you fell asleep, had a bad dream, took a strange drug? But then why are you lying on the floor here. And … who is that?
You turn around and see your own face. Merciful adrenalin snaps the entire world into crystalline focus, time freezing as your body is propelled backwards across the floor. Your real body that is, the one you just moved when you scrambled back. Not that doll, mannequin, monstrosity on the floor in front of you.
It’s bleeding from its wrists. Its skull is caved in.
You, though, you are fine. You are pushing your naked back against a rough wall. Staring, staring, and staring. No way to know how long before thoughts start surfacing again.
Who is that?
I must be high.
Oh, this must be what it’s like to be crazy.
You focus on your breathing. In and out. It does no good.
You move you fingers. Then your toes. That works at least.
You stretch your arms and then your legs, careful to not touch the pool of blood stagnant on the wooden floor.
You push yourself up against the wall, plowing painful rivulets into your bare back. The pain wakes you further.
What’s happening?
Your mind can’t make sense of it, but you are standing now at least. Breathing and moving worked. You are naked though. The other face is wearing your bathrobe shrouded in a pool of blood.
I guess that’s ruined now.
You get up and walk to the kitchen. You make yourself a cup of coffee, calmly. Sit at table and sip. Your dead body lying in the hallway.
I’m either crazy or something amazing just happened.
Crazy is more likely, but in that case the body isn’t really there. Well, either that or it’s someone you just murdered and there is another face on them.
Should I call the cops?
If there is nothing there, they’ll give you meds. If you killed someone they’ll lock you up. And if you did just cheat death by creating a new body then… then…
Ok, I’m crazy or I killed someone.
In that case, better to hide the body. If you are crazy, then you are just LARPing a nightmare for a night. And if you are a murderer, well … You can’t fathom why you’d kill anyone so there was probably a good reason or a bad accident. Either way, it’s better to have more time to figure that out than have police swarming in right this moment.
…
Your mind flinches away from the obvious conclusion. “Hiding bodies” was not part of your 2026 resolutions. Though you’ve seen enough TV shows about it to have some hunches on how to go about it.
So you get to work, pragmatically, methodically, and with clothes on now. It’s the middle of the night and you wheel out the body in a trash container, pull it into your minivan, and drive it over to your parents farm. There there is a small river that runs along the edge, and a small pier that runs into it, with small boats that don’t run at all. One sags half into the water, disappointed at never being used. Another lists precariously, doubtfully able to sustain the weight of twice yourself.
So you sit at the pier, legs dangling down above the water, the container with a body waiting patiently next to you, the light from your phone the only thing giving you away.
Funny how the world isn’t screaming.
Everything looks peaceful instead. A cat meows somewhere. An owl hoots. The stars shine down on either your insanity or your crime.
Sorry to confuse you though. This story isn’t about you. It is about me. It’s how there are two of me now and I don’t know what to do about that. One with a slit wrist and a dent in her head and one…
I look down at my wrist, unblemished, then feel along my skull. I remember the pain, the cut, the fall.
Not the stairs though.
I was at the bottom of the stairs, in the hallway, opening a box.
I…
Is my mind still damaged?
I keep feeling along my skull as the horror inside me mounts.
Do I have brain damage?
Panic rises in me like an electric fire shooting out from my stomach. I scramble back from the edge of the pier, not trusting myself so close to the water.
No, fuck, what happened?! Am I crazy? Do I have amnesia?
My nails are digging into my skull now, the pain only a ghost of the memory when I cracked it.
Memory?!
Then I freeze.
Denying the moment.
Denying the reality.
I am not crazy. I don’t have amnesia. I don’t have brain damage!
It’s impossible to accept so I resist instead, curling my body around a truth that doesn’t exist till agony explodes all across my body, just before everything fades away again. A … stroke?
And then I come to, wind hugging my face, someone’s arms hugging my waist.
Fuck.
2026-01-02 05:36:37
Published on January 1, 2026 9:36 PM GMT
A loss of control scenario would likely result in rogue AI replicating themselves across the internet, as discussed here: https://metr.org/blog/2024-11-12-rogue-replication-threat-model/
Under fast takeoff models, the first rogue AGI posing a serious takeover/extinction risk to humanity would very likely be the last, with no chance for serious opposition (e.g. Sable). This model seems theoretically compelling to me.
However, there is some recent empirical evidence that the basin of "roughly human" intelligence may not be trivial to escape. LLM agents seem increasingly competent and general, but continue to lag behind humans on long-term planning. If capabilities continue to develop in a highly jagged fashion, we may face rather dangerous rogue AI that still have some exploitable weaknesses. Also, the current (neuro-scaffold) paradigm is compute/data hungry, and perhaps not easily amenable to RSI. Though I suspect strongly superhuman models would be able to invent a much more efficient paradigm, it does seem reasonable to give some weight to the possibility that early rogue neuro-scaffold AGI will undergo a relatively slow takeoff.[1]
Therefore, a competent civilization would have a governmental agency (or team) designated to rapidly shut down (and thoroughly purging/containing) rogue AGI. My question is which agencies currently hold that responsibility?
Surprisingly, I have not been able to find much previous discussion on practical aspects of this question (ex. legal aspects of shutting down a rogue AI running on AWS).
Ideally, such an agency would be international since rogue AGI can easily cross borders and may even negotiate with / bribe / blackmail governments. However, I would guess that some cybercrime unit within the (U.S.) DoD is probably the best candidate. While the UK AISI seems most "on the ball," as far as I know they are not very well equipped to aggressively pursue rogue AGI across borders, which may require a very quick response / escalation across cyber-defense and conventional strikes on data-centers.
At a bare minimum, a strong candidate for this role should actually perform drills simulating shutdown attempts against rogue AGI, which will probably be possible to carry out in a somewhat useful form very soon (or now, with red team human assistance).
If neuro-scaffold AI is inherently too weak to reach AGI then the first rogue AGI may arise from a more dangerous paradigm, e.g. "brain-like-AGI". This would be unfortunate, is likely, and is not the focus of this post.
2026-01-02 04:53:58
Published on January 1, 2026 8:53 PM GMT
Here are the results of our New Year Write-Like-Lsusr Masquerade.
Meditations on Suffering by MeditationsOnShrimp technically satisfies all of the competition criteria. Congratulations on beating the ~8 billion people who did not participate in this tournament. You are in the top 0.00000002%.
MeditationsOnShrimp wins this participation trophy. 🏆
This post felt familiar. Something about the facing pacing felt like the kind of thing I would write in the early phase of my writing, when I had only 2-3 years of blogging experience rather than the 6 years I have now, back before I learned how to wield indirection and deliberate ambiguity.
I think this post was written by someone who has read a lot of my writings and even watched some of the videos.
This post is obviously not written by the real lsusr because it demonstrates a level of self-awareness and humility far beyond the real lsusr. I don't think this was a serious competition entry. I think this was is a savage takedown that uses the competition as a pretext to make fun of me. This post missed the Moon, because it wasn't aiming for the Moon. It flew among the stars.
This post wins the $100 bonus prize for making me laugh the hardest.
From: Lsusr2
Date: Mon, Dec 22, 2025 at 6:05 PM
Subject: Hilarious Plots
To: Lsusr
I feel like this was meant for you. It is a rather ironic message to be received by someone who is not you. I wonder how they got my email. it would be funny for me to ghostwrite a response for you, (and of course tell this poor lost soul that I am)
---------- Forwarded message ---------
From: Emet Hirsch <[email protected]>
Date: Mon, Dec 22, 2025 at 5:54 PM
Subject: Hilarious Plots
To: Lsusr2
Hello,
I am a long-time reader of your blog.
I notice a loophole in your rules which I suspect you left intentionally. I can submit someone else's posts and win the competition. That person can be you, as you are neither **manipulating the prediction markets** nor **using a ghostwriter**. You're merely being a ghostwriter.
You can pretend to be me pretending to be you. This is funny, which is my primary motivation. Whatever prize I win goes to PIH as you describe.
If my loophole is **not allowed** I ask that you explain it and announce it.
Thanks,
Emet Hirsch
From: Lsusr
Date: Mon, Dec 22, 2025 at 7:02 PM
Subject: Re: Hilarious Plots
To: Lsusr2
Hahaha!
Plagiarism is disallowed, as it is a violation of writing ethics and the "trivially verifiable as not lsusr" clause. Consensual ghostwriting is allowed.
It is technically allowed by the rules for me (lsusr) to ghostwrite for Emet Hirsch. If this happened, the respective prediction markets would resolve to YES and Emet would (possibly) place among the finalists.
However. Emet is incorrect that ghostwriting is an intentional loophole used for me, lsusr, to enter the tournament. It is perfectly allowed to Emet to hire whoever he wants to ghostwrite for him. That includes me. However, I am expensive, and hiring me as a ghostwriter would cost at least an order of magnitude more than $500. Not because my writing is worth that much, but because that would ruin my fun.
The ACTUAL loophole is that I, myself, am eligible for prizes. I have no need to launder posts through someone else.
What Lsusr2 and Emet Hirsch choose to do with this information is up to them.
Thank you Lsusr2 for two wonderful Christmas Presents. (The other present was a homebrew Post-Modernist Dungeons & Dragons game set in 9th Century Japan.) This gambit was brilliant. Had it succeeded, the respective prediction market would have resolved YES and I would have lost the competition.
This story is good. I had to read it more than once.
I read this post on January 1, 2026, and therefore missed my opportunity to become a copy of Lsusr. Consequently, I cannot validate whether these instructions work(ed).
M_Chouchani wins the Secure, Contain, Protect Award.
This was my entry. As the 3rd place prediction market score, this post wins $50. Instead of $50 by Venmo, I am instead choosing to receive a 120% = $60 donation to Partners in Health.
I forced myself to finish and then just hit submit without an editing pass.
Congratulations abstractapplic on not just replicating my writing, but also replicating my writing process. You win $100.
2026-01-02 04:51:39
Published on January 1, 2026 8:51 PM GMT
There's many debates about "what counts as AGI" or "what counts as superintelligence?".
Some people might consider those arguments "goalpost moving." Some people were using "superintelligence" to mean "overwhelmingly smarter than humanity". So, it may feel to them like it's watering it down if you use it to mean "spikily good at some coding tasks while still not really successfully generalizing or maintaining focus."
I think there's just actually a wide range of concepts that need to get talked about. And, right now, most of the AIs that people will wanna talk about are kinda general and kinda superintelligent and kinda aligned.
If you have an specific concept you wanna protect, I think it's better to just give it a clunky name that people don't want to use in casual conversation,[1] rather than pumping against entropy to defend a simple term that could be defined to mean other things.
Previously OpenPhil had used "Transformative AI" to mean "AI that is, you know, powerful enough to radically transform society, somehow." I think that's a useful term. But, it's not exactly what If Anyone Builds It is cautioning about.
The type of AI I'm most directly worried about is "overwhelmingly superhuman compared to humanity." (And, AIs that might quickly bootstrap to become overwhelmingly superhuman).
I've been lately calling that Overwhelming Superintelligence.
Overwhelming Superintelligence is scary both because it's capable of strategically outthinking humanity, and, because any subtle flaws or incompatibilities between what it wants, and what humans want, will get driven to extreme levels.
I think if anyone builds Overwhelmed Superintelligence without hitting a pretty narrow alignment target, everyone probably dies. (And, if not, the future is probably quite bad).
I am separately worried about "Carefully Controlled Moderate Superintelligences that we're running at scale, each instance of which is not threatening, but, we're running a lot of them, giving them lots of room to maneuver."
This is threatening partly because at some point that they may give rise to Overwhelming Superintelligence, but, also because sharing the planet with a slightly smarter species still doesn't seem like it bodes well. (See humans, neanderthals, chimpanzees). They don't have to do anything directly threatening, just keep being very useful while subtly steering things such that they get more power in the future.
I actually think AIdon'tkilleveryoneism is pretty good.
2026-01-02 04:13:57
Published on January 1, 2026 8:13 PM GMT
old literature-review research task commissioned by @Raj Thimmiah
Epistemic status: This is not medical advice. Pharmacological speculations of a high-schooler, informed by studies done mainly on rodents. Pls don't kill yourself by doing anything suggested in this post, a lot of these substances and combinations of them can be severely dangerous.
TL;DR
An MDMA analogue like 5-MAPB or 4-MMC with low-dose selegiline seems to be the combination with the best MDMA-likeness to neurotoxicity ratio. (targets the two main mechanisms (if hyperthermia is physically avoided) - toxic metabolites and serotonergic neurotoxicity caused by simultaneous dopamine release). Taking selegiline should have the additional effect of a longer/stronger dopaminergic effect due to slowed dopamine degradation.
Vitamin C, vitamin E, ALA, and agmatine likely provide further neuroprotection. Antipsychotics like clozapine are an effective measure for MDMA-overdose-caused hyperthermia (only as an emergency measure; otherwise it would dull the effects significantly).
why selegiline
Selegiline is a drug prescribed for Parkinson's disease and depression (for which the patch form - EMSAM - is used in the US).
Mechanism
In a 1995 study, it was shown using selegiline and the SSRI fluoxetine, that damage to neuronal membranes from MDMA stems largely from the uptake of dopamine by serotonin transporters, thus causing dopamine to accumulate in serotonergic neurons, where it is broken down mainly by MAO-B (whereas elsewhere, it's metabolised mostly by MAO-A). This deamination by MAO-B creates hydrogen peroxide, which is claimed to be responsible for much of MDMA's neurotoxicity.
Selegiline pharmacology
Selegiline is an MAOi; it inhibits the enzymes that metabolise monoamines, such as dopamine, serotonin, norepinephrine, and trace amines, increasing their intersynaptic concentration.
Selegiline, along with safinamide and rasagiline, is selective for the MAO-B subtype at certain dosages. The MAO-B enzyme metabolises mostly beta-phenethylamine and dopamine, though it has been found, that MAO-A is mostly responsible for dopamine breakdown, however, it seems likely that it is indeed MAO-B which metabolises dopamine in serotonergic nerve terminals. In addition, there seems to be evidence that MAO-B metabolises serotonin in serotonergic neurons as well, also producing hydrogen peroxide.
Selegiline, as well as the beta-phenethylamine it increases (the "endogenous amphetamine"), are agonists of TAAR1. This is also a target of amphetamine, probably being responsible for part of its action. TAAR1 agonism may be responsible for selegiline's catecholaminergic activity enhancer (CAE) activity.[1]
In addition, selegiline (especially orally) is metabolised into the levorotary forms of amphetamine and methamphetamine, which act as norepinephrine and dopamine releasing agents, though much weaker in terms of dopamine release than their dextrorotary "conventional" counterparts (detroamphetamine and dextromethamphetamine).[2]
Selegiline's CAE effect, amphetamine metabolites, and decreased dopamine metabolism suggest it might enhance MDMA's effect, even in the absence of functional MAO-A inhibition, though it seems from the above-linked studies, that for rodents no significant additional hyperthermia or head-twitch response is observed. This might be due to the fact that most dopamine is metabolised by MAO-A in blood platelets, rather than MAO-B in serotonergic neurons, and thus only the small fraction of dopamine breakdown, that is responsible for neurotoxic effects, is targeted by selegiline administration.
Still, it is a potentially risky practice to add selegiline to MDMA use, with possible individual variation in drug metabolism causing MAO-A inhibition at dosages that usually only inhibit MAO-B. Therefore, low dosages of <10 mg, maybe 5 mg, are more reasonable.
Evidence
Aside from the Sprague 1995 study linked above, which showed that selegiline (also called Deprenyl) alleviated markers of neurotoxicity in MDMA-exposed rats, in vitro culture had significantly reduced free radical formation when administered selegiline before MDMA, and MAO-B deficient rats where shown to have no serotonin depletion from MDMA (indicating lacking damage to serotonergic neurons - the main targets of MDMA neurotoxicity). Another study from 2007 showed MAO-B dependent damage to mitochondria (including their DNA), alleviated by selegiline.
Notably, I didn't find any study testing the combination in humans, nor any anecdotal experience report.
Selectivity/dosage:
At dosages of <10 mg/day (orally), selegiline is selective for MAO-B, thus not posing a significant risk of serotonin syndrome[3] (BUT maybe your body works differently and is highly sensitive). If you want to try this potentially dangerous combination, ideally microdose the selegiline at dosages below 5 mg.
Patches (EMSAM) might theoretically be useful due to a lower amount of metabolites (reported 70% reduction), but they are risky due to their much higher bioavailability, up to 50-fold, and thus simultaneous MAO-A inhibition at normal dosages (which is the goal of the patches, intended as antidepressants).[4] In addition, it releases the drug slowly over the course of a day, making it less predictable when planning a specific dosage in combination with MDMA.
safety of selected MDMA analogues
Which pharmacological aspects of MDMA do we look for?
Besides the dopamine and norepinephrine release and reuptake inhibition, which causes stimulation and euphoria, the specifics of MDMA's effects are likely due to interaction with serotonin receptors. However, it is not entirely clear how serotonin release leads to prosocial, enactogenic effects. Experiments with receptor antagonists have shown that the psychedelic receptor 5-HT2A (which modulates dopamine and prolactin release) is relevant for this effect, as well as 5-HT1B and 5-HT1A, which has downstream effects on increased oxytocin release.[5] Notably, it not only indirectly stimulates but also directly binds to, as a partial agonist, to these receptors, in addition to 5-HT2B and the sigma receptors, which might be responsible for some of its effects. It also binds to alpha-adrenergic receptors, possibly contributing to its anxiolytic effects.[6]
Hormonally, MDMA has been shown to elevate the neuropeptides oxytocin and vasopressin, as well as the steroids DHEA and cortisol. The increase in oxytocin seems to be correlated with prosocial effects, and the increase in DHEA with euphoric ones[6] (maybe one should try to supplement DHEA or intranasal oxytocin?). The hormonal effects are, however, much less studied in MDMA analogues than in MDMA itself, so I'll focus on the activity as a triple monoamine releaser and serotonergic receptor activity instead.
Analogues
The four following MDMA analogues belong into the classes of benzofurans (5-MAPB and 6-APB) and cathinones (4-MMC and 3-MMC), meaning their cores are different from that of MDMA, and thus form different metabolites.
All of them are triple monoamine releasing agents and (except for 5-MAPB) their reuptake inhibitor - leading to increased extracellular concentration of serotonin, dopamine and norepinephrine (noradrenaline). At the same time, all have affinity to the above-mentioned serotonin receptors, mostly as partial agonists (just as MDMA).
Importantly, they have none of the metabolites of MDMA, such as alpha-methyldopamine, HHA or HHMA, which are neurotoxic through their auto-oxidation into quinones and their binding to gluthanione, forming neurotoxic thioether conjugates.[7] Therefore, unless there are yet-to-be-discovered neurotoxic metabolites of these drugs, their damage must come primarily from hyperthermia, dopamine breakdown by MAO-B, or RNS formation, which can be alleviated with the methods described in the section below.
5-MAPB
It is metabolised into 5-APB (which is a very similar MDMA analogue, however with stronger 5-HT2A agonist and thus likely stronger psychedelic effects), which is subsequently metabolised into 3-carboxymethyl-4-hydroxy amphetamine, and another product is 3-carboxymethyl-4-hydroxy methamphetamine.[8] No catechols or MDA are formed, and so the conversion to quinones or thioether conjugates doesn't happen. However, 5-APB is a potent agonist of the 5-HT2B receptor[9], which might lead to cardiotoxicity with regular use[10] (not recommened for neurotoxicity and monoamine depletion reasons anyway).
It has a halflife of 6.5 hours.[11]
In terms of effects, the potent 5-HT1B agonism[12] might make this a particularly empathogenic/pro-social compound.[13] However, the lack of direct serotonin 1A receptor activity might make it less oxytocin-releasing, though this mighe be alleviated by stronger serotonin releasing activity (but lower NE activity), and thus indirect 5-HT1A agonism[14], as well as the metabolite 5-APB's activity at the receptor. The lower norepinephrine-releasing activity makes this compound likely less stimulating.
5-MAPB has been found to create hyperthermia (and hypertension, tremor and convulsions) in humans[15], though this is likely to be a case of an overdose. In rat liver cells, 5-MAPB and it's metabolite 5-APB have been shown to cause cell death (cytotoxicity), greater than MDMA.[16]
From Wikipedia[17]
The Borax combo, as well as 5-MAPB and MDAI, have been advertised as non-neurotoxic alternatives to MDMA.[1][2][5] However, 5-MAPB has subsequently been found to be a serotonergic neurotoxin in rodents similarly to MDMA.[5] It is thought that the serotonergic neurotoxicity of MDMA and related drugs may be dependent on simultaneous induction of serotonin and dopamine release, as combination of a non-neurotoxic serotonin releasing agent like MDAI or MMAI with amphetamine results in serotonergic neurotoxicity similar to that of MDMA.[8][21][22][23] Besides the case of simultaneous induction of serotonin and dopamine release, serotonergic psychedelics (i.e., serotonin 5-HT2 receptor agonists) have been found to augment MDMA-induced striatal dopamine release and serotonergic neurotoxicity in rodents as well.
Confirming the hypothesis of neurotoxicity largely stemming from dopamine breakdown in serotonergic nerves following simultaneous serotonin and dopamine release, such that low-dose selegiline would be protective. If this is the main mechanism of 5-MAPB neurotoxicity, as this suggests, MDMA shouldn't be much worse in comparison, and both should be basically equivalent in terms of their toxicity in combination with an MAO-B inhibitor. However, it is unclear what the role of neurotoxic MDMA metabolites is - it might contribute to neurotoxicity as well, making analogues such as 5-MAPB safer.
In humans, I found one report of fatal intoxication, though it has been in combination with several other compounds.[18]
In rodents, 5-MAPB caused similar serotonin depletion as MDMA.[19]
However, much of the toxicity of 5-MAPB compared to MDMA might be caused by use of the same amount of each compound in these studies, even though 5-MAPB is a cca. 3x stronger monoamine releaser than MDMA at the same dose[20][21]. This might simply mean a way too high dosage has been used, leading to more serotonergic hyperthermia + the SERT-mediated toxic dopamine breakdown by MAO-B. Thus at a 3 times lower dosage, it might be a safer alternative to MDMA, especially in combination with low-dose selegiline and hypothermic compounds such as agmatine, alleviating most of the remaining neurotoxicity potential.
6-APB
It is much stronger than MDMA - 12x more potent than at the dopamine transporter, 6.5x stronger at the noradrenaline transporter, and 2.4x stronger at the serotonin transporter.[22] With this altered ratio of monoamine release, it can be expected to be more akin to a stimulant like methamphetamine in it's effects. In terms of total monoamine increase measured, all tested benzofurans were about 3x more potent than MDA (so about 9x more potent than MDMA[23]), and 6-APB has been shown to be the most potent benzofuran in terms of dopamine release.[24]
In addition, 6-APB was found to bind with high affinity to alpha-adrenergic receptors (similar to MDMA - potentially calming), to 5-HT2A receptors (psychedelic), 5-HT1A receptors (oxytocin-mediating), and, most strongly, to 5-HT2B receptors, which poses potential cardiotoxic risks.[25] The alpha-adrenergic and 5-HT2A agonism make 6-APB a potentially more hyperthermia-inducing drug (which can lead to significant damage, but can also relatively simply be avoided by staying in a cool environment).
The effects begin within 1-2 hours and last for about 7 hours.[26]
It does not form quinone or thioether metabolites, which contribute to MDMA neurotoxicity (the main 6-APB metabolite was 4-carboxymethyl-3-hydroxy amphetamine).[27]
No cytotoxic effects have been found in one cell culture study[28]. There exists a report of 6-APB-caused psychosis, though this has been in combination with cannabis.[29]
Overall, 6-APB seems like a more stimulant and psychedelic analogue, with little data on neurotoxicity, though by its similarity to 5-APB it can be assumed to have similar cytotoxic oxidative effects, but less so (it has been found to be less toxic to liver cells than 5-APB, the active 5-MAPB metabolite)[30]
4-MMC aka mephedrone
Mephedrone a triple monoamine reuptake inhibitor and releasing agent (as is MDMA, though mephedrone is more of a reuptake inhibitor).[31] It is also a strong 5-HT2A agonist, suggesting it might have psychedelic properties (though strangely, it is not a proper hallucinogen). The lack of direct actiity on the 5-HT1A receptor might mean lower oxytocin release.
It is a relatively short-acting drug, with effects beginning after 15 minutes, and lasting 2-3 hours (when taken orally). 
Mephedrone is commonly insufflated, and is reported to have effects similar to MDMA.[31]
It's metabolites are mostly nor-mephedrone, which is psychoactive itself, as a stimulant (DAT and NET inhibition with less SERT inhibition), DHMMC (which has a similar but weaker profile), and several mostly inactive metabolites like 5-hydroxy-mephedrone.[33] Again, no quinones or thioethers are produced, and none of the studied metabolites has been shown to have neurotoxic properties.
Interestingly the article "Clinical Pharmacology of the Synthetic Cathinone Mephedrone"[34] from 2017 reports:
Regarding the possible long-term toxicity of mephedrone, the fact that the drug possesses structural and pharmacological similarities to MDMA, amphetamines, and cathinone suggests the likelihood that repeated and/or prolonged use produces similar consequences on neurochemical and neuropsychological function. From the limited results to date, it should be pointed out that repeated mephedrone administration in experimental animals has not shown evidence of neurotoxicity to monoaminergic systems in the brain [42, 88–91[35]].
One study reports decreased serotonin transporter function in rats administered 4-MMC, but the rats were purposefully kept in a high-temperature environment.[36]
Mephedrone induces hyperthermia[37] and potentiates the neurotoxicity of methamphetamine and MDMA, but does not itself cause dopaminergic neurotoxicity. This has lead to the conclusion that mephedrone functions atypically at the dopamine transporter[38] (which might possibly be the reason behind its relative non-neurotoxicity).
One rat study showed oxidative damage to rat neurons as well as dopamine receptor downregulation.[39]
As opposed to MDMA, mephedrone has not been shown to cause microglial activation, thus the pathway leading to RNS damage is likely nonexistent for mephedrone.[40] Cognitive damage (working memory worsening) has been found in mice after "binge-treatment" of mephedrone.[41] There have been some deaths due to mephedrone overdoses.[42]
Overall, mephedrone seems like a surprisingly safer MDMA alternative, if hyperthermia is avoided (many studies showing harm in rodents used elevated ambient temperature). The working memory deficits shown in rats are concerning, but likely a consequence of high dosages and/or hyperthermia.
3-MMC
3-MMC aka metaphedrone is commonly insufflated
3-MMC inhibits the serotonin transporter much less than mephedrone or MDMA, while significantly inhibiting DAT and NET, suggesting a more stimulant, rather than enactogenic effect.[43] However, the 5-HT1 agonism may lead to oxytocin release, leading to empathogenic effects, confirmed by users.[44] It binds strongly to alpha-adrenergic receptors, which might pose vasoconstriction risk, but the lack of 5-HT2A agonism makes the risk of hyperthermia lower.[43] It is capable of producing hyperthermia, it lasts for around an hourwhen insufflated, and is reported to be a weaker version of mephedrone or MDMA in terms of its effects. The main metabolites are 3-methylephedrine and 3-methylnorephedrine, with no known neurotoxic effect.[45] 3-MMC has been shown to create ROS (and RNS), and damage liver cells.[46] Inhibition of the enzyme CYP2D6 has been shown to be protective, suggesting that genetic variations in the expression of this enzyme may affect the toxicity of 3-MMC use, with "extensive and ultrarapid metabolisers" experiencing significantly more toxicity[45] (which is likely true of MDMA and its other analogues too).
Two deaths due to 3-MMC (likely in combination with other drugs) have been reported in Sweden[47], 5 severe poisonings in the Netherlands[48], and adeath following pure 3-MMC exposure in France.[49]
Overall, 3-MMC appears to be an inferior alternative to 4-MMC, having a short halflife, shown oxidative stress toxicity, and potentially neurotoxic metabolites.
Taking MDMA has a tradeoff; One gains a euphoric and potentially therapeutic experience, and damages some neurons. The following is a review of the mechanisms by which the cost of MDMA use occurs, and ways to target them.
MDMA induces the release of serotonin, dopamine, acetylcholine and activates histamine receptors, but the main victims of MDMA neurotoxicity appear to be serotonergic (5-HT) axon terminals.[50] There has been a paper claiming dopaminergic neurons are damaged too, but later it was found out that they used meth instead of MDMA.[51] However, some studies do show dopaminergic neurotoxicity of MDMA in rodents as well.[52] Besides damage to axon terminals, damage to the targets of MDMA, the serotonin transporter (SERT) and the dopamine transporter (DAT) has been found, potentially affecting long-term neurotransmitter release and uptake.[53]
This post doesn't cover monoamine depletion, which is a short-term effect following MDMA's massive monoamine release, causing the well-known temporary depression and lethargy after MDMA use.
The main mechanisms by which MDMA can be neurotoxic:
MDA is metabolized to a-MeDA that can react either with glutathione (GSH) to form 5-(GSH)-a-MeDA or with N-acetylcysteine (NAC) to form 5-(NAC)-a-MeDA, and these compounds might be the main metabolites responsible for the neurotoxic effects of MDMA observed in rats.[58]
4. The microglia-caused inflammation upregulating iNOS, producing NO and subsequently reactive nitrogen species (RNS) including peroxynitrite (which reacts to form nitrotyrosine), which cause oxidative damage to mitochondria[59], cell membranes and proteins (along with the ROS)[60][61]
5. (Rarely, hyponatremia, causing brain swelling. This is more likely with high estrogen exposure)[62]
What can be done:
ALC administration was found to reduce MDMA-induced protein carbonyl formation (a marker of oxidative protein damage), decrease the incidence of mitochondrial DNA (mtDNA) deletions, and improve the expression of key mitochondrial respiratory chain components (such as subunits of Complex I and Complex IV) [93]
studies referenced:
42. Baumann MH, Ayestas Jr MA, Partilla JS, et al. (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37:1192–1203
88. Angoa-Pe´rez M, Kane MJ, Francescutti DM, et al. (2012) Mephedrone, an abused psychoactive component of ‘bath salts’ and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum. J Neurochem 120:1097–1107 89.
89. Angoa-Pe´rez M, Kane MJ, Briggs DI, et al. (2013) Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA. J Neurochem 125:102–110 90.
90. den Hollander B, Rozov S, Linden AM, et al. (2013) Long-term cognitive and neurochemical effects of “bath salt” designer drugs methylone and mephedrone. Pharmacol Biochem Behav 103:501–509 91.
91. Shortall SE, Green AR, Fone KC, et al. (2016) Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats. J Psychopharmacol 30:698–706
The simultaneous large release of dopamine and serotonin causes the serotonin transporter (SERT) to take up some of the dopamine and transport it into the serotonergic nerve, where it is broken down by MAO-B (usually MAO-A breaks down dopamine and serotonin, but MAO-B is found in the serotonergic neurons and is responsible for the breakdown of the residual monoamines). This creates free radicals that can cause damage to the membranes and mitochondria of neurons. That's why the inventor of Selegiline, an MAO-B inhibitor, promoted its preventative use as a longevity drug (he did live until the age of 92).