Enthea

The Capitol

2021-01-19T19:00:00-08:00

Around this time two weeks ago, Trump supporters were in the process of storming the US Capitol.

A Capitol triptych (hi-res source).

To the extent that we can, let's set aside our feelings about the storming and spend a few moments studying the image above.

There's a lot going on in it! A true triptych: on the left, a standard-bearer marches down the hall flying the Confederate battle flag. To the right, a bust of Richard M. Nixon, unmolested. And on the center couch a fur-clad protestor rests, holding a wooden staff and a riot shield emblazoned with the insignia of the United States Capitol Police, presumably wrestled from an officer during an earlier skirmish.

Our countrymen! Our Capitol!

We've talked before about how the "normal" world seems to be getting stranger whilst psychedelics are becoming more normal. I take last Wednesday as confirmatory evidence of that view. This is the world we're living in! Let's not look away. And let's not come to judgment too quickly.

You might be wondering what any of this has to do with psychedelics. I think there's actually a ton of overlap, even if we overlook the obviously psychedelic overtones of the Q Shaman et al. But I'm not yet able to unpack it all, so for now I'll just touch on a couple topics I've been meditating on since the storming.

Virtualism. Last year, a political theorist named Bruno Maçães wrote a very interesting book which put forward the hypothesis of "virtualism."

Virtualism is basically the idea that America is developing "virtual" spaces as a way of addressing the restrictiveness of the prevailing liberal order without abandoning the functional aspects of liberalism. Virtual spaces are spaces where we can act out our convictions & frustrations without bearing the consequences those actions would bring if they were carried out in a thoroughgoing way.

Under virtualism, protestors in Seattle can set up an "autonomous zone" while still benefiting from municipal services. Portland can undergo months of protests without making any substantive changes to the city council or the city charter. And protestors can storm the US Capitol intent on interrupting the proceedings of Congress, only to have those proceedings go off without a hitch the next day.

Under virtualism, things can look very much like they're going off the rails while under the surface all the important processes just keep chugging along.

I want to learn more about the dynamics of this theory... where does it fall down? What doesn't it explain? At what point does a "virtual" event tip over into its "real" counterpart?

It seems that the difference between last week's "coup" and a proper coup could come down to the decision-making of a small number of American military commanders. So I also want to learn more about the psychologies of those military commanders and the incentive structures they are embedded in.

Inferential distance. Briefly, inferential distance is the number of inferences that separate the viewpoints of two people (i.e. how many inferential "hops" you'd have to make to arrive at their view from the view you start with).

There's currently an enormous amount of inferential distance in America's social graph. (I can't speak for you, dear reader, but I would certainly have to be seeing things very differently in order to feel like breaking into the US Capitol to disrupt the electoral vote count was a good use of my time. And yet many of us did think that that was a good use of their time!)

Bridging inferential distance is a good contender for being the most important problem we face. It goes by other names too – improving coordination mechanisms, resolving iterated prisoner's dilemmas, defeating Moloch, fixing market failures, internalizing externalities, escaping moral mazes... even the proliferation of labels gesturing at the same cluster of ideas indicates the challenge.

To the extent that people have the same starting point and make the same inferences, they will want to organize their lives in the same way. And it's (much) easier to cooperate with people who want to set up their life/country/world in the same way that you'd like to set up yours.

Psychedelics clearly have some sort of role to play here, though from my perspective we're still very much sorting out what their contribution will be. (I recently covered some early work in this direction: 1, 2)

I'm more sympathetic to Grof's view of psychedelics being "nonspecific amplifiers" of neural processes than I am to the idea that psychedelics necessarily push towards any particular political affiliation, metaphysics, or worldview. (More precisely, I think that if psychedelics do push towards a single worldview, it is a complex one that subverts attempts to taxonomify it.)

To the extent that Grof's view is correct, it means that getting set, setting, and intentions right is very important as we bring the psychedelic experience into our institutional structures. (A truism, sure, but a true one.)

Think again to those people in the photo at the top of this letter. Those are people, who came to their views via a process as complicated as the process that brought you to yours. For most of you, those are your countrymen. You & I are engaged in a vast project of cooperation with them. How are we going to reach these people, our countrymen? How are we going to communicate with them at all?

(And it's same question if you perceive yourself to be on the other side of this: how are you going to communicate with me?)

What kind of country are we all going to build together from here? By what processes & what norms will we build it?

Qualia Research Institute & the Symmetry Theory of Valence

2020-12-19T11:00:00-08:00

This is a guest post by Andrew Zuckerman, Director of Operations at the Qualia Research Institute.

QRI is one of the most interesting research projects we've encountered – we're excited to be able to present an introduction to their work.

There’s a famous 1973 paper by geneticist Theodosius Dobzhansky called Nothing in Biology Makes Sense Except in the Light of Evolution. We at the Qualia Research Institute (QRI) are investigating an analogous claim: nothing in the psychedelic experience makes sense except in light of the Symmetry Theory of Valence.

What is the Symmetry Theory of Valence (STV)? It’s one of the core theories we’re exploring at QRI, and we'll unpack it below. Mike Johnson, one of the co-founders of QRI, first proposed STV in his 2016 work Principia Qualia.

Andrés Gómez Emilsson, another QRI co-founder, recently gave a talk on STV at the Centre for Psychedelic Research of Imperial College London. Below we’ll discuss two slides from this lecture. You can also watch the full presentation and read annotated slides from the talk.

Let’s first look at what we’re talking about when we talk about “valence” –

So what is valence? Is it… how the brain represents value? Something involved with how reinforcement learning operates in the brain? Or simply a feeling caused by opioids and/or particular brain regions?

These are all popular understandings, especially the dopamine = pleasure story. And there are lots of explanations of valence in the neuroscience literature that point to the mesolimbic reward system, reinforcement learning, and “hedonic hotspots” of the brain, like the nucleus accumbens.

But these explanations all seem somewhat lacking. Here’s Andrés on the matter:

There are a lot of theories of what valence is. Mike looked at the literature, did a deep dive into it and realized that they're usually unsatisfactory, or at the very least, they don't get at the true core of what an explanation for valence should be like.

You have these accounts of, for example, valence being how the brain represents value. Ultimately, that's just a correlation. Value is a fuzzy abstraction.

Some people think valence is the presence of opioids in the brain. But if you inject opioids in different parts of the brain, it doesn't always feel good. They actually need to be injected in a very narrow strip in the pleasure centers – otherwise, they just cause strange feelings or wanting. So they're not the signature of valence itself.

Or, for example, the pleasure centers. Just because you're calling something the pleasure center, and it's correlated with feeling good, it doesn't mean you have an explanation – it's not a very insightful, illuminating account of valence.

The explanations we’ve discussed so far are either nebulous & imprecise or are just imperfect correlations of valence when it shows up in mammalian brains.

It’s wonderful that we know so much about valence and its relation to human physiology, but these theories aren’t truly universal. A universal theory is one that has something to say no matter where we are in the universe! Or for this topic, something to say no matter what brain architecture an organism has. Discovering these universal laws is desirable because they help us both understand data that we have already seen and make predictions about data yet to be uncovered.

Let’s imagine that some alien arrives on earth with no nucleus accumbens, no dopaminergic pathways, and because we haven’t spent enough time with the alien, we don’t know anything about its values & beliefs. What can these aforementioned theories say about the valence that this alien might be experiencing? Absolutely nothing.

A complete theory of valence would be able to predict how pleasant or unpleasant it is to be that alien, because it'd be subject to the same laws of the universe that we are.

This brings us to the Symmetry Theory of Valence –

As Mike postulated in Principia Qualia, “Given a mathematical object isomorphic to the qualia of a system, the mathematical property which corresponds to how pleasant it is to be that system is that object’s symmetry.”

Let’s break that down. What does it mean for “a mathematical object [to be] isomorphic to the qualia of a system”? Essentially, it’s the assumption that for any slice of conscious experience, there is a unique mathematical representation that corresponds to that experience.

The second part of STV is then relatively straightforward – how good a subjective experience feels will relate to the symmetry of the mathematical object that corresponds to the experience, with symmetry being a well-established concept in both mathematics and physics. (You can think of mathematical symmetry as a more general version of the mirror symmetry you're probably familiar with already.)

If this is true, then we should expect that when a conscious being is experiencing a high-valence state, we would find a lot of symmetry in their brain data. And this would be true whether that conscious being is a human, an animal, or an alien.

This leads to clear experimental predictions, for example:

In STV, pleasure centers are like tuning knobs. They are these bridges that, when they get activated, enable global large-scale synchrony in the brain.

Ultimately, this is very testable. Because if you can activate the pleasure centers while inhibiting the whole brain harmony, we predict that is going to actually negate the positive valence effects of the pleasure centers.

Likewise, if we can induce large scale harmony, without activating the pleasure centers, or maybe even inhibiting the pleasure centers, we expect that to be a high valence state.

So it's a testable interpretation of what the pleasure centers even are.

You can learn about other predictions that arise from STV by watching the presentation and/or reading the annotated slides.

What about existing evidence in support of the Symmetry Theory of Valence? One example is the phenomenology of extremely blissful (i.e. high-valence) states, like those reported from 5-MeO-DMT experiences, or those experienced in advanced meditative states (known as jhanas). Experiences like this tend to have extremely low information content, which implies high symmetry:

There seems to be this projection of less and less information content in your experience. Going from having all of your attention concentrated into one point to then experiencing completely perfectly smooth, boundless space to then “experiencing” just pure consciousness, and then the “experience” of neither nothing nor something. In a sense, that's kind of approaching the limit of zero information.

There also seems to be a link between symmetrical stimuli and valence:

If you don't have a perfectly symmetrical face, but you add symmetrical face paint with beautiful patterns, you're going to be judged as more beautiful. It's just such a strong effect, that it can actually modify your perception of how beautiful somebody is. Likewise, if you add asymmetrical patterns, you tend to be perceived as less beautiful.

Why is deeply understanding valence so important? The most direct reason is that a mechanistic understanding of valence will allow us to quantify experience. Today, we don’t have much basis for objectively understanding what other people or animals are experiencing – a “9 out of 10” on my pain scale may be a “4 out of 10” on yours. The Symmetry Theory of Valence attempts to bridge that gap.

More fully understanding valence would also:

Help us find first-principles solutions to hard-to-treat mental health & chronic pain conditions.
Allow us to build better neurotechnology by crisply articulating the brain states we would like to target.
Create more rigorous measures of philanthropic & economic utility and upgrade imperfect measures of well-being such as the QALY (Quality-Adjusted Life Year), which could drastically improve economic policymaking and the efficiency of our resource allocation.
Help us more accurately measure the quality of life of animals and non-linguistic humans.
Improve social coordination by helping people operate from the same basic understanding of what is real and what is valuable.
In the field of AI alignment – make progress on the value-loading problem (what values we should instill into an artificial general intelligence), and avoid accidentally creating immense suffering in future superintelligences (i.e. “mind crimes”).

QRI begins executing on its roadmap to empirically test the Symmetry Theory Valence in 2021. If you’re interested in learning more, don’t hesitate to get in touch – we’re excited to chat with anyone who has questions about our approach!

Founders Pledge report: psychedelics & subjective well-being

2020-10-30T13:00:00-07:00

Founders Pledge is a nonprofit that supports entrepreneurs who have pledged to donate a portion of their wealth to high-impact causes. They recently published a research report recommending the Usona Institute. Here's their blog post about the report (a). Here's the full report (a).

This is good news! Many wealthy entrepreneurs look to Founders Pledge to inform their philanthropic giving, so this report could forerun a substantial inflow of donor dollars into the space.

Founders Pledge is also affiliated with the Effective Altruism community – the Open Philanthropy Project is one of its primary funders. We've put a lot of energy into making the case for psychedelics to EA audiences, and this has often been met with skepticism (Exhibit A). The Founders Pledge report is the first time an EA-affiliated organization has formally recognized the effectiveness of psychedelic interventions, which is something of a milestone, and great to see.

Psychedelics & subjective well-being

The Founders Pledge report can serve as a jumping-off point into many interesting topics, but let's zero in on just one for now – whether or not psychedelics can boost subjective well-being.

The FP researchers considered two basic benefits that psychedelic interventions might have: 1. Their ability to treat pathologized mental health conditions (e.g. depression) 2. Their ability to improve subjective well-being

Here's an excerpt about subjective well-being from the FP report:

The evidence on increased prosocial attitudes and behaviours and improvements in subjective well-being is weak. We found only one experimental study that used direct subjective well-being measures before and after taking a psychedelic, and it found no statistically significant improvement.[51] That said, two studies—a prospective[52] and an unpublished[53] one—found improvements on a composite well-being scale and multiple studies found self-reported, self-attributed improvements of subjective well-being, i.e. participants stated that they think the psychedelic experience improved their well-being and prosocial behaviour and attitudes.

I basically disagree with Founders Pledge here – from my perspective it seems that there is actually quite a lot of evidence suggesting that psychedelics can improve subjective well-being.

Let's dig into the study FP cites as finding "no statistically significant improvement" in direct subjective well-being – Griffiths et al. 2006.

Griffiths et al. 2006 is a landmark psychedelic study – it found that psilocybin could occasion mystical experiences in healthy people, and its follow-up (Griffiths et al. 2008) found that folks continued to view these experiences as intensely meaningful for a long time.

In their study, Griffiths et al. assessed subjective well-being in three ways:

Direct measurement of affective balance using PANAS, administered before and after the psilocybin session
Participant self-assessment of whether their moods & attitudes had been affected by the session
Observations by other people who knew the participant – did they notice a change in the participant's attitudes and behavior after the session?

When Founders Pledge says that Griffiths et al. 2006 found no evidence of direct subjective well-being improvement, they're pointing to (1). And it's true – Griffiths et al. didn't find any change in PANAS scores that they could attribute to the psilocybin session:

None of the factors on the two widely used questionnaires assessing five factors of personality (NEO and PI-R) and measures of general positive and negative affect (PANAS-X) was differentially affected by psilocybin. At screening and at 2 months after session 1, there were no significant differences between the group that received psilocybin on the first session (N=15) and the group that received methylphenidate on the first session (N=15)

But Griffiths et al. did find that the psilocybin session improved participants' self-assessments, and community observers did notice statistically significant improvements in participants' behavior and attitudes – items (2) and (3). You can see all of these results in Table 4 of the paper.

So what's going on here? How is it that participants felt that psilocybin improved their mood & attitudes, and that other people in their life noticed positive improvements, but they still scored about the same when they took the PANAS after the psilocybin session?

One possibility is that the session deluded the participant – it caused them to think that things have improved (and caused people who knew the participant to think things have improved too?), but there was in fact no objective improvement in their affect when it was measured. The FP report doesn't get into it, but I suspect this is sorta what the Founders Pledge researchers believe.

Another possibility is that the psilocybin experience caused participants to reevaluate how they think about their lives, and this reevaluation messed with the psychometrics.

Here's what I mean: imagine that someone has an experience (say, a psychedelic trip), and this experience causes them to re-conceptualize the scale they use when they think about their well-being.

e.g. They used to assess themselves as an 8 out of 10 on some scale. Then they have this experience, and they think "Oh wow, now it seems that the scale I was using was wrong. I had been thinking that I was close to as good as I could be (8 out of 10), but now it feels like 'as good as I can be' is actually way higher than I thought..."

So they bump up the top end of the scale they're using. Now they assess themselves as 8 out of 50, not because they think their life has gotten worse, but because they're conceptualizing "as good as I can be" differently.

But this shift isn't reflected in the psychometric instrument they've been using, so when they assess themselves again, they have to normalize their new view to match the instrument's scale:

"I used to feel like I was 8 out of 10, and that matched up pretty well with this 10-point scale, so I recorded myself as 8 out of 10"
"Then I had an experience that caused me to believe that the potential upside can be way, way higher, so now I feel like I'm 8 out of 50"
"I have to fill out another one of these 10-point scales – should I still say I'm 8 out of 10? Or should I say I'm 2 out of 10, because that's proportional to my new internal assessment? But recording 2 out of 10 makes it seem like my life has gotten way worse since I last filled out an assessment, and that's not true..."

Something like this is probably going on when participants take the PANAS, have a psychedelic experience, and then take the PANAS again. This dynamic would explain why the "after" measurement didn't detect a substantial change from the "before" measurement – because experience causes the participants to relate to the scale differently.

Borissova et al. 2020 – MDMA, cooperation, and candles in the dark

2020-09-14T16:00:00-07:00

Like Gabay et al. 2018 and Gabay et al. 2019, Borissova et al. 2020 is a randomized controlled trial looking at the effects of MDMA on cooperative decision-making.

But Borissova et al. didn't find the same increase in cooperativeness that Gabay et al. did. Why not?

The study had two goals:

We aimed firstly to extend and replicate the findings from a naturalistic study of recreational MDMA’s acute prosocial effects (Stewart et al. 2014) in a controlled laboratory experiment, using measures of empathy, trust and cooperative behaviour.

Secondly, we aimed to assess subacute changes to mood three days after MDMA administration.

Goal 1: do MDMA's prosocial effects replicate in an RCT?
Goal 2: do the infamous "mid-week blues" show up when MDMA is administered in a laboratory setting?

Their first goal is more relevant for our present purposes – it's the same big question that Gabay et al. looked into.

(As an aside, the Borissova study participants didn't report lower mood in the days after their MDMA session – some evidence that the "mid-week blues" come from taking MDMA alongside drinking, dancing and not getting enough sleep, rather than just from taking MDMA on its own. Sessa 2017 has a good discussion of this.)

Borissova et al. tested MDMA's potential prosocial effects by giving participants a bunch of social tasks: listening to emotional stories & rating how good the stories made them feel, looking at pictures of faces & rating how trustworthy they seemed, playing a "public project" game, a "dictator" game, and the ultimatum game we talked about last time. (The prisoner's dilemma wasn't one of the tasks, so we can't directly compare Borissova's results to Gabay et al. 2019.)

It's really good that Borissova et al. published these results, even though they complicate the picture. Our knowledge production apparatus doesn't really incentivize publishing null results as it's currently configured, so the file drawer remains a serious problem (exciting positive results are published & publicized while boring null results don't ever make it into the literature).

What's going on here? How is it that Gabay found strong prosocial effects and Borissova found none?

From the paper:

Some differences between the tasks in our study and previous ones yield important insights. In the ultimatum game, we asked participants to respond with the minimum offer they would accept. This – as opposed to the ‘direct-response’ method used by Gabay et al. 2018 where participants are presented with different offers to accept or reject – can lead to less punishment of unfair offers. Indeed, our participants were willing to accept offers that were below 40% of the total stake – below what is considered to be a ‘fair’ offer...

We also used a ‘one-shot’ task for our cooperative behaviour games. This contrasts to Gabay et al. 2018 and Gabay et al. 2019, where participants received feedback on their performance over multiple rounds. Such feedback might be important to more closely match real-world social interaction and allow for detection of an effect of MDMA. This again suggests there may be an important role for context, whereby true social feedback may be necessary to elicit effects of this drug – but this would need to be tested experimentally.

Two things here:

The studies used different versions of the ultimatum game. In Gabay, participants played live with another person. In Borissova, participants were asked to think abstractly about the minimum offer they'd accept, but they didn't actually play the game with another person. If our hypothesis is that MDMA increases cooperation by boosting the salience of direct relationships with other people (which is about where we left things), then we should expect to see less effect on hypothetical reasoning about an abstract problem.
In the Gabay experiment, participants played the ultimatum game dozens of times. In Borissova, they answered one hypothetical question about how they would play the game. This structure doesn't give any opportunity for players to change their behavior over time, as they see the dynamics of the game in action and learn more about their partner.

These are important points, but I don't think they let us straightforwardly side with the Gabay et al. results to say that MDMA definitely increases cooperative decision-making. And we also can't straightforwardly follow the Borissova et al. results to say that MDMA obviously doesn't have any effect on prosocial behavior.

The best takeaway at this point is something like "It's plausible that MDMA increases cooperative decision-making, but we're not sure yet. Running bigger RCTs on the question would help us learn a lot more."

But I notice that a part of me wants to compress things down into a simple answer... does MDMA increase cooperation, or doesn't it? It's uncomfortable to not know for sure.

I really do believe in science as a candle in the dark. We can use scientific processes to actually figure things out, which is amazing! Careful theorizing can generate interesting hypotheses, RCTs can determine the causality of many questions (even questions about complicated systems like human beings), and literature reviews & meta-analyses can roll up these results into an overall state of the art that continually improves over time.

But this wonderful process isn't straightforward, and there are many opportunities for motivated reasoning. A psychedelic skeptic can point to Borissova et al. 2020 to back up their point that psychedelics don't produce any real benefit, just a momentary good feeling. An MDMA advocate can pick up Gabay et al. 2018 to show that ecstasy can help us all get along better. Neither are wrong (in a narrow sense), but they're both missing the bigger picture.

A casual reader can go astray even if they're not trying to prove a particular point. If they bump into Borissova et al. 2020 first (or Kuypers et al. 2014, or Schmid et al. 2014), they'll learn that in reality, MDMA doesn't increase prosocial behavior. But if instead they bump into Gabay et al. 2018 first (or Stewart et al. 2014, or Kirkpatrick et al. 2015), they'll see that MDMA does in fact increase prosocial behavior.

So what's a poor ol' consumer of scientific research to do?

I think a good place to start is improving our ability to notice when we have impulses toward quick, sure-thing answers.

Reality has a surprising amount of detail, and in any domain it takes a lot of work to figure out what's going on. Headlines announcing new results will never convey the full story, and neither will paper abstracts. Knowing this, and then starting to notice when you're looking for a quick answer rather than actually trying to figure something out – this seems like a good first step.

Gabay et al. 2018 – MDMA and cooperation: the ultimatum game

2020-08-23T16:00:00-07:00

Continuing on from our discussion of Gabay et al. 2019, which looked into how MDMA affects decision-making in prisoner's dilemmas.

(A quick refresher: they found that MDMA boosts cooperative behavior when playing with trustworthy partners, but not when playing with untrustworthy partners. Participants were still able to protect themselves from being exploited while on MDMA!)

In the same study (though published separately as Gabay et al. 2018), Gabay's team also looked at another game – the ultimatum game.

In the ultimatum game, one player ("the proposer") is given a sum of money and must offer some amount to the other player, then keeps the rest. The second player ("the decider") can either accept this offer, in which case both players receive their share of the money, or reject it, in which case nobody gets any money. (Here's a webcomic that gives a good walkthrough.)

The ultimatum game is interesting because it puts rational self-interest in tension with our ideas about fairness. If you're the decider, it is always more economically rational to accept what you're offered, even if it's not a fair split (getting some money, even a little, is better than getting no money). But in practice, many people reject unfair offers.

As with the iterated prisoner's dilemmas, Gabay et al. compared participants on MDMA to participants on a placebo. They tested three situations:

First-person – the participant makes the decision and gets to keep the money
Third-party – the participant makes the decision on behalf of another person
Random-generated – the participant plays against a computer that makes random proposals

Here's what they found:

The chart shows results for unfair offers (where the decider would receive < 20% of the total). The white dots (to the left) are placebo, the orange dots are MDMA.

As in the prisoner's dilemmas, participants responded very differently when they thought they were playing with another human (first-person & third-party) vs. a computer (random-generated). When playing with the random generator, there was no difference between MDMA participants and placebo participants – almost everyone accepted whatever the computer offered every time, even if it was "unfair."

This makes sense! If you were playing a game where each round a machine offered you money and you could either take the money or not, you would take the money. (It wouldn't be much of a game, but you would take the money every time.)

When participants thought they were playing against another human, there was more variation. MDMA participants accepted considerably more unfair offers than placebo when in the first-person situation, and somewhat more offers in the third-party situation, though that result didn't quite reach significance (p = 0.057).

At first brush, we might conclude that MDMA made participants more rationally self-interested (remember: it's rational to never reject an offer). But that's not what's happening here:

This interpretation is at odds with the finding that MDMA increased the amount offered when participants acted as proposers. Economic rationality suggests that one would offer the lowest amount possible. As such, we believe that the effect of MDMA on offers further supports the interpretation that these compounds alter social reward processing in the [Ultimatum Game].

When playing as the proposer, MDMA participants offered more money to their partner. That's not economically rational at all!

So what's going on? What is MDMA doing to make people more willing to accept unfair offers and more likely to propose generous offers?

I think it has to do with compassion.

Gabay et al. think something similar:

We argue that [MDMA] altered participants’ conceptualisation of ‘social reward’, placing more emphasis on the direct relationship with interacting partners.

When you're playing something like the ultimatum game with another person, a part of you is imagining what it must be like from their perspective. And you're not just modeling their perspective in order to more effectively exploit them. You're empathizing with them!

When you're playing the ultimatum game on behalf of another person (the "third-party" situation), a part of you is imagining both what it's like to be the other player and what it's like to be the third party. You have empathy towards both of them! And because they are in opposing roles, you need to take both of their perspectives into account when making your decision. (This explains why the third-party result is not as dramatic as the first-person result.)

If MDMA boosts empathy, it would increase the weight given to other people's perspectives when playing the ultimatum game. But it wouldn't change anything about how you play the game with a robot. And that's exactly what we see in Gabay et al. 2018.

This lines up with the results of Gabay et al. 2019 too – MDMA boosts empathy & cooperation in decision-making, but it doesn't make you uncritical and exploitable. Next time we'll look at Borissova et al. 2020 and why its null result doesn't knock this down.

Rollout

2020-07-22T14:00:00-07:00

Where do psychedelics fit in our culture?

Big question. Let's assume that they have a role to play – helping us unwind our trauma, helping us heal, helping us see our situation more clearly. Giving us a vision to orient towards. Something like that. (Here's an essay backing this up; start at Section 3 to skip the throat-clearing.)

So how do we work towards that?

My model is that there are three kinds of work to be done:

Drug discovery – finding novel compounds that seem likely to be safe, interesting, and helpful. Sasha Shulgin is archetypal of one approach here; high-throughput screening is an alternate route.
Drug development – shepherding a promising compound through clinical trials and bureaucratic approvals. MAPS is currently doing this with MDMA; Usona and Compass with psilocybin.
Rollout – building infrastructure to scale the safe administration of a drug once it's approved.

My current take is that rollout is the thing to focus on.

We know that psilocybin & MDMA can be used in safe + interesting + helpful ways. And they're powerful enough that discovering alternative substances doesn't seem critical (though a less toxic MDMA would be no small thing, as would a psilocybin with fewer bad trips but all the benefit).

The clinical trials are already proving out safety & efficacy across hundreds of people, and it seems likely that these results will hold up during Phase 3.

But what happens after FDA approval? The thinking here isn't as developed. Dropping acid on the playa doesn't seem like quite the right model, and neither does ketamine IV drips in a fluorescent-lit clinic.

And the complicating factors pile on fast:

So much of the hands-on knowledge of how to work with psychedelics is carried by underground practitioners, but most of the underground doesn't have therapeutic licensure. How to incorporate this knowledge and these practitioners into mainstream practice without unjustly penalizing them?
The holistic nature of the psychedelic experience doesn't play nicely with the taxonomy of the DSM-5, but the medical system is the primary vehicle we're using to bring psychedelics into the mainstream.
There are obvious frictions between the for-profit capitalistic model and the radically unifying, liberating, surrendering vision of a psychedelic society. It's too early to say whether public-benefit corporations are enough to bridge the distance here (I'd be surprised if PBCs were sufficient – any structure can be corrupted).
Every indigenous society with a longstanding psychedelic tradition carefully controls their use. Maybe there's a selection effect here: the societies that didn't control use didn't last long enough for us to notice them.
As with anything that's gaining cultural capital, there is an increasing incentive to act as if you care about the thing, even if you don't actually care about the thing.

... and there's more! It's a big tangled knot, and we don't know how to unwind it yet.

Gabay et al. 2019 – MDMA and cooperation

2020-07-19T13:00:00-07:00

Here's a big question: can intentional psychedelic use create enduring behavior change here in the everyday world?

For helping with mental health issues like addiction, depression, and PTSD, the provisional answer seems to be "Yes, yes it can."

But what about for simpler stuff? Can psychedelics help us be kinder & more cooperative in our everyday lives?

Enter Gabay et al. 2019, an RCT where participants took MDMA, then played iterated prisoner's dilemmas while in a brain scanner. (Science!)

The prisoner's dilemma is a canonical piece of game theory. Here's a quick recap:

You find yourself in a situation (let's say... being questioned at your local police precinct) where you can choose whether or not to cooperate with your partner in crime, but you can't communicate with them as you decide (they're being questioned in a different interrogation room)
If you choose to cooperate (you stay silent) but they don't cooperate back (they rat you out), you receive an intense punishment (a 30-year sentence! You two have been up to some no-good stuff)
If you don't cooperate (you rat them out), but they cooperate with you (by staying silent), they receive the intense punishment (they get the 30-year sentence) and you get to go free
If you both cooperate (stay silent), you both get a reduced punishment (10 years in prison apiece)
If neither of you cooperate (you both rat each other out), you each get a heavy punishment, though not quite as intense as you would have if you were taking the fall all on your own (20 years apiece)

Here's a chart representing the situation:

So what's the best thing to do? That's the dilemma.

Ideally you would both cooperate – that yields the best outcome for both you & your partner. It's the smallest amount of punishment overall.

But if you just consider your own situation, it might better to throw your partner under the bus (if you think they're going to cooperate) – if they stay silent, you would get to go free! However, if your partner follows that same logic, you would both receive a 20-year sentence.

This is a toy example, but the dynamic shows up everywhere. We're constantly confronted with situations where it'd be better overall to act in one way (telling the truth, showing up to meetings on time, following through on commitments), but better for us in the moment to act in a different way (a white lie to spare someone's feelings, being late, breaking commitments when convenient).

The stakes usually aren't as high as a 30-year prison sentence, so you get to play the game repeatedly, often with the same set of people. Over time, you get a feel for the different people you're playing with – some seem to be mostly cooperative, others only looking out for themselves. In game theory, this is modeled as an iterated prisoner's dilemma.

It's not a big stretch to imagine us all enmeshed in a web of interlaced iterated prisoner's dilemmas – a continual stream of decisions about whether we're going to cooperate with others in good faith, or instead find a way to defect & save ourselves. The aggregation of all these decisions is the world we end up living in.

We want to end up in the world where we're mostly cooperating with each other – that's better for everyone, by definition. Unfortunately, the rationally self-interested thing to do in an iterated dilemma is to defect, though the best move superrationally is to cooperate. (Superrationality is a bit of a slippery concept... it essentially means imagining yourself as one of a group of rational decision-makers, each of whom is imagining itself as one of a group of rational decision-makers.)

Because we want to end up in cooperate-world, an important project is finding ways to move out of an equilibrium that assumes game-theoretic rationality and to move towards an equilibrium that assumes (and cultivates) superrationality. If we could develop methods of reliably cultivating superrationality (or heuristics that approximate it), that would be extremely helpful.

Might MDMA be such a method? That's what Gabay et al. was investigating. Participants played six 15-round prisoner's dilemmas with three different kinds of partners – a trustworthy human who mostly cooperated, an untrustworthy human who mostly defected, and a game server who made a random decision each time. (In reality the "human" partners were also computer programs, but the participants apparently believed they were playing against other humans.)

Importantly, the trustworthy & untrustworthy partners weren't labelled as such... participants just saw that they were paired with "Greg" or whoever, and then had to discern the trustworthiness of their partner as they played.

Here's what they found:

The green dots (to the left) are the placebo results, the red dots are the MDMA results.

A few things stand out:

There's not much difference between the placebo & MDMA sessions when partnered with a game server, and the amount of cooperation for the game server is lower than when partnered with a "human." This makes sense! If you're paired with a random-choice generator, you have no way to signal that you want to cooperate – it's just going to make a random choice each round. You might as well try to get what you can for yourself, seeing as there's no way to build trust.
Both the MDMA & placebo groups cooperated more when paired with a "human" partner, even an untrustworthy one. When playing with a human, you can signal your intentions to cooperate.
There wasn't a significant difference between the MDMA & placebo groups when playing with an untrustworthy partner, but there was a significant difference when playing with a trustworthy one – in that situation, the MDMA group cooperated more.

That last point is so interesting.

I think there's a worry floating around that drugs, especially drugs like MDMA, will make you uncritical, dull, and dumb. You might grow more content & peaceful, sure, but at what cost?

That doesn't seem to be the case here. Participants on MDMA were more likely to cooperate when they thought they were paired with a cooperative player, but no more likely to cooperate when they thought their partner was defecting. They were still able to discern which players were cooperative while on MDMA, and they were able to protect themselves from being exploited when working with untrustworthy partners.

Gabay et al. isn't the final word on MDMA and cooperation – it's a small study that has limitations, and other papers have found contrary results (we'll talk more soon about how we might roll all these together into an overall picture about what's going on here).

But it's such a striking result – perhaps MDMA can boost goodwill & cooperation without a concomitant increase in naïvety. That would be a powerful thing.

Cutting through spiritual colonialism

2020-06-09T16:00:00-07:00

Vinay Gupta's Cutting through spiritual colonialism (a) recently came crashing across my computer screen.

Gupta's essay is wide-ranging, provocative, and important to read if you're interested in psychedelics in the West. Especially important if you happen to live in California.

Here's a taste (emphasis Gupta's):

One of the byproducts of the CIA soaking California in LSD in the 1960s was the formation of the Great Awakening Myth. The GAM was well established by the Victorians and earlier occult writers: the Age of Aquarius was long in the tooth long before the musical Hair made it into a catchphrase. But the combination of LSD, cultural unrest (fuelled by people being drafted and sent to Vietnam, plus desegregation), and a huge influx of teachers of Buddhism, Hinduism, Taoism and more, fused into a sticky, tarry mess in the form of the Great Awakening Myth. This is a beast that will not die. It dies in the 1960s as reality crashes in and a wave of heroin and Altamont-style disasters contaminates the entire perception that the Age of Aquarius is nigh upon us. But it’s reborn in the 1990s all over again, now wrapped around That Thing In The Desert (hip speak for Burning Man, not Coachella.) The “Burner Exceptionalism” collides with the SF tech boom, and the Iraq war. The result is a near-reproduction of the conditions of the 1960s, but now the hippies have money, and communes can support themselves by computer programming. AIDS has cramped the Free Love stuff substantially, but polyamory is at least affordable love, and the whole shambolic mess restarts.

...

What I have seen is an endless parade of people who’ve been brainwashed by the same spiritual vision: a world of spiritual oneness in which some kind of advanced techno-tribal civilisation runs without ecological offence, in a paradise of peace and plenty. And, while I have no doubt that such a world is possible, it is my severe duty to tell you drugs will not get you there.

The Asian traditions were not short of access to drugs. Soma is legendary in Yoga, indeed one old name for the Yogis is apparently “those who have drunk the soma and know.” But.

Carved out of the traditional Asian context, particularly the guru-disciple tradition, what the drugs do for most people is cause massive psychological distortions. The Ayahuasca download makes no sense at all and, in this world, if you can’t represent it on a spreadsheet it is not happening. There’s simply no way forwards towards that goal for people who aren’t sitting on trust funds, and coincidentally most of the people who are most profoundly sold on the Californian Ayahuasca vision of the future are sitting on top of trust funds.

What they’re looking for is a vision of the future in which they can live a life of luxury and pleasure, flying round the world taking drugs with their friends, and feel this is directly contributing to saving the world by ushering in The Great Awakening.

I know some of these people. I’d consider them my friends (at least until they read this.) But the bottom line is that awakening individually takes 20 years of diligent effort for most people, and I don’t think it’s much different in South America. They might be able to whack people a couple of times with the Big Shiny Rainbow Mallet a couple of times to get them to understand that there is work to be done, but if it was instant enlightenment, South America would have been a utopia decades ago, if not centuries. And I’m sure the Amazonian Indians and the Peruvians and so on were doing great, at times, but the odds that entitled white people are going to absorb that culture and tradition by doing the same drugs is as absurd as people thinking that taking cocaine will let them dance like John Travolta in Saturday Night Fever.

Now, this is not to say that it’s impossible for Californians etc. to study with the South Americans and learn their ways over time. I’m sure there are good teachers and good students doing diligent work over decades to achieve an intercultural spiritual understanding of depth, integrity and deep mutual respect. But these brave few people are lost in this vast swamp of corrupted idiots trying to wash their hands in a river of nonsense just because they saw a vision of a better world on a bunch of drugs. If the drugs can ship that kind of change, they would have already. Clinical use to treat PTSD and depression is a paradigm with clinical data to support it. But mass awakening? Progress towards that goal should be visible by now if it worked, and it just isn’t. The test of spirituality is what people do: not what they see, not what they say, not what they tell you is coming. California has been steeped in hippie values and every drug, drug cult, and drug culture known to man for 60 years, two full generations, and there is absolutely no sign of mass awakening, as you can see from the treatment of San Francisco’s homeless population.

If there is no human solidarity, then no awakening has occurred.

It’s a simple and utterly reliable test. Whatever San Francisco got from 60 years of the Great Awakening Myth, it was not awakening.

Okay, powerful stuff. There's much more in the essay (a), and not all of it polemic.

Here's my summary of Gupta's argument:

Western society used to be pretty bad at coordinating, but had a basic meaning-making orientation (Christianity) and functional methods of laundering personal responsibility (e.g. Catholic confession, e.g. Protestant predestination).
With industrialization, and then again with the computing revolution, Western society got a lot better at coordinating.
Alongside industrialization & modernization, Western society began to lose its meaning-making orientation and its methods of laundering responsibility began to lose efficacy.
So now we're in a place where we're much better at coordinating than we were before, but we don't have wholesome targets to coordinate towards, and we're for the most part operating as though our legacy structures of managing personal responsibility are still intact.
- This is bad.
Lately some of our coordinating power has turned towards "colonizing" spiritual practices of other cultures, i.e. it's trying to adopt a version of them that could replace our legacy personal-responsibility-management structures.
- This isn't going very well, because the spiritual structures we're interested in are a fundamentally different shape than the ones we're trying to replace, and we're more interested in shoehorning the new (from our perspective) structures into the legacy forms rather than adapting our expectations to the new structures (adapting our expectations would be much harder).

I don't agree with the entirety of Gupta's argument (the "Where do we go from here?" section could especially use more work; Freinacht has a good counterpoint here), but the general thrust seems right. It's definitely the sort of thing that calls for a good measure of reflection from folks pursuing the psychedelic path. It's the sort of critique that requires a specific response.

We're not operating in territory where it's sufficient to say "Oh, I'm sure it'll all work out in the end."

We live in a world where things happen for specific reasons. Doing helpful work in such a world requires specific plans (determinate optimism, in Thielian jargon). Working with psychedelics doesn't exempt us from that.

I'm sure there will be more to say about all this. For now, I'll leave you with Gupta's diagnosis of the essential problems we're facing:

Technological acceleration is simply that our underlying capacity to manipulate and control matter and energy has been on an exponential curve since the industrial revolution or a little before. 20 years ago a terabyte is an unthinkable amount of storage, packed into a raid array of 250 gig drives. Now you can have it as a MicroSD card, and that single drive is 16 gig. Brain scanning. Genetic engineering, solar panels, self-driving cars, drones, you name it. Rocket ships and VR gear. Even retina displays. Every year that the machine keeps running, more innovation in these kinds of areas. Each generation of gore-tex is a little better, a little more nanotechnology, a little more amazing.

We have no capability to understand, much less manage, most of this change. Even if you try to keep up, it’s too much innovation over too much front to really keep an eye on. Even if you watch self driving cars like a hawk, what’s happening in immunotherapy? Have you seen the unthinkable transformation in cancer treatments?

Limits to growth is as easy as pie: an average American puts out about 15 tons of CO2 per year. Best guess at a sustainable emissions level is 3 tons. If you emit more carbon than the sustainable level, the world gets warmer every year, and eventually that starts to reduce your ability to do things like grow food. This story repeats for basically every natural resource. There are some high quality of life, ultra-low consumption enclaves in the world: Kerala in India is below one planet of consumption, and has demographics right in line with Europe. Cuba is another famous example: they were forced to decarbonise at the fall of the Soviet Union when their oil supply got cut off and built an extremely lean and efficient society as a result. We all know these examples exist, for hundreds of millions of people, but there’s very little interest in scaling them. The world has not exactly beaten a path to Kerala’s door saying “how did you do it?”

Why not?

The invisible hierarchy of abuse is the answer to most of these questions, but it’s a little harder to see: consider this question. “How much child abuse goes on in boarding schools?” That’s your Etons and Harrows I’m asking about. Is the answer “none?” I don’t think so. Once in a few years, an awful story will break: a sports coach, or a choir master, or a headmaster. And that’s just the staff. Non-sexual student on student abuse is practically an institution in many of these places, and one does not assume those lines stay strictly drawn. Why is it invisible? Why don’t we have some kind of measured dialogue on these issues?

Well, I’m typing this on a Mac that I know for-damn-sure involves actions that I would consider criminal: no labour organization allowed in that supply chain, and the ever-present worry of conflict minerals down the chain there too. Never mind that my dinner will contain meat, and I know damn well where that came from.

This ability, to turn a blind eye “because we have to” is what makes the hierarchy of abuse invisible. It’s what allows a game which is almost entire made of losers to continue to be played by everybody, as if they were winning.

Hibicke et al. 2020 – Rats in tubes

2020-06-04T13:00:00-07:00

Hibicke et al. 2020 engages with big questions about the nature of mind, healing, and psychopharmacology.

It does so by getting rats very high, and then, several days later, forcing them to swim.

I'm still digesting this paper, so for now I'll just make a couple points about method and philosophy of science.

When we study brains, drugs, and psychological models, we mostly care about the impact these things have on the subjective experience of humans.

(There's a tangent here about how instead we sometimes do science for its own sake... discovery as an aesthetic pursuit! Fair enough, but let's leave that to the side for now. "Science to better understand the nature of human subjective experience" captures a lot of what motivates current scientific inquiry.)

It is very difficult to directly study human subjective experience using objective methods, so a lot of scientific work is done on things that we think contribute to human subjective experience (e.g. blood oxygen levels in the brain), or on things that we think approximate things that contribute to human subjective experience (e.g. the behavior of rats).

Both of these approaches produce work that's fun to think about & contributes to our understanding of the world. But there are big questions around how far specific results can take us, i.e. how much any specific result can tell us about what we really care about at the end of the day: the nature of the subjective experience of humans.

We can make pretty pictures of how blood moves through the brain, but it's not trivial to connect those pictures to an understanding of how brain states relate to conscious experience. We can observe that spiders on LSD weave more regular webs than sober spiders, but how does that connect to the experiences that humans have on LSD? (This Slate Star Codex piece on adult neurogenesis does a great job drawing out some of the difficulties here.)

Okay, back to Hibicke et al. 2020. We're finding out that both ketamine and psilocybin can treat depression more quickly than our current standard-of-care antidepressants (depressed patients can respond to ketamine and psilocybin treatment within minutes or hours; patients usually take weeks to start responding to SSRIs).

This is interesting because ketamine & psilocybin have different mechanisms of action – psilocybin & other classical psychedelics are 5-HT_2A receptor agonists, while ketamine is a NMDA receptor antagonist (though ketamine may also potentiate 5-HT_2A response? I don't yet have enough neurochemistry to sort this all out).

Also interesting: ketamine's antidepressant effect tend to fade after a couple weeks, whereas psilocybin's antidepressant effect can last for months.

Why do these drugs act more quickly than traditional antidepressants? Why does the antidepressant effect of psilocybin last for so much longer (on average) than that of ketamine?

More profoundly: is the antidepressant effect of these drugs caused by the subjective experience of being on the drug? Or is it purely physiological?

These are big questions. Carefully designed human trials with longterm follow-ups & qualitative interviews could probably go a long towards answering them, or at least giving us better answers than we have currently.

Unfortunately, it's hard to create well-designed studies. And human trials with longterm follow-ups & qualitative interviews are extremely expensive and bureaucratically fraught, especially when psychoactive drugs are in the mix (just ask MAPS; see also My IRB Nightmare).

So a lot of research is done using "animal models" (in this case, giving drugs to rats). These are much cheaper & faster to run than human trials, so they're attractive to career researchers who have h-indices to think of.

But studying animals is obviously further away from what we care about (human subjective experience) than studying humans. So what can we learn from rats about the dynamics of psilocybin & ketamine's antidepressant effects in humans? How could we go about inferring anything?

Enter the forced swim test:

As you can gather from that image, in the forced swim test, rats are put in tubes full of water such that they can't touch bottom. If the rat just floats there ("immobility"), that's considered a "depression-like" response. If the rat swims around or tries to climb out, that's considered a less depressed response. If rats who were given an intervention swim and/or climb more than rats who were given a placebo, that's considered an "antidepressant-like effect" of that intervention.

The limitations here are probably obvious – a lab rat in tube of water is quite different from a human who scores highly on a QIDS questionnaire. What can we learn from the rat that applies to the human? What do we assume about the rat, and what do we assume about the human?

Here's some of what Hibicke et al. assumed about their rats:

Despite having a rudimentary default mode network,(34) and showing interest in mirrors, video feed, and still images of other rats,(35) rats are not commonly believed to be among the menagerie of self-aware animals. Thus, as far as modern science is able to determine, rats do not have a sense of self and are incapable of having existential anxiety, pondering the meaning behind their own existence or fearing a reality in which they, as individuals, do not exist. No one knows what the subjective experience of a rat is after being given a psychedelic, but it is highly unlikely that they are able to place that within the context of their life experiences and utilize that knowledge therapeutically to improve their affective state.

Notice the lack of citation after "not commonly believed to be among the menagerie of self-aware animals." The authors are simply asserting that rats are not self-aware, for some definition of self-awareness. (A good discussion of animal consciousness here, though note that consciousness & self-awareness are different.)

Another assumption from that passage: if the benefits of psychedelics are caused by the subjective experience of the psychedelic, those benefits arise from the subject utilizing that experience therapeutically. The content of the subjective experience is something to be used for therapeutic improvement by the subject, not something that happens to the subject or is done for them.

This is getting somewhat semantic, and a little far out. To bring it back to earth, let's just note that there's a temptation to conflate "the subjective experience of a psychedelic reduces depression" with "the subjective experience of a psychedelic reduces depression because the subject uses the experience to do so," but those are actually different claims.

Okay, that's enough for now. There's a lot here, and I should probably read more Kuhn before continuing on in this direction.

LSD overdoses, or "For Tusko"

2020-04-08T14:00:00-07:00

tl;dr: Taking too much LSD can be very intense, but is physiologically safe unless you're an elephant and your handler overdoses you on tranquilizers right after giving you an enormous dose of LSD.

Haden & Woods 2020 is a short discussion of three cases of people taking way too much LSD. It's in the tradition of Klock et al. 1973, a case study of eight people who were admitted to SF General after snorting lines of LSD (having mistook them for cocaine) at what was likely a very far-out party.

Case reports like this are interesting because we can't run prospective human studies of taking too much of a drug (for obvious ethical reasons). Because we can't run prospective studies it's hard to confidently assess how dangerous a drug is / what its LD₅₀ is.

Given this limitation, cases that happened "in the wild" are one of our better sources of information (we also sometimes do prospective animal studies but ethical considerations are at play there too, as well as the question of how generalizable effects in animals are to humans).

Like Klock et al. before them, Haden & Woods found no longterm negative effects in the cases they looked at, though there were alarming acute effects like vomiting & "blacking out." They also found some longterm positive effects, which is interesting.

Let's take a quick look at the three cases:

A 15-year-old girl with a bipolar diagnosis takes 1,000 micrograms of liquid LSD, equivalent to ~10 tabs, at a summer solstice party (someone at the party had intended to prepare 100 micrograms glasses but accidentally 10x'd the dose). The girl has an intense experience which results in an ambulance being called and her going to the hospital. She recovers fully, and afterwards experiences a sustained reduction in her bipolar symptoms.
At the same summer solstice party, a 26-year-old woman drinks a half-glass of the liquid LSD (so ~500 micrograms, or ~5 tabs). She has an intense experience but isn't hospitalized, recovers fully by the morning. Turns out she was two weeks pregnant (she didn't know this at the time). Her son is now 18 and is high-functioning ("A" student, exercises a lot, has friends).
In a separate incident, a 46-year-old woman snorted a line of LSD thinking it was cocaine (I don't recommend snorting cocaine, but if you're going to snort cocaine please make sure it is actually cocaine). This was about 55 milligrams of LSD, or about 550x more than a normal one-tab dose. She "blacked out" for 12 hours, then regained speech and continued to trip for another 12 hours. Happily a friend was around and able to take care of her. Fully recovered. Interestingly, the day after a chronic pain in the woman's foot was gone and she stopped using morphine for a while (which she had been using to manage the pain). The foot pain eventually returned.

Let's look a bit closer at Case 1, which has the most interesting long-run effects and is also the best-documented, because we have notes from the girl's (pseudonym "AV") hospitalization.

When the girl's father arrived at the hospital:

AV’s father reported that when he entered the hospital room the next morning, AV stated, “It’s over.” He believed she was referring to the LSD overdose incident, but she clarified that she meant her bipolar illness was cured.

From AV's mental health team case notes:

July 11, 2000 [shortly after the experience]: AV “came in today with a lovely fine balance and a glint in her eye and she is maintaining a happy and credible mood balance ever since the unfortunate incident that provoked her seizure three weeks ago” and AV “has not presented with as easy and healthy a presentation in many, many months.”

...

September 6, 2000: “She has remained remarkably stable this summer with no evidence of recurrent depression or mania” and AV “is doing remarkably well even compared to last year at this time when she was noticeably depressed.”

...

May 30, 2001: AV “has gone off her lithium and there are more mood instabilities as a result of that but no evidence of clinical hypomania or depression” and “we spoke carefully with mother, father, and AV – it is clear that no one has seen symptoms of clinical depression...” and “she has had a fairly successful school year other than the one term out of four and has not had a breakthrough of clinical levels of depression or mania.”

The LSD experience seems to have been a inflection point in AV's life:

AV’s father observed that his daughter appeared to be completely recovered from her mental health concerns after the overdose incident.

AV reports that she was free from all mental illness symptoms (bipolar or other) for the subsequent 13 years until she gave birth and experienced postpartum depression. The birth of her second child in 2017 was also associated with a turbulent emotional period. AV reports that after the LSD overdose incident she experienced life with a “normal” brain, whereas her brain felt chemically unbalanced before the incident.

So that's interesting.

Most infamous in the literature of LSD overdose reports is the case of Tusko the elephant, first reported in West et al. 1962.

This was a study of musth, a phenomenon wherein adult male elephants temporarily become very aggressive and start secreting a mysterious substance from the sides of their heads. West et al. were apparently trying to assess whether this secretion was causing the aggressive behavior, and decided to use LSD to induce a "pseudo-musth" state. (Who knows what they were actually thinking.)

Tusko, an elephant at a zoo in Oklahoma City, was given 297 milligrams of LSD (5x the amount that Case 3 snorted, which in turn was 550x a normal human dose). Things didn't go well:

The image of Judy coming over to support Tusko is so sad.

It's a little unclear what happened here. Tusko was given a lot of LSD. 20 minutes later he was given Thorazine (~10x a human dose). Soon after that he was given an unspecified amount of pentobarbital. Then he died.

Who knows exactly why Tusko died, though it probably wasn't because of an LSD overdose. In 1984 another researcher gave only LSD to two elephants and both survived.

RIP Tusko.

IP 34 – Oregon's psychedelic ballot initiative

2020-04-01T12:00:00-07:00

It’s a moment of high drama for Oregon’s psilocybin services ballot initiative, IP 34 (ballotpedia, campaign website).

From a recent IP 34 campaign update:

Just two weeks ago, our signature drive was cruising to qualification. We believed we'd meet our goals in mid-April and qualify the Oregon Psilocybin Services Initiative for November. But then the world stopped.

There's no other way to say it: the dangers of the coronavirus have put our ability to qualify at risk and we need your help.

...

We have gathered 127,730 petitions for the November ballot. Our internal tracking tells us that we need to gather 145,000 total petitions, 17,000 more, to have enough valid signatures to make the ballot in November. Without being able to reach people on the street, our campaign is now turning to an online campaign to gather our remaining goal.

The world went into COVID-19 hibernation just as the Oregon campaign was approaching its signature target.

Obviously COVID-19 has disrupted a huge number of things. This is a blog about psychedelics, and IP 34 is one of the most interesting things happening in psychedelia at present, so let’s spend a little time on it.

Some background: IP 34 is a grassroots ballot initiative led by Tom & Sheri Eckert, therapists who live in Portland, Oregon. We learned about it in late 2018, and last year we did a fairly deep dive on the v1 initiative text. Since then, the initiative text has been reworked and the campaign has continued to gather steam.

From an August 2019 campaign update:

The goal was to bring real healing and real change to Oregon in 2020, using the ballot initiative as a vehicle. We drew up a detailed framework, worked with the Legislative Counsel, and ultimately submitted the first legislative language of its kind. We attained a Certified Ballot Title and began mobilizing volunteers.

...

During that time frame we also connected with Dr. Bronner’s Magic Soaps – one of the great activist companies in the world. They had been tracking us for some time. We immediately clicked with David Bronner and Les Szabo, as well as their close confidante Graham Boyd of the Psychedelic Science Funders Collaborative. We began teleconferencing and strategizing. They too saw benefit in revising the language, for the same reasons as Emerge did.

With the clock ticking, and a potential rewrite in the works, we conveyed that we’d need some assurances of financial support to help knock out the required 112,200 valid petition signatures on time. David provided those assurances.

Meanwhile, we learned that the Drug Policy Alliance (DPA) is exploring possible ballot measures to decriminalize possession for personal use of all drugs in several states, including Oregon. We support their powerful vision of addressing drug use through a health approach instead of treating it as a criminal problem. So, we made up our minds. Rather than duplicate the same effort as DPA, we would produce a new and improved bill to legalize psilocybin assisted therapy and drop the decriminalization aspect.

We had our marching orders. We hunkered down with Emerge and teleconferenced with David and Graham, and, over the course of a couple months, we drafted the most complete and dialed-in revision imaginable to legalize psilocybin therapy – a unique, world-class document. Much of the content reflects the earlier version, only cleaner, including:
- A framework for accessing psilocybin services
- Safety, practice, and ethical standards
- Services open to anyone who is not medically contraindicated
- An affordable, community-based framework outside the medical / pharma system
- Trained and competent facilitators (without requiring previous credentialing)
- Use of organic materials (mushrooms), not just synthetic psilocybin

Other inclusions were either new or augmented the previous provisions, while addressing a variety of concerns from the community. Some new highlights include:
- A strengthened Advisory Board, with directives to work with state and federal officials to create an environment of cooperation
- An extended development period so that the OHA can successfully roll out the program
- Prohibition of cannabis-style branding and marketing of psilocybin products
- Iron-clad protections against big corporate influences, including limiting business entities to a single production facility of limited size, or maximum five service centers (no big chains)

We haven’t poked into the v2 initiative text yet, but the v1 text seemed like a reasonable first pass at creating a state-level legalization framework for psychedelics, and I’ve gotten only positive signals from the campaign since then.

We'll probably write more about IP 34 and why it matters in the coming months. The short story is that if passed, IP 34 would help move psilocybin out of the “heroin” bucket (Schedule I drugs that are illegal in every state) and into the “cannabis” bucket (Schedule I drugs that are legal in some states such that the federal government leaves enforcement up to the states). This would have implications beyond Oregon – see e.g. the Cole memo.

The campaign has until July 2nd to hit its collection target (17,000 more signatures), and it has to do this via distributed signature collection. By normal measures July 2nd isn’t too far off, but in corona-time it’s eons away. So despite COVID-19, it’s still plausible that IP 34 qualifies for the ballot, and that would be a big deal.

For now, here are a couple calls to action:

If you are a resident of Oregon and you haven't yet signed the petition, you should consider doing that! Here's a link for signing.
Regardless of where you reside, you can support the initiative by liking the campaign's facebook page and/or making a donation.

Pala

2019-12-16T14:00:00-08:00

The Auryn Fund recently came onto the scene in a big way with their story, We Will Call It Pala (a).

I was taken aback when I saw it. A beautiful message, prescient, wrapped in an elegant design. Psychedelia corporatized, commoditized, trivialized.

Then I chatted with a friend about it, and my friend was like, "Nah, man, it's not a big problem."

II.

The story is about Learie (get it?), an entrepreneur who starts a psychedelic clinic business called Gaia Health.

Learie starts Gaia Health for the right reasons – the world is pain; psychedelics helped her see this and come to terms with it; they can do the same for others. Psychedelics can help the world heal.

Gaia Heath rides the wave of the psychedelic renaissance. The plans get more ambitious, the capital raises bigger, the product more tech-enabled, the competition fiercer. Learie finds herself selling a mental health commodity, little different from her competitors except that her pricing is a bit higher and her hiring policy slightly more rigorous.

Eventually, Learie is forced out. A suit is brought in to run the show. Learie looks around, not recognizing the world she helped usher in.

The essay leaves us with a call to action: what will you do now to help realize the world you want want to see? (Subtext: what will you do now to work against the corporatization of psychedelics?)

But I think another question should come before that: what's so bad about the corporatization of psychedelics?

III.

The world Learie helps build is a dark one – impersonal psychedelic clinics staffed by former nursing home employees, 5-MeO-DMT nasal spray muscled to center stage because a 5-MeO trip only lasts a few minutes (think of the unit economics!), marginalized communities pushed further to the margin as big pharma moves into the space.

The world is portrayed with Orwellian undertones (more World State than Pala), but who in it is worse off? Who is harmed in this vision of psychedelia gone off the rails?

Learie builds a successful psychedelic business and walks away with $52 million from its exit
People seeking mental health treatment have access to psychedelic therapy, and this therapy is genuinely helpful
People who used to work as nursing home attendants now have the option to work as psychedelic facilitators
Using psychedelics becomes a more normal part of our culture
Big pharma takes psychedelic therapy seriously and works to professionalize it
More money flows into psychedelic research
Overdrawn psychedelic resources (e.g. peyote cacti, banisteriopsis caapi vines, Sonoran Desert toads) get some relief as synthetic alternatives come online

The essay hints at marginalized groups like refugees being worse off, but it's not clear how or why that happens.

Learie's world is definitely imperfect, but it's plausibly a real improvement over the present state of affairs.

IV.

I think the main thing that's sad about Learie's world is that basically everyone misses the point.

Psychedelics have the potential to be transformative. I don't mean that in some vague, New Agey sort of way. I mean that psychedelic experiences can literally change how you think about your life, your story, and the world you live in.

Transformative potential like this is powerful, and it's not guaranteed to go in a positive way (though interestingly it tends to skew positive). This is a huge topic and I won't dive into it here. For now, I just want to observe that what generates a lot of interest in psychedelics is not the thought that psychedelic therapy will be somewhat better than the current standard of care, but that psychedelics could be radically transformative (see the Griffiths quote at end of Michael Pollan's New Yorker essay).

The same dynamic is at play for contemplative practices like meditation. People who get really enthusiastic about meditation tend to be excited about its transformative potential (1, 2, 3, 4, 5). This doesn't mesh neatly with how corporate business models work, so we end up with palliative presentations like Headspace.

(To be clear, I think things like Headspace are good & helpful to lots of people. The world where Headspace exists is better than the world where it doesn't, ceteris paribus. Yet alongside that, there's a melancholy that arises from seeing a potentially transformative thing being handled as a palliative.)

This dynamic arises in straitlaced domains too. In 1930, Keynes predicted that by 2030 most people would be living lives of leisure. And though we have gotten much wealthier over that span, most people don't spend most of their time on leisure presently, and it's very unlikely that this will change by 2030.

The interesting question here is "Why not?"

Given how much surplus we have, why don't most people spend most of their time on leisure? (Sure, you can say that it's a distribution problem, but that only pushes the question back a level – why is there a distribution problem?)
Why don't the most popular meditation apps talk about the transformative potential of that practice?
Why are social-impact VCs seeking 10x returns? ("They need to pay back their LPs" – okay, fine, but why are the LPs seeking outsized returns? What do they need that money for, specifically?)

These are foundational questions (echoes of Moloch), and I don't yet have intelligible answers.

This sense of loss, this feeling of missing out on massive upside, is what's troubling about Learie's world. But it's also a troubling thing about our world!

I appreciate We Will Call It Pala for painting a specific vision of a suboptimal psychedelic future. It would be sad for us to collectively miss the point as we bring psychedelics more into our culture. But I think an imperfect rollout would still be a good thing.

Report: psychedelics for addiction

2019-10-12T08:30:00-07:00

We've completed a report looking into psychedelics as a treatment for addiction, focusing on ibogaine, ketamine, and psilocybin.

From the report's introduction:

So smoking, alcohol, and abuse of other drugs caused 16.8% of DALYs in the US in 2017. That’s one-sixth of the total health burden of the US.

Addictive disorders are a substantial portion of the global DALY burden, too. It’s hard to get a clear picture of the exact global DALY burden attributable to addictive disorders – developing-world health data is less reliable than US or European health data. Also, in the developing world a large portion of COPD is caused by cooking fires, not smoking, so attributing the entirety of developing-world COPD to addictive disorders would be inaccurate.

This review will focus on the US & Canada, as we have the most experience with & knowledge of those landscapes. There’s also a mimetic argument whereby many countries seem to follow the US in policy matters, either making direct use of US innovations or creating country-specific copies of them. So affecting the US situation may have knock-on effects in many other geographies.

We're not releasing the main text of the report publicly, as it contains analysis of business & philanthropic opportunities that is somewhat sensitive.

If you'd like to review the full report, shoot an email to info@enthea.net requesting access.

Carhart-Harris & Friston 2019 – REBUS and the Anarchic Brain

2019-08-27T09:00:00-07:00

Drs. Robin Carhart-Harris and Karl Friston recently published a beautiful paper – REBUS and the Anarchic Brain (a).

It's great for two reasons:

It presents a plausible unified theory of how psychedelics work.
It's a wonderful jumping-off point into the literature. Every paragraph is full of pointers to research that's come out in the last 5 years, and boy are there a lot of rabbit holes to go down – it's filled out my reading list for the next several months.

Carhart-Harris is the director of Imperial College London's newly minted Centre for Psychedelic Research; Friston is a famous neuroscientist.

REBUS is a (somewhat dubious) acronym for RElaxed Beliefs Under pSychedelics. The basic idea: psychedelics reduce the weight of held beliefs and increase the weight of incoming sensory input, allowing the beliefs to be more readily changed by the new sensory information.

REBUS pulls together Carhart-Harris' Entropic Brain theory and Friston's Free Energy Principle, both of which relate to the hierarchical predictive coding model of cognition. There's a lot of jargon & nuance here, but the essential idea of hierarchical predictive coding is pretty straightforward:

The brain generates mental models that predict upcoming sensory inputs. (The predictions are called "priors," as in "prior beliefs.")
These predictive models are layered on top of each other in a hierarchy – the higher levels send predictions down the hierarchy; the lower levels report sense data upwards.
In cases where the model's top-down predictions do not match the bottom-up sensory input, the model either (a) updates its priors based on the new sense data, or (b) ignores the sense data and maintains its priors.

(Scott Alexander's review of Surfing Uncertainty has a lot more on predictive coding.)

Carhart-Harris & Friston theorize that the main thing psychedelics are doing is relaxing the weight of the brain's top-down prediction-making ("REBUS") and increasing the weight of the bottom-up sense information ("the Anarchic Brain"). This allows bottom-up information to have more influence on our conscious experience, and also on the configuration of the hierarchy overall.

Carhart-Harris & Friston analogize this process to annealing – heating up a metal dissolves its crystalline structure, then a new structure recrystallizes as the metal cools:

The hypothesized flattening of the brain’s (variational free) energy landscape under psychedelics can be seen as analogous to the phenomenon of simulated annealing in computer science – which itself is analogous to annealing in metallurgy, whereby a system is heated (i.e., instantiated by increased neural excitability), such that it attains a state of heightened plasticity, in which the discovery of new energy minima (relatively stable places/trajectories for the system to visit/reside in for a period of time) is accelerated (Wang and Smith, 1998).

Subsequently, as the drug is metabolized and the system cools, its dynamics begin to stabilize – and attractor basins begin to steepen again (Carhart-Harris et al., 2017). This process may result in the emergence of a new energy landscape with revised properties.

Psychedelics "heat up" the brain, increasing plasticity and weakening the influence of prior beliefs. As the psychedelic stops being active, the brain "cools" – the hierarchy re-forms, though perhaps in a different configuration than the pre-psychedelic configuration.

This explains how psychedelic trips can cause changes that last long after the substance has exited the body – in those cases, the psychedelic facilitated a change in the organization of the brain's cognitive hierarchy.

Psychedelic therapy is showing promise for mental disorders associated with too-rigid thought patterns – depression, anxiety, addictions, maybe OCD, maybe eating disorders. In predictive-coding lingo, "disorders that may rest on particularly rigid high-level priors that dominate cognition."

In these disorders, new information can't revise the existing story of how things are, because strong priors suppress the new info before it can update anything.

The REBUS model straightforwardly explains how psychedelics help with disorder like this – by relaxing the strong top-down priors and boosting the bottom-up inputs, bottom-up inputs have more ability to effect the system. Here's an illustration from the paper:

The top sketch is a brain where strong top-down priors dominate. New sensory inputs are suppressed and can't update the hierarchy. The bottom sketch is the same brain while on a psychedelic – the top-down priors have been relaxed and bottom-up sensory information flows more freely through the system, causing a bigger impact.

Okay, nice theory, but can we observe this in the brain? Is there any evidence for it?

Carhart-Harris & Friston place the default mode network at top of the brain's predictive hierarchy. The default mode network is the network of brain regions that's most active when the brain isn't engaged with any specific task. It also appears to be the seat of one's sense of self. The default mode network is intensely relaxed by strong psychedelic experiences – this is subjectively felt as ego dissolution, and allows for the propagation of bottom-up sense data (which are also boosted by psychedelics).

Carhart-Harris & Friston identify two mechanisms by which psychedelics may relax the default mode network – activation of 5-HT2AR serotonin receptors (there are lots of these receptors in the default mode network), and disruption of α and β wave patterns, which seem to propagate top-down expectations through the brain (and are correlated with default mode network activity).

In addition to the brain-scan-style evidence they cite throughout the paper, Carhart-Harris & Friston dedicate a long section to behavioral evidence ("Behavioral Evidence of Relaxed Priors under Psychedelics"). Briefly, there are several studies showing that surprise & consistency-making responses to sensory stimuli are reduced while on psychedelics, which is what we'd expect if the influence of top-down priors was lessened.

To sum up, REBUS and the Anarchic Brain places psychedelics in a predictive coding framework to give a unified theory of what psychedelics do – they decrease the influence of top-down prediction-making and increase the influence of bottom-up sense data. The theory has the nice quality of tying many disparate psychedelic phenomena together with an underlying explanation of what's going on. Plus, it gives a brain-based explanation for why psychedelic therapy is helpful for disorders like depression, anxiety, and addiction.

Towards a safer MDMA protocol

2019-07-28T13:00:00-07:00

Editor's note: As previously discussed, MDMA may be physiologically harmful when used regularly (though it appears to be less harmful than alcohol (a), cf. this critique of comparative-harm analysis (a)).

The research below was prepared by an anonymous collaborator, and published here with the author's permission.

This post is about my personal take on the best psychedelic stack and protocol after reviewing the relevant literature, consulting with neuro-focused medical researchers, comparing to existing protocols in use by psychedelic therapy training programs, and conducting some experiments.

I was dissatisfied with the scattered nature of the relevant info online. This post is obviously for educational purposes only. If at some point in the far future such substances were legalized this could be a useful guide to using such things for self-administered or peer-assisted therapy if a reliable facilitator is not available.

MDMA pharmacology:

Rick Doblin, founder of MAPS, recently gave an inspiring TED talk. From the talk:

Now, how does MDMA work? How did MDMA help Marcela? People who have PTSD have brains that are different from those of us who don't have PTSD. They have a hyperactive amygdala, where we process fear. They have reduced activity in the prefrontal cortex, where we think logically. And they have reduced activity in the hippocampus, where we store memories into long-term storage. MDMA changes the brain in the opposite way. MDMA reduces activity in the amygdala, increases activity in the prefrontal cortex and increases connectivity between the amygdala and the hippocampus to remit traumatic memories to move into long-term storage.

You may have heard that MDMA has been granted breakthrough treatment status for PTSD, and that [the Usona Institute and Compass Pathways are] working on similar Phase 3 trials for psilocybin for treatment-resistant depression. Obviously in the medical trials these substances are being tested separately, but I actually think they're highly synergistic.

Here's why: a large proportion of the psychedelic effects of MDMA seem to come from its conversion in the body to MDA (Kalant 2001). Obviously people like these effects, but the problem is that MDA appears to be many times more neurotoxic than MDMA (Colado et al. 1995, Hearn et al. 1988).

Though the reality is more complicated and other metabolites are in play, the relevant causal mechanisms are covered by what we're doing here so we don't need to get into it.

One could inhibit the conversion of MDMA to MDA by taking a CYP3A4 inhibitor, but where would one get something this exotic?

[Editor's note: A neuropharmacology expert notes that people have widely varying levels of CYP3A4 activity. For people who have low CYP3A4 activity, inhibiting CYP3A4 may actually increase the toxicity of MDMA. This expert is generally supportive of using supplements with MDMA, but skeptical of using CYP3A4 inhibitors to improve MDMA safety.]

Luckily some of the enzymes in grapefruit juice/peel are quite potent in this regard, and appear to block about 90% of the conversion (Kolbrich et al. 2009). Preventing the conversion of MDMA-to-MDA also means that there is more MDMA circulating in your system. Which means one can reduce the dosage, and potentially mitigate any other dose dependent neurotoxic effects we might not know about. Based on surveys, people report the best effects with 80 mg (as opposed to the 100-150 mg doses often taken recreationally).

[Note that grapefruit juice interacts with many medications in ways that can sometimes produce serious side effects. Definitely check for interactions with grapefruit if you take other medications.]

MDMA paired with psilocybin:

Now the problem is that without said conversion, the MDMA isn't going to have the same psychedelic kick as before, though it will still have an emotional effect. If we presume that the psychedelic effect is at least partially responsible for the good effects of MDMA therapy we wouldn't like to lose this, so what do we do? You can probably guess what comes next. Stacking the MDMA with low-dose psilocybin allows us to precisely control how strong we want the psychedelic effect to be without any of the downsides of MDA (my guess is that MDA is more responsible for MDMA hangovers than the MDMA itself).

To do psychotherapeutic work, one wants to be lucid enough to be able to follow chains of emotional reasoning and be able to communicate with one's facilitator. People respond differently, but this generally corresponds to about 10-20 mg of psilocybin (Griffiths et al. 2011). This also corresponds to about 1-2 grams of dry weight mushrooms, though obviously this can vary a bit too depending on conditions.

Other supplements:

There is milder evidence for some other supplements lowering signs of neurotoxicity, and they're harmless and cheap enough to take. They are:

na-r-ala (amino acid, present in foods) [See also ala vs. na-r-ala]
alcar (amino acid, present in foods)
ginger
magnesium
egcg (green tea) [afterwards, not during]
coq10 (enzyme present in fish, vegetables, seeds)
niacinamide (vitamin b3)
melatonin (sleep hormone, after come down, before bed)

There are companies selling stacks for convenient though expensive dosing:

VitaPlur (grapefruit gum)
RaveBox

Body temperature & other approaches:

Keeping core temperature cool also seems to ameliorate toxicity effects. Staying hydrated and not being excessively active (e.g. not dancing for hours) helps a lot with this.

If one finds oneself overheating, cool (not too cold) water on the palms/wrists rapidly lowers core body temperature. Gel packs kept in the fridge rather than the freezer are also about the right temperature to rapidly cool without being so cold that they activate the bodies natural "preserve heat" response which is counterproductive.

Some people try to optimize the timing of all sorts of peak blood concentration curves for various substances based on various pieces of available evidence. I don't see compelling evidence this makes much a difference. You can take it all at the same time (except the melatonin).

What about 5-htp at night or the next day? I'm pretty underwhelmed by this supplement, to be honest. Why is a long complicated topic, suffice to say if you're doing everything else right I think any benefits from this would be quite small and not worth the mild risks.

(Tangent: in studies on the neurotoxocity of MDMA one of the comparisons they use is the known to be highly neurotoxic methamphetamine. If you or someone you know is on it, I'd recommend they take l-tyrosine along with the above on a regular basis. People report it helps with adderall hangovers. While I worry that sharing such info will actually make people more likely to stay on adderall, I can't justify not sharing things that impact brain health and leaving the decisions to them.)

Conclusion:

Trip reports of people using this stack say that they did not experience a hangover, and in fact experienced the opposite, a pleasant afterglow that lasted for several days.

I think both the emotional component and the psychedelic component of an MDMA trip are important. Why?

The emotional component creates the space to have self-compassion (one person reported that on MDMA they felt like they actually understood the idea of self care for the first time, that they deserved as much consideration as they would give to others facing a difficult situation).

The psychedelic component creates the possibility of seeing things from a broader perspective and the neuroplasticity for this new perspective to stick. [See Carhart-Harris & Friston 2019 for a possible mechanism of this neuroplasticity boost.]

"LSD and the Mind of the Universe"

2019-06-30T13:30:00-07:00

Notes from Dr. Chris Bache's talk at the 2019 Intercollegiate Psychedelics Summit, summarizing some of his forthcoming book: LSD and the Mind of the Universe: Diamonds from Heaven.

(Published with the author's permission. These are our notes from Bache's talk, not his own words.)

Warning: this is far-out stuff. Those allergic to intensely speculative theoretical frameworks are advised accordingly.

Background

Bache did 73 high-dose LSD trips over 20 years
Bache divided his life in half:
- Daytime job – professor of religion, studying transpersonal theory
- Nighttime job – 20 years of psychedelic exploration, kept private
Stan Grof 1976: Realms of the Human Unconscious. Grof proposes three levels of consciousness:
- Psycho-dynamic
- Peri-natal
- Transpersonal
Grof 1980: LSD Psychotherapy
All of Bache's work followed Grof’s protocol:
- By himself, high-dose, inward-looking
- Made a record of the account within 24 hours
- Then do analytic work in dialogue with others
Distinction between two forms of LSD therapy:
- Psycholytic therapy – 50-300 micrograms per session, therapeutic course of 70+ sessions
- Psychedelic therapy – high-dose (300+ micrograms), developed working with terminally ill patients, overwhelm the psychodynamic consciousness, try to trigger a near-death experience, therapeutic course of (at maximum) three experiences
Bache wondered: what happens if you do more than three high-dose experiences?
- He did about five sessions a year for 10 years
- Always had a sitter, his wife
- High-dose LSD generates phenomena & affects that don’t usually come up; it's very demanding work
- If he were to do it again, would do it differently. He'd balance LSD sessions with more grounded psychedelics like psilocybin, and would be more gentle with himself
- Standardized set & setting. "The more you standardize set & setting, the more you stabilize the grounds for the dialogue that you’re about to have with the universe"
- There was continuity between sessions. "A deepening of the process"
- He'd use 500-600 micrograms per session (very high doses)
- He kept detailed notes. In total, 400 pages of session notes
Bache's story is not primarily a personal story. It's primarily a cosmological story
- Insights into personal life occurred at the beginning & ending of sessions. During the peak of each experience, content was more cosmological, a "cosmological dance"
There's a lot to learn from psychedelic cultures – peyote culture, ayahuasca culture – about what happens with years of being in deep conversation with the universe. Western culture is just getting started with this
A lot of questions come up about the reliability & advisability of this path. His book goes into that

1. Crossing the boundary of birth & death

Crossing the perinatal plane.

Intense fetal experiences; intense confrontations with death & meaninglessness
- A lot of this, over & over again
- Physical detox, emotional detox
- Lasted 2.5 years & 10 sessions
- Resulted in ego death – we’re proud of our egos but it’s pretty easy to kill them. "The Universe snapped mine in half like a twig"
Every session has two phases:
- 1) detox then it peaks, peak is frightening, if you run away from the peak you can get trapped in hell for a long time...
- 2) if you go through / towards the peak, you get spun out into a transpersonal space

2. The ocean of suffering

Pain & suffering like I’ve never seen before.

Excruciating, difficult, much worse than the perinatal level. Experiencing all the pain of the species, held in the collective unconscious
"I have to learn how to sustain suffering of this magnitude"
During this, Bache took a six-year break, then returned to high-dose LSD & it picked up right where he left it, back in the hell realms

3. Deep time & the soul

Simultaneous experience of my entire life, all experienced as one "now."

Couldn’t remember it after the first time it happened. Got better recollection on return trips. "Have to train yourself to stay conscious in extremely non-ordinary states"
"We usually speak of these as profound states of consciousness, but they are profound states of body"
- You have to prepare your body. Watch your body, watch your diet. Do yoga
- If you jump in carelessly, you’re gonna pay a price. It'll be chaotic
The model of healing just myself, personal healing, was too narrow
- If you’re willing to open yourself up, you can help heal the entire reality
- If you’re given an opportunity to help on this magnitude, you do what you can. "I choose to help, and it wasn’t really for me. It was for children who have not yet been born"

4. Archetypal reality

A reality more real than time & space.

It was unnerving to realize how unreal time & space felt, in comparison
Lots of "cleansing" involved. "When you move into a deeper level of reality, you have to go through a purification process"
Incomprehensible "platonic" experiences
More comprehensible experiences of being an individual creature enmeshed in a world-system
- Experience of our planet & species going through the pulse of reincarnation

5. Benediction of blessings

A year of one ecstatic blessing after another.

6. Diamond luminosity

A reincarnation process going between spirit & matter, matter & spirit.

Eventually the entirety of the spirit becomes integrated into our material universe
- A new type of human experience, a new human founded on new bases
Bache was shown that we’re in a time of labor, socially
- The fundamental architecture of the human psyche is being changed. A crescendo of the human story – not the final crescendo (we’re in this for the long haul) but a substantial one
“For there to be a great awakening, there has to be a great death”
Beginning of the 21st century is a dark night of our collective soul. But it’s not an ending, it’s a trial by fire
- We are birthing the future human, which will take the form of the diamond soul
- A planet of Buddhas, a planet of Christs
This "diamond reality" only arose 4 times during Bache's work (always during extremely high-dose sessions)

7. The “goodbye sessions”

An overview of all of his work
The structure of these sessions provided the narrative structure of Bache's book

Two dissimilarities with the Portugal model of drug decriminalization

2019-06-19T12:30:00-07:00

Portugal's drug policy is often pointed to as a model of how drug decriminalization could work in the US.

In Portugal, all drugs are decriminalized. If a law enforcement officer encounters someone using drugs, the officer sends the user to a "Dissuasion Commission", where the user is assessed as either a "problematic" drug user or a "non-problematic" drug user.

"Non-problematic" users are given advice & educational material about the drugs they are using. "Problematic" users are referred to addiction treatment services. (See p. 239-43 of Chasing the Scream for more on Portugal's system).

It seems useful to study Portugal's system, though we worry that the US drug policy reform community is benchmarking too heavily on Portugal as a model for what reforms the US should target.

Below are two dissimilarities of the situation in Portugal and the situation in the US.

We feel it's important to keep these factors in mind when drawing comparisons between the two policies – due to dissimilarities like this, what worked in Portugal may not work in the US.

1: Transnational cartels supply the bulk of illicit drugs used in the US.

Following a simple economic model, decriminalizing all drugs in the US would increase demand (because it becomes less risky, i.e. less costly, to buy drugs), but wouldn't introduce a legal method of supply.

Currently, transnational cartels supply a large portion of the illicit drugs that are used in the US.

From the 2018 National Drug Threat Assessment (a), on p. 105:

Mexican [transnational crime organizations (TCOs)] will most likely continue to maintain a dominant influence over the wholesale importation and distribution of cocaine, heroin, marijuana, methamphetamine, and fentanyl in U.S. markets in the near term.

No other criminal organization currently possesses a logistical infrastructure that can rival that of Mexican TCOs. Mexican TCOs will continue to grow in the United States through expansion of distribution networks and interaction with local criminal groups and gangs.

Cartels would probably benefit from the increased demand, as they are the default suppliers of illicit drugs to the US market.

If decriminalization doesn't introduce a legal, regulated alternative to cartel-supplied drugs, it seems plausible that decriminalization in the US would increase the income & influence of cartels. This would be undesirable for a variety of reasons.

Portugal is a much smaller market than the US, so effects of Portuguese decriminalization on cartel suppliers have probably been much smaller than the effect of US drug decriminalization would be.

It's possible that decriminalization would not lead to an increase in the overall rates of drug use. But because simple economic reasoning implies that decriminalization would increase use (decreased risk leads to increased demand), we would want to better understand the mechanism(s) by which all-drug decriminalization does not lead to increased use before no longer holding this as a concern.

2: Portugal has better public health infrastructure than the US.

Under the Portugal model, "problematic" drug users are routed into a system of government-sponsored treatment & social services (see p. 241-5 of Chasing the Scream).

Under the present US policy, drug users are routed into the incarceration system. This is clearly suboptimal, but it's unclear where "problematic" drug users would be routed otherwise. US healthcare & social service systems are less well-ordered than their Portuguese counterparts, and routing a large population of drug users into these systems without reforming their structure may lead to unintended & undesired consequences.

It seems very possible to design a drug policy reform that addresses this concern, but a viable design would need to include a plan for changing US healthcare & social service systems such that they become able to robustly handle an influx of "problematic" drug users (who would no longer be routed into the US prison system).

Erik Davis on the psychedelic Dharma

2019-03-25T16:00:00-07:00

Erik Davis, host of the excellent Expanding Mind podcast, did a solo show riffing on "psychedelic Dharma" – the concept as well as the new organization (a) he's standing up.

The whole thing is great (and delivered impromptu!) – this bit near the end is particularly good:

Our desires to reduce stress, our desires to heal our wounds, are not innocent. Nothing is innocent in this stage of the game. And it doesn't mean you don't pursue those things, but we have to become more conscious & more critical of how we're pursuing them...

I believe a good combination of these two things [psychedelics & the Dharma] can actually set us going in the right way. I want to spend the last few minutes talking about that – about how Buddhism can help psychedelic seekers, as well as how psychedelics can help Buddhist seekers.

...

It's a little easier to see the first one. How people who really go into psychedelics can be helped by the Dharma. One of the things that can happen really easily with excessive psychedelic use is a sort of "deluded" character, a way of believing the visions, let's say. A kind of psychological inflation, a kind of magical thinking, that in small doses, and sometimes in big doses but for short periods of time is really groovy, but as a lifestyle can be very problematic.

And what you find within... psychedelic culture as I've known it, is that there's not a lot of checking going on. There's not a lot of negative feedback mechanisms that might interrupt your new trip.

Because it's such a goofy, and in some ways lazy & uninformed space, it's really easy to run with whatever idea you're going with. But there are people and ideas and processes and (especially) collective operations that can help push against that. Those kind of mechanisms have been improving very noticeable over the years, over the decades, as people try to figure out "how do we become mature in this practice?"

I think a lot of the elements of Buddhism [can help]: the commitment to a daily practice; the serious mind-training (outside of any wild experience), so when you go in there you have a better-trained mind and when you come down you're much better able to integrate the scary stuff & the beautiful stuff simply because you've been devoted to a certain idea of mind training.

[And] I also think there are elements within the Dharma, within the philosophical dimension of Buddhism, which are extremely helpful – lessons of no-self which keep you from the void of nihilism, [as well as] the goofiness of believing you're everything.

...

Finally, I believe that Buddhism, properly practiced... Buddhism swallowed deeply is a critical practice – criticism, critique, questioning, sometimes lacerating questions are part of the practice. Not the whole thing. If it were there whole thing, it wouldn't work. But it's a very significant part of it... "Buddhism is stressful."

...

And on the flip side, I also believe that for some Buddhist practitioners, only for some... I suspect that psychedelics have a lot of [offer]. For one, they open up realms of emotion, intense emotion, that are very powerful, sometimes very scary, but potentially transformative. People don't talk enough about that – they talk about the visions, or the entities, or the peak experiences...

Buddhists can have a place to experience wonder, intensity, deeply embodied energetic flowerings, of gestures, ideas & practices that otherwise can get a bit dry, a bit repetitive.

Psychedelic Sangha is just getting started. They are hosting events in San Francisco & NYC.

Report: PSI 2020 ballot initiative summary

2019-03-01T01:00:00-08:00

We've published a summary report on the Psilocybin Service Initiative of Oregon, or "PSI 2020" for short.

The PSI 2020 campaign website
The initiative's ballotpedia page
The full text of the initiative

You can read our report here.

Intercollegiate Psychedelics Summit 2019

2019-02-25T13:00:00-08:00

The freshly minted University of Pennsylvania Psychedelics Club is hosting an Intercollegiate Psychedelics Summit from April 4-5, on the UPenn Campus.

I believe this will be the first intercollegiate Ivy League psychedelics event since the 1960s!

They've assembled an impressive speaker lineup, including:

David Nutt – director of the Neuropsychopharmacology Unit in the Division of Brain Sciences at Imperial College London
Manoj Doss – postdoctoral researcher at the Johns Hopkins Psychedelics Research Unit
Matt Brown – practicing psychiatrist and founder of the Chicago Psychedelics and the Future of Psychiatry club
David Yaden – transcendent experiences researcher at the Penn Positive Psychology Center

You can apply to attend the conference here.

Differences between psychedelics and drugs

2018-12-07T11:45:00-08:00

From Trip: Psychedelics, Alienation, and Change, on p. 65-7:

Seven differences:

Drugs are, on average, more habit-forming than psychedelics, which can also, like almost anything, be habit-forming, but, unlike drugs, can also dissolve habits.

Drugs don't cause mystical experiences at safe doses; psychedelics do...

For me, drugs stopped feeling amazing after the first few times – and never felt profound – but psychedelics consistently feel both amazing and profound...

Drugs don't seem to guarantee relief from boredom. Psychedelics I would immediately rate 10 on a 1-10 scale for boredom relief, even for the easily bored, because they seem to catalyze the imagination through stimulation, like some drugs, but also at least two other ways, bringing in emotion and the unconscious.

... one difference was that drugs affected my energy levels, mood, focus, and other attributes – calmness, patience – that I experienced noticeable fluctuations in while sober, for example depending on how much I'd slept. Psychedelics seemed to affect aspects of consciousness that normally changed only slightly, if at all.

Another difference seemed to be that drugs increased my current levels by taking from the future. When the future arrived, I felt the lack of what I'd already used. Psychedelics... didn't seem to take from the future.

... I watched a 2015 talk by Kathleen Harrison in which she said psychedelics awakened compassion in her. I realized they did in me also, and that drugs did not... Peaking on large doses of Adderall alone in my room, I've never sobbed while thinking fondly and lovingly about my parents, as I have on cannabis and psilocybin.

Titling

2018-12-03T13:30:00-08:00

Apparently Terence McKenna's first book was called Crypto-Rap: Meta-Electrical Speculations on Culture.

Simultaneously amazing & nonsensical.

Kilindi Iyi on what's next

2018-11-29T21:00:00-08:00

From Kilindi Iyi's interview on Expanding Mind (a), starting around 41:00:

Iyi: We've progressed technologically to a place where the next level of the human and then the level outside of the human is right in front of our faces.

It's possible, with artificial intelligence, the merging of the computer, cyborgs, things like this. It's right in front of us. We're in a time – it's only been a minute since chipping flint to quantum computers and artificial intelligence and things like this.

And so going to the next step, out of the human, is what I'm most interested in.

Because being human, you can't do anything. You want to go to New York, you got to get on a plane, you gotta worry about these folks crashing the plane, you gotta worry about all these things with time.

If I want to go to New York, I just want to be in New York. If I want to go to California, I just want to be in California.

But once I've breached the human, those things would only last a minute. I wouldn't want to go anywhere – because I'd be in all places all the time. And be able to experience all possibilities, any time.

Also this gem, from near the end:

Davis: What is it that you think you're bringing?

Iyi: I think it's the sensibility of the explorer. As opposed to "I'm sick and I need some help, and maybe this medicine will help me get over my earthly human problems" – into "Out there. To go where no one has gone before. To see things that no one has seen. To experience things that no one else that's ever existed has experienced."

And that's really what it is. In this place & time we have very little [chance] to be a Magellan... we don't have that anymore... to be able to really go into the unknown, that's something that's very, very rare. But it's available to anybody who has the ability to go onto YouTube and the wherewithal to grow mushrooms.

Polito et al. 2018 – Microdosing

2018-11-02T11:30:00-07:00

Polito et al. 2018 is a new study of microdosing. It uses self-report surveys of microdosers, a methodology that doesn't tell us very much.

Still, the literature around microdosing is very slim and the hype is strong. So Polito 2018 is a welcome addition.

What did they find?

Increased subjective well-being & declines in depression (in healthy-typed participants)
Decreased mind-wandering & increased absorption
No increase in creativity, which is a common claim of microdosing advocates

These results matched with participants expectations, except for creativity (which participants expected to increase).

So the microdosing didn't do precisely what the participants were expecting, though it did have positive-valence effects & the participants were generally expecting something positive.

Unfortunately, there was no blinding, so all of these results are vulnerable to placebo & expectancy effects.

Gwern's self-experiment with LSD microdosing (a) is the only blinded study of microdosing we know of, and that found a null result. (Do get in touch if you know of other blinded microdosing studies!)

Let's close with this story (a) about Sasha Shulgin & orange juice, to drive home the power of placebo effects:

His interest in pharmacology dates to 1944, when a military nurse gave him some orange juice just before his surgery for a thumb infection. Convinced that the undissolved crystals at the bottom of the glass were a sedative, Shulgin fell unconscious, only to find upon waking that the substance had been sugar. It was a revelatory, tantalizing hint of the mind's odd strength.

A new perspective – pillars of religion

2018-10-20T12:15:00-07:00

In Bob Jesse's talk on the MAPS podcast (a), starting around 25:00:

And then you have this eye-opening experience. Is it fair to say you've either learned something or at least gotten a new perspective on ultimate reality?

Well, if so, a new perspective on ultimate reality is the first little bit of doctrine.

"Wow, things are more connected than I thought they were!" That's a doctrine – something that you know think is true about the world. That's one of the pillars of religion.

So, once you have this doctrine... maybe that calls for you to live your life a little differently. Make different decisions about your self and your livelihood and your relationships and your health and what not.

Well, decisions about what to do and what not to do – there's the seed of ethics.

Let's suppose that these changes... you find them enlivening. It's a quality of life improvement. This is a major gift you've been given, actually. And you'd like to give thanks for it. That gives rise to ritual.

Brother David (a), anyhow, asserts that those are the three major elements of religion. And they come from the non-dual, "beyond" experience.

MDMA literature review

2018-09-28T11:30:00-07:00

Aceso Under Glass recently published a literature review of MDMA (a), their notes underpinning the review.

The takeaway is that MDMA is quite dangerous, though as always more research is needed:

Unfortunately the evidence is very strongly on the side of “dangerous”.

Retrospective studies of long term [MDMA] users show cognitive deficits not found in other drug users, while animal studies show brain damage and inconsistent cognitive deficits.

The one bright spot is the MAPS study, which reported no drop in cognitive function after a therapeutic dose of MDMA, but we’ll talk about the problems with that later.

Johnson et al. 2017 – Psilocybin for smoking cessation

2018-09-11T15:00:00-07:00

tl;dr:

Johnson et al. 2017 is a long-term follow-up to a pilot study that looked at psilocybin for smoking cessation (Johnson et al. 2014)
Out of the 15 (long-term, heavy) smokers who underwent psilocybin therapy, 10 were confirmed smoke-free a year after the therapy (!)
There's also a naturalistic survey about psilocybin for smoking cessation, but it's not very informative because naturalistic surveys aren't very informative about causal questions
More studies (with larger sizes & control groups) are needed to generate more evidence on the question of psilocybin for smoking cessation

Johnson et al. 2017 is a follow-up to Johnson et al. 2014, a pilot study looking at high-dose psilocybin therapy for smoking cessation.

The 15 participants of the pilot study received two or three psilocybin trips, along with four preparatory cognitive-behavioral therapy sessions. Johnson and friends then followed up with participants for about two years after their trips, tracking their smoking behavior.

So, what'd they find?

All 15 participants completed a 12-month follow-up. Twelve (80%) returned for a long-term follow-up (mean 30 months post-target quit date (TQD); range = 16–57 months) and provided data regarding current smoking and past treatment experience.

At 12-month follow-up, 10 participants (67%) were biologically confirmed as smoking abstinent, with 8 of these participants reporting continuous abstinence since their TQD. At long-term follow-up, nine participants (60%) were biologically confirmed as smoking abstinent, with 7 of these participants reporting continuous abstinence since their TQD.

67% abstinence a year out is pretty impressive, given that these were very heavy smokers – on average 19 cigarettes a day, 31 years smoking, 6 previous quit attempts.

Johnson et al. 2017 tracked biomarker outcomes in addition to self-reported behavior, which is pretty cool:

Participants were judged abstinent if breath CO value was ≤6ppm, urinary cotinine was <200 ng/mL, and if no smoking was reported... for the previous 7 days.

So we can be confident that the participants actually did quit; we're not just relying on self-report.

Johnson et al. 2017 indicates that psilocybin is promising as a smoking cessation intervention, but it's a very small study (n = 15), and open label.

Is there other evidence that psilocybin helps people quit smoking?

Well, the same authors also conducted a survey of naturalistic psilocybin use for smoking cessation.

From the abstract of that survey:

This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago.

On average, participants smoked 14 cigarettes/ day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years’ abstinence.

Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking.

Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3–6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups.

The average reduction in "reducers" is huge – 300 cigs a month down to 1 per month!

It's probably fair to group the "reducers" and "quitters" into a larger category of "people who's relationship with smoking meaningfully changed", which includes 66% of the people surveyed.

Of course, this is a naturalistic, retrospective survey, so it doesn't tell us very much. Survey participants were selected who "quit or reduced smoking after a psychedelic experience." We have no idea what the base rate is – all the people who tried psilocybin and didn't have success weren't included in this survey.

The most we can say from the survey is that some people found psilocybin useful for quitting smoking.

Summing up, Johnson et al. 2017 provides promising but preliminary evidence that psilocybin can be a useful smoking cessation intervention. As always, more studies (especially bigger ones with control groups) are needed.

The survey by the same authors doesn't add much to this view, as it only surveyed people who reported a positive experience with psilocybin for smoking cessation.

McGlothlin et al. 1967 – Long-lasting effects of LSD on normals

2018-08-18T10:30:00-07:00

tl;dr:

McGlothlin et al. 1967 gave high-dose LSD to healthy grad students and surveyed them 6 months later, comparing to control groups
Some survey results were different between LSD group and control:
- Greater aesthetic appreciation
- Lower anxiety
- Greater creativity (not statistically significant)
... but there are issues:
- no random assignment to treatment / control groups
- many survey tests so the ones that appear significant may just be due to chance
They also used galvanic skin response to measure objective changes in anxiety levels
- Six months after treatment, the LSD group registered as less anxious on this measure, which is pretty cool

Far before the current psychedelic renaissance, before the research freeze of the 80s and 90s, there was the first wave of psychedelic research. It was a glorious time, a time when researchers could publish journal articles about "normals" and no one would bat an eye.

McGlothlin et al. 1967 is from this happy before-time.

McGlothlin and friends recruited 72 graduate healthy-typed students & divided them into three groups:

24 received 200 µg of LSD (the experimental group)
24 received 25 µg of LSD (as an active placebo)
24 received 20 µg of amphetamine (as another active placebo)

Group assignment wasn't random, instead was "on the basis of six matching variables: knowledge of hallucinogens; expectations (enthusiastic, neutral, fearful); experience with marihuana; hypnotic susceptibility score; sensing-intuition score; and judgment-perception score."

... which seems like a crazy way to do group assignment.

Set & setting was a comfortably decorated room, in groups of either 2 or 4 people. Music was played during the session.

Acute effects of higher-dose LSD were clear:

The 200/µg LSD group spent about 80% of the session day lying quietly on the couch. By comparison, the amphetamine and 25/µg LSD groups both spent about 40% of the time lying quietly and the remainder talking or reading.

All 24 subjects in the amphetamine group finished the three drug sessions. In the 25/µg LSD group, two subjects failed to complete the three sessions for reasons unrelated to the experiment. In the 200/µg LSD group, six subjects withdrew after the first drug session and a seventh was terminated by the experimenter.

3 exp. group didn't complete because their friends convinced them not to
3 exp. group didn't complete because of frightening anxiety reactions during their first trip
1 didn't complete because of "grandiose paranoid tendencies" during their first trip so the researcher decided to terminate

But the people who didn't complete all three sessions still did the follow-up surveys (at 2 weeks and 6 months after the sessions).

These surveys asked a bunch of questions, and the psychological tests they were applying are pretty different from the tests they use today.

Things that high-dose LSD seemed to do, following self-report –

Lower anxiety. "At the six-month testing, 33% of the 200/µg LSD group subjectively reported lower anxiety and tension which they attributed to the drug experiences. The comparable percentages for the amphetamine and 25/µg LSD groups were 13 and 9."

Increased aesthetic sensibility. This was pretty pronounced:

Increased creativity, maybe? "At the six month testing, 25% of the 200/µg LSD group felt that the drug experience had resulted in enhanced creativity in their work, as compared to 9% and 0% for the amphetamine and 25 µg LSD groups respectively."

But this wasn't statistically significant.

They applied so many tests to a small sample, maybe there was no difference at all? "The number of statistically significant differences between the experimental and control groups are not grossly inconsistent with the hypothesis that they arose from chance, considering that 22 tests were administered, some of which had multiple subscales, and all tests yielded two different scores."

Okay, so the groups weren't randomized & participants were surveyed out the wazoo, so there's not too much to safely infer from the McGlothlin 1967 surveys.

This is the kind of result that would be called "suggestive" – if the researchers were enterprising enough, they would proceed to put together a larger study to see what's what.

But this was the late 60s – the hammer was coming down on psychedelic research. No follow-up study was done, as far as I know.

The most interesting part of McGlothlin 1967 is the galvanic skin response (a) they took during the follow-up studies to get a more objective read on the anxiolytic effects.

Basically they hooked the participants up to a machine that registered electrical activity on the skin (I think? I don't really know how it works), then subjected the participants to a variety of exercises designed to provoke anxiety:

The first consisted of a list of 20 words from Rapaport's word association list read at 20-second intervals. Eight words were classified as traumatic (eg, masturbate) and 12 as neutral (eg, book). Subjects were asked to repeat words aloud.

The second stimulus requested the subject to repeat a series of digit spans which started slightly beyond his ability (spans began at 8 digits and went to 10). The third stimulus requested the subject to give all the proper names he could think of ending in a given letter, such as "D." Both of these tasks were intended to produce embarrassment due to the subject's perceived poor performance...

The fourth stimulus involved mental arithmetic (continuing to add 8 to a given number).

Here's a nice visualization of the results:

Basically, the high-dose LSD group had much lower galvanic skin response (implying lower anxiety levels) at 6 months than they did at baseline. The control groups didn't have as much movement.

(Note that the high-dose LSD group had much higher anxiety at baseline than control, due to chance. McGlothlin tried to correct for this by comparing to a "selected control" group of the control participants who had highest GSR response at baseline.)

This effect was especially pronounced for the digit span, arithmetic, and proper name tasks, though it also occurs for the traumatic words. (And not for the neutral words, as we'd expect.)

So that's pretty cool. Not only do the high-dose participants report less anxiety 6 months later, one of their physiological indicators also registers as less anxious 6 months out.

Belser et al. 2017 – Interviews with psilocybin-treated cancer patients

2018-07-23T16:00:00-07:00

tl;dr:

Belser et al. 2017 conducted qualitative interviews with cancer patients who tripped
On the one hand, everyone interviewed is very positive about their psilocybin experience & feels like it was important to them
But there's not much evidence of concrete behavior change:
- One guy proposed to his girlfriend
- One woman recommitted to her YMCA membership and lost a lot of weight
But all these people have life-threatening cancer! There's a lot about their lives that they can't change the external circumstance of, only their stance towards
- Not sure how much of a confounder this is; it feels big

Belser et al. 2017 interviewed 13 participants of Ross et al. 2016, a double-blind trial of psilocybin for depression & anxiety in cancer patients which found big + persisting antidepressant & anxiolytic effects.

I don't know much about qualitative academic research methodology – it looks like they basically talked to a bunch of people who tripped, recorded the interviews, then summarized themes that appeared across conversations.

So what did the cancer patients who tripped have to say?

Relationships came up a lot:

There were no questions in the interviews regarding relationships, but, without prompting, all the interviewees addressed crucial relational aspects of their experiences. These relationships were most likely to concern the participant’s father or mother (seven participants), or romantic partner (five participants).

... Relationships were woven throughout participant narratives—throughout the histories, memories, hopes, feelings, visions, and realizations as reported by the participants.

Some relational behavior change was self-reported:

Five participants described how their ways of relating to other people changed as a result of their involvement in the study. One participant said that he “stayed in touch with more people as a result of the study” and strove to “show people that you care about them, be kind to other people, take care of the people in your life.”

Another described how she now spends more time being with her daughter, talking to her: “I changed. I just was different. I just felt happier.” Edna described “a greater understanding of the people around me”

One guy proposed to his girlfriend:

"I was appreciating the pureness of her, if you will, her being, in a way. In a way, I had not allowed myself, or not realized, or whatever the case was. And so that was pretty much immediate, but I felt like that had a lasting effect. I feel that kind of changed my perception of our relationship over the ensuing weeks in a way. It allowed me to be more open with her, express my appreciation a lot for her in way that I had not. I think it had a positive effect – kind of a bit of a snowball effect."

Dan reflected that the state of mind into which he entered helped him become “more emotionally open” to his girlfriend. Within 3 months, Dan bought an engagement ring and proposed marriage to her.

Catharsis experiences happened for 5 of the 13:

Five participants reported having access to long-held strong or repressed emotions such as grief, sadness, and traumatic pain. Adam, a young medical student, had previously dismissed the feeling emotions altogether because “it doesn’t solve anything, and you have to be strong, or that is what I used to think.”

During his psilocybin session, Adam grieved a broken relationship with his father. For the first time since he was 6 years old, Adam cried, weeping tears of grief and sadness, which he had held in abeyance for nearly two decades. This catharsis provided him with a profound sense of relief.

Most people thought their experience had an ineffable quality, yet produced enduring insights to which they could return to when sober:

Despite this difficulty in accurately articulating each experience, eight participants felt that their insights arrived from an inner or otherwise enduring source, to which they could return in ordinary states of consciousness.

Three participants expressed the need to actively integrate their psilocybin insights into their daily lives in order to continue deriving meaning from them.

Unfortunately Belser doesn't give details about what "integrating the insights into daily life" looks like.

Most interesting for our purposes is the "Lasting Impact" section...

All study participants reported experiencing benefits related to their lifestyle and quality of life after the treatment sessions. Some of the participants expressed coming to honor a different side of themselves, a more still, emotional, or spiritual side that involved connecting to the simplicity of the present moment:

"The percentage of my life that I am able to be present in just a moment has increased dramatically, and it’s really just been restored from almost nonexistent to often existent ... it is unique and monumental in a way."

...

Participants described a shift in their life priorities away from the busy demands of modern work life, to find a deeper or more authentic mode of existence: “It has made me more aware that: I cannot just live for material stuff and success.”

And:

Augusta share[d] how participating in the study has helped her “wake up in the most profound way.”

She also reported better practical outcomes, like feeling less alone, having less “tunnel vision” and feeling more confident.

The trip also appears to have helped some people with time management:

... some participants reported that the psilocybin experience afforded them greater confidence to put up boundaries against various stressors in their life and the ability to overcome barriers that were impeding life goals, allowing a greater sense of peace and freedom.

...

When one participant was asked, in what ways you feel the study has affected your life since undergoing the sessions, she replied:

"Just tremendously, tremendously. I am so much more able to do things that I wanted to do, and didn’t feel I could, something always holding me back ... I really want to enjoy every minute. I want to enjoy being alive, and I knew that before the study, but afterwards I became able to do it much more often. I have found ways to make that happen."

This participant, who struggled with emotional/compulsive eating following her cancer diagnosis, reported gaining confidence to commit to dietary goals and a YMCA membership, losing 30 pounds as a result, an outcome she attributed directly to her psilocybin session.

The post-trip outcomes of three of the 13 weren't as good, though all three said they'd do the trip again:

One reported ambiguity regarding his experience, saying, “I still have to work on my problems myself ... [the psilocybin experience] confirms certain thoughts and hopes, ah, about who we are. Who I am. What’s important to me.”

Another participant reported persisting anxiety: “I still worry. It’s not like life is so perfect now, but it’s better. It’s just better ... I just don’t think that I feel as sad as I used to feel.”

A third participant reported prolonged difficulty following her session, which required intensive support in integration psychotherapy sessions with her therapists to process a childhood trauma.

Of these three participants who continued to struggle to integrate their experiences, all three reported that they would repeat the psilocybin dosage session.

So what do we make of all this?

On the one hand, everyone interviewed is very positive about their psilocybin experience & feels like it was important to them
But there's not much evidence of concrete behavior change:
- One guy proposed to his girlfriend soon after his trip
- One woman recommitted to her YMCA membership and lost a lot of weight
- But mostly the change appears to be a matter of their stance towards life – things seem more okay and less anxiety provoking, people feel more empowered to do things
But on the third hand, all these people have life-threatening cancer! There's a lot about their lives that they can't change the external circumstance of, only their stance towards
- I'm not sure how much of a confounder this is; it feels big

Psychedelics for Judaic return

2018-07-12T10:15:00-07:00

In Joanna Steinhardt's interview on Expanding Mind (a), starting around 18:30:

Davis: ... an example of how open-ended the results of psychedelics can be... You were in Israel studying American Jews who found their way back, or not even necessarily back but came to embrace hardcore orthodox Judaism in the full-on Israeli mode, which is no joke... and you discovered that some of the motivations that brought them there were sometimes psychedelics.

That's not part of that normal set-and-setting matrix for your average 19-year-old who eats mushrooms at a university. That really fascinates me...

Steinhardt: ... a lot of those [people], a lot of them were young men but some were young women, they were experimenting with psychedelics as teenagers or at colleges, which was also my experience. And it opened them up to this realm of experience that they then wanted answers for. Or they wanted to channel in some way (which is using their language).

I think a lot of it also comes from American identity politics – that they were squeamish about appropriating someone else's culture. There was also this question of "what do I have?", "what can I bring to this?", "what was our tradition?"...

And then they start studying Judaism and they stumble on Shlomo Carlebach [either this one or that one]. And Carlebach, his whole thing was finding these hippies in the 60s & 70s and bringing Hasidism to them... this mystical philosophy that takes the Kabbalah, the mystical tradition... and he used to say that giving Hasidism to these people was like giving them heroin, in a way... it was like they were so hungry for something. And you see that too with the younger people.

So there is this return narrative, of returning to Judaism. And that's one of the things that resonants across the American countercultural uses of psychedelics – of people trying to return to some other state of harmony where they're aligned with the universe, and somehow that opens them up.

Erritzoe et al. 2018 – Effects of psilocybin therapy on personality structure

2018-07-10T12:00:00-07:00

tl;dr:

Erritzoe et al. 2018 looks at Big Five personality trait change in very depressed people who underwent psilocybin treatment
Big-Five trait Neuroticism decreased, Extraversion, Openness, and Conscientiousness increased
- Extraversion and Neuroticism changes are probably explained by the people becoming less depressed, the same thing happens with traditional anti-depressants
- Openness change is not explained by becoming less depressed, traditional anti-depressants don't effect Openness
Increasing Openness seems good ("increased in permissiveness, open-mindedness, tolerance, being ready to try new things")
- More work needed to link these changes up real-world behavior change

Erritzoe et al. 2018 is follow-on analysis of Carhart-Harris et al. 2017, a small open-label trial of psilocybin for treatment-resistant depression.

Carhart-Harris 2017 gave psilocybin to 20 people with severe, unipolar depression that hadn't responded to two kinds of antidepressants (thus, "treatment-resistant"). So basically, very sad people who weren't responding to things their doctors were trying.

Here's what they found:

18 of the 20 participants scored "severely" or "very severely" depressed at baseline. The other two scored "moderately" depressed
- These people had been depressed for a long time:
  
  The mean duration of illness of the sample was 17.7 ± 8.4 years (range = 7–30 years), as assessed by the question: "For how long has your current depression lasted?"
19 of the participants completed all the study follow-ups, one dropped off

The black bars are the mean "QIDS" score of the 19 participants who completed all the follow-ups
- QIDS is a self-assessed measure of how depressed you feel
- Scores fell steeply 1 weeks after treatment, then slowly rose over the next 6 months (but remained far below baseline)

I wondered how this result was distributed – did every participant have a pretty good reduction in their depression, or did some people have a massive reduction and others have no/minimal reduction? Here's a much messy version of the graph:

Each line is an individual participant's QIDS score
- Eyeballing it, it looks like everyone had a big reduction in QIDS 1 week after psilocybin...
- This big reduction persisted for about 2/3rds of the people 6 months later & didn't persist for the remaining 3rd

So Carhart 2017 shows that psilocybin shows promise for treatment-resistant depression.

But we're interested in behavior change in healthy-typed people, not alleviation of depression. So why are we looking at this?

Well, Erritzoe 2018 assesses personality trait change in the Carhart-Harris 2017 participants (specifically changes in Big Five (a) traits, which as far as I know is the most evidence-based categorization of personality).

Erritzoe finds:

Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy ... Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend-level increases, and Agreeableness did not change.

... changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy.

This is interesting because changes in Big Five traits are kind of rare – personality tends to evolve over one's lifetime (a), and maybe major life events sometimes cause lasting personality change (a), but in general the Big Five seem to be basically stable for each individual (set point (a) models of personality seem to be in vogue).

So a chemical that can reproducibly cause change in Big Five traits would be pretty unique. Is psilocybin such a chemical?

Here's a chart of the Big Five for Erritzoe 2018's 19 participants, at baseline (solid line) and 3-months after psilocybin (dotted line):

The 19 people's Big Five traits are distributed in a sharp triangle spiking towards neuroticism, probably because they're all very depressed.

Three months after treatment:

The basic sharp triangle shape remains
Neuroticism has decreased a little
Extraversion, Conscientiousness, and Openness have all increased somewhat.
Agreeableness didn't move

So there's a change in the Big Five survey results of these people 3 months after psilocybin, and the change is in seemingly positive direction (less neurotic, more extraverted & open; yes I'm making a value judgment).

A big concern here is whether the personality change can be separated out from the reduction in depression symptoms.

Erritzoe says:

Pre- to post-treatment changes in Neuroticism, a known vulnerability marker for affective disorders (44, 45), and increases in Extraversion, a trait associated with general positive affect (46), have previously been found to be significantly correlated with SSRI/SNRI-induced reduction in depression severity

Basically SSRI's for depression have also been shown to reduce Neuroticism and increase Extraversion in depressed people.

But SSRI's haven't been show to change Openness:

In contrast, increased Openness did not correlate with treatment response and neither was it different between responders and non-responders. This is consistent with the principle that Openness to Experience is orthogonal to anxiety or depression symptoms

So probably the Neuroticism and Extraversion changes just comes from participants becoming less depressed, whereas perhaps the Openness change occurs even in people who aren't depressed.

(Maclean et al. 2011, an analysis of psilocybin given to healthy-typed people, also found a persisting increase in Openness. However, Griffiths et al. 2017, also psilocybin for healthy-typed people, found no persisting increase in Openness. So maybe psilocybin causes greater Openness but only sometimes? As always more research is needed.)

Erritzoe 2018 doesn't discuss the Conscientiousness trait change very much, probably because the change wasn't statistically significant at p < 0.05. (The other trait changes were significant.)

Why would increasing Big-Five Openness matter? Erritzoe engages with that too:

... the facets Openness to Actions and to Values significantly increased in our study. The facet Openness to Actions pertains to not being set in one’s way, and instead, being ready to try and do new things. Openness to Values is about valuing permissiveness, open-mindedness, and tolerance. These two facets therefore reflect an active approach on the part of the individual to try new ways of doing things and consider other peoples’ values and/or worldviews.

And:

It is well established that trait Openness correlates reliably with liberal political perspective... The apparent link between Openness and a generally liberal worldview may be attributed to the notion that people who are more open to new experiences are also less personally constrained by convention and that this freedom of attitude extends into every aspect of a person’s life, including their political orientation.

From where I sit, this all looks pretty good, though there's more work to do to flesh out the connection between "increases in permissiveness, open-mindedness, tolerance, being ready to try new things, etc." to "changing how you make major life decisions."

Carhart-Harris et al. 2016 – Psychological effects of LSD

2018-07-06T17:00:00-07:00

tl;dr:

Carhart-Harris et al. 2016 gave LSD to 20 healthy-typed people using a placebo design
Two weeks after the LSD session, they found significant increases in Big-Five Openness and optimism, but no increase in delusional thinking
- These increases didn't occur after the placebo session

Carhart-Harris et al. 2016 gave LSD to 20 healthy-typed participants who had previously had a psychedelic experience.

Then they slid the participants into an MRI scanner and imaged their brains. Two weeks later, the participants filled out a bunch of surveys about their psychology.

Actually Carhart-Harris did something cleverer than that – they slid each participant into the MRI machine twice: once after injecting them with LSD, and once after injecting them with a placebo.

As you probably expect, the LSD-injected MRI scans were very different from the placebo-injected MRI scans (examples in this other 2016 Carhart-Harris et al. paper... the man authors a lot of papers).

But that's not very surprising. Of course a person's brain activity looks different while tripping!

For our purposes, Carhart-Harris 2016 is interesting because of the stuff it found in its psychological surveys:

The LOT-R was chosen as it is a well-validated measure of trait or dispositional optimism (Scheier et al. 1994), the NEO PI-R [NEO Personality Inventory] was chosen as it is well-validated and previous research has shown its sensitivity to the enduring effects of psychedelics (MacLean et al. 2011), and the PDI [Peters’ Delusions Inventory] was chosen as it is a well-validated measure of delusional thinking that has shown to be sensitive to psychotic-like symptoms in the general population (Peters et al. 1999).

Carhart-Harris found:

Optimism was significantly increased 2 weeks after LSD (t=2.91, df=18, p=0.005, Cohen’s d=0.56), as was trait Openness (t=1.95, df=19, p=0.03, Cohen’s d = 0.16) (Fig. 3), and there were no such changes in optimism or personality post-placebo.

Recall that Openness is one of the Big-Five psychological traits, which are tracked by the NEO PI-R.

Implicit here is that the other 4 Big-Five traits did not change after the LSD trip.

Here's a chart of the result:

Each node is a participant
Most (but not all) participants became more optimistic and more Open two weeks after the LSD trip
Some people became way more optimistic after LSD
The increase in Openness isn't as dramatic
Both results were significant at p = 0.05

Oh, and they also found that participants weren't more delusional two weeks after LSD than two weeks after placebo, even though the LSD trip itself does resemble psychosis.

So we can take Carhart-Harris as some evidence that an LSD trip will make most healthy-typed people more optimistic and more Open, two weeks later.

It gets bonus points for being placebo-controlled; most psychedelic studies to date have been open-label (i.e. no placebo).

A few limitations to this study:

Being inside an MRI tube for 1+ hours during your LSD trip sounds pretty terrible and definitely would effect the trip experience
- I'm sorta surprised that the Openness and optimism results came through despite the clinical setting of the trips
- Actually this might be evidence in favor of the robustness of the Openness result
n = 20, which is very small
All participants had previously used psychedelics, which probably biases the sample
- The research team screened for this intentionally for "safety considerations" (i.e. to try to avoid having someone have a bad trip while in a whirring MRI scanner)
The placebo was only a single-blind (researchers knew who was getting LSD when; participants didn't)
- Blinding is a difficult problem for psychedelic research because the effects of the drugs break the blind soon after they set in
Follow-up was short – surveys administered only two weeks after the trip
- They say a longer-term follow-up is underway, which we're excited to see :-)

Pausing monthly updates

2018-06-27T09:00:00-07:00

Most recent monthly update here.

Most of our work in recent months has been sensitive enough that we have been unable to share public updates about it.

We expect this to be the case going forward for the foreseeable future, so we are pausing monthly updates at this time. We plan to continue periodically publishing posts about developments in psychedelic research.

January 2018 update

2018-01-31T23:00:00-08:00

Previous update here.

In January, we continued work on theoretical considerations underlying the project. We expect to complete this work by the end of February.

We did some roadmapping exercises in January, and now have a good sense of what work to prioritize when.

There was no forward movement in our discussions with the Drug Policy Alliance. While we remain excited to work with DPA, we are deprioritizing further efforts to establish a collaboration.

Also in January, we published a best-guess cost-effectiveness analysis for a California ballot initiative that increases access to psychedelic drugs. Details here.

Looking forward, in February 2018 we plan to:

Complete our theoretical work
Begin reaching out to potential funders
More granularly map out plans for 2018, 2019, and 2020

December 2017 update

2017-12-31T16:00:00-08:00

In December, holiday vacation & other commitments were prioritized above work on Enthea.

Discussion continued with the Drug Policy Alliance about possible collaborations.

We continued thinking about the theoretical underpinnings of the project.

Looking forward, in January 2018 we plan to:

Complete our work on the relevant theoretical considerations
Continue our discussion with DPA
Sketch out a roadmap for 2018 and 2019

November 2017 update

2017-11-30T16:00:00-08:00

In November, other commitments were often prioritized above work on Enthea. That said, progress was made on a few fronts.

We continued thinking about the tractability of various routes towards psychedelic normalization. An all-drug decriminalization ballot initiative continues to stand out in terms of tractability.

We began discussing possibilities for collaboration with the Drug Policy Alliance (DPA), a major organization in the drug policy reform space. Working with DPA is plausibly a great opportunity to learn the mechanics of the ballot initiative process.

Also in November, we took a step back to reflect on some theoretical considerations that bear on our view of the impact of psychedelic normalization.

We intended to spend time better understanding the mechanics of the FDA approval process for MDMA-assisted psychotherapy and psilocybin-assisted psychotherapy, but did not get around to this in November.

Looking forward, we plan to spend December:

Continuing work on the theory underpinning our views
Continuing our discussion with DPA

October 2017 update

2017-10-29T10:00:00-07:00

October was mostly spent at drug policy conferences. These were helpful platforms for meeting in person with collaborators, and for better understanding the organizations involved in US drug policy & how they relate to one another.

All-drug decriminalization now seems to be most leveraged & neglected path towards psychedelic liberalization in the US (see DPA's recent report (a) for more on all-drug decrim). We may write more about this in the coming weeks.

Looking forward, we plan to spend November:

Running further polling to more granularly understand public support for drug liberalization strategies
Learning more about the mechanics & process of ballot initiatives
Learning more about how possible FDA approval of MDMA-assisted psychotherapy for PTSD (a) and psilocybin-assisted psychotherapy for depression (a) would interact with the impact of all-drug decriminalization efforts

More on Griffiths et al. 2017

2017-10-15T19:00:00-07:00

Some thoughts on Griffiths et al. 2017, the new paper looking at effects of psilocybin coupled with spiritual practice on healthy study participants. See here for a summary the study results.

Reasons this study is exciting:

Large effect sizes on a bigger sample. Griffiths et al. 2008 had 36 participants complete the study. Griffiths et al. 2017 had 75 participants complete, and found large increases in altruism, positive behavior change, and spirituality in the psilocybin groups (see Figure 5, p. 14).
Unlikely to be a placebo effect. Griffiths et al. 2008 compared a high psilocybin dose to a active placebo of methylphenidate (Ritalin). Ritalin has a pretty different psychoactive profile than psilocybin, so study participants may have been able to determine which drug they were given, exposing them to expectancy effects. In contrast, the new study compared a very low dose of psilocybin (1 mg / 70 kg) to higher doses of psilocybin (20 and 30 mg / 70 kg). A very low dose of psilocybin has a similar (though much subtler) psychoactive profile to a high dose, so blinding was less likely to be broken than in previous studies.
Not p-hacked. The study measured many variables; many of these showed significant differences between the low-dose and high-dose groups at p < 0.001 (see Table 5 on p. 13 and Table 6 on p. 15). All results were planned comparisons. Because of the number of p < 0.001 significant results, it's highly unlikely that the results were p-hacked.

And a couple notes of caution:

No increase in Openness. MacLean et al. 2011, a follow-up to Griffiths et al. 2008, made waves by finding increases in psychological Openness 14 months after the psilocybin session. The new study followed a similar protocol, but did not find an increase in Openness at 6-month follow-up. The study authors didn't give a compelling reason for not finding an increase – from p. 15, "The failure to observe significant increases in Openness in the current study may be attributable to engagement in the program of spiritual practices or to some other aspect of the study design."
No change in day-to-day spiritual practice. Griffiths et al. 2017 tested psilocybin administration alongside a regimen of spiritual practices (meditation, introspective journaling, etc.). Though the high-dose psilocybin groups experienced greater subjective spirituality, "The study did not provide evidence that psilocybin dose affected engagement with spiritual practices." (p. 13). So psilocybin administered in this format may not cause behavior change; the value of subjective assessments of experience relative to the value of concrete behavior changes is likely a disputed topic.

New study finds psilocybin coupled with spiritual practice produces durable positive changes

2017-10-12T18:00:00-07:00

Griffiths et al. 2017 just came out yesterday. It had some impressive results, measured over a 6-month study period:

The study collected data from numerous measures, and many robust between-group differences were found. Here are the effect sizes (Cohen’s d) of some of these differences:

Altruism: Comparing LD-SS [low dose, standard support] to HD-SS [high dose, standard support], the effect size was 1.36, which statisticians consider “very large.” Comparing LD-SS to HD-HS [high dose, high support], the effect size was 1.95, considered “very large,” almost “huge.”

Trait Forgiveness Scale: Comparing LD-SS to HD-HS, the effect size was 0.55, and comparing LD-SS to HD-HS, the effect size was 0.64. Both are considered “medium” effect sizes.

Interpersonal Closeness: Comparing LD-SS to HD-SS, the effect size was 0.82 (considered “large”). No significant difference was found between HD-SS and HD-HS.

“How personally meaningful was the experience?” This measure yielded the largest effect size seen in the study, 2.47 (considered “huge”), shown between the LD-SS and HD-HS conditions.

On the Revised NEO Personality Inventory, the HD-HS group showed a significant increase in Openness from baseline to 6 months. No significant between-group differences were found in Openness or the other four NEO scales.

Participants were asked to rate the spiritual significance of their experience in the study. Consistent with the positive changes in various traits, 12% of the LD-SS group, 76% of the HD-SS group, and 96% of the HD-HS group rated their experience as among the top 5 most spiritually significant of their lives. Zero percent, 40%, and 56%, respectively, rated it as the single most spiritually significant.

Summary from this article. We'll probably write more about this after we've had time to digest the study.

Horizons 2017: Notes on Dr. Michael Bogenschutz's psilocybin for alcoholism talk

2017-10-07T20:10:00-07:00

Rough notes from Dr. Michael Bogenschutz's psilocybin for alcoholism talk at Horizons 2017:

Bogenschutz and Ross conducting a double-blind study at NYU. 100 participants; comparing effect of benadryl (placebo) to psilocybin for alcoholism, also looking at the mechanism of action
- Recruited 43 participants so far
3 components to the model
- Motivational Enhancement and Taking Action therapy
- Preparation, Support and Integration
- Drug Administration sessions
- 2 therapists present for all sessions
Drug session in a living-room-type space, two therapists by the bedside, eyeshades and earphones. Light physical reassurance offered
Case studies
- High variation of experience between patients, and also between sessions with same patient
- Blinding usually broken by end of session
Case 1: Mark
- 25 y/o man, working at an investment firm, binge drinker frequent blackouts; 6 drinking days out of 84 days, 22 drinks per drinking day; 200+ AA meetings, MDMA 3x previously; really wanted help with his problem
- Couldn't identify a narrative or series of events, wondered if he got the psilocybin or not
- Surprised and pleased after first session about how easy it was to refrain from drinking; totally abstinent
- Second session, higher dose, significant anxiety; faced with guilt & shame from past alcohol use. "Experience akin to dying and being reborn"
- Continued reports of abstinence after the second session. little desire for alcohol. Also better able to let go of things that would have previously led to resentment + anger
- 7 months later, open-label session. Still abstinent, promotion at work had been causing a lot of anxiety, hoping for relief from that. Third session dose same as second, but felt higher.
- 54 weeks from first meeting is last meeting. Reported continued abstinence, life was going well, very grateful for the experience.
- "I wouldn't be surprised if I never drank again ... I got exactly what I needed from the experience"

Horizons 2017: Notes on Dr. Thomas Brown's ibogaine talk

2017-10-07T20:05:00-07:00

Rough notes from Dr. Thomas Brown's's ibogaine talk at Horizons 2017:

Iboga: a drug native to West Africa; religious sacrament in Cameroon and Gabon
Opioid crisis now the leading cause of deaths for people under 50 in the US
- Opioid mortality over time chart; 28-44 years of life lost per patient on average from opioid use
- Standard treatment right now is opioid replacement therapy. Take treatment each day for years, if they stop using strong likelihood of relapse. Hard to retain people in treatment programs
Howard Lotsof discovered ibogaine treatment for addiction serendipitously, June 1962. No heroin withdrawal after 30 hours of taking ibogaine
- Animal studies in the 1990s showing efficacy. Also noribogaine and 18-MC (a "rationally designed drug"), possibly not psychoactive
Brown and Alper 2017
- Is ibogaine effective in opioid detox? (SOWS instrument)
- Is treatment effective later on... (ASI instrument)
- Effect size comparable to methadone for detox
- Improvement in ASI relative to baseline at all follow-up points (by how much?)
Qualitative accounts, personal experiences of treatment and life after treatment (not included in Brown and Alper 2017)
- Sandi Hartman
  - First person Brown interviewed, in 2009
  - Sold her farm and drove cross-country to ibogaine clinic for her 60th birthday
  - Now Opioid-free
  - Went on to found her own treatment center, focusing on after-case for ibogaine treatment
- Generalizations about patients' lives before treatment
  - Often suicidal
    - "If ibogaine doesn't work, I'm checking out"
  - Sense that opioids are killing them
    - "It was a slow suicide"
    - Giving up interests
  - Feeling numb, unmotivated, depressed
    - "You don't feel joy, you don't feel pain, you don't feel love, you don't feel at all"
    - "I had no motivation to do anything. Nothing was fun or interesting"
- Generalizations about the ibogaine experience
  - Lengthy, physically, and emotionally difficult (ataxia, vomiting, regrets, reliving troubling experiences)
  - Alleviation of withdrawal experiences
  - Dream-like visions, panoramic viewpoint
  - Insights about the roots of one's addiction
  - Visions of an alternate present or a possible future
  - Mystical experiences – "Out of body experience... certainty of life after death"
  - Regrets; reconciliation and forgiveness
- Generalizations about the post-treatment experience
  - Sense of renewal
  - Sense of purpose
    - People starting clinics after they are treated
    - Max had "Ibogaine" tattooed on his forearm
Why not available in the US?
- It's illegal & Schedule 1
- Stigma about it being psychoactive; some scientists view this as a harmful side effect
- Risks associated with ibogaine treatment (see below)
- Little incentive for pharmaceutical companies to pursue ibogaine; it's naturally occurring (can't be patented) and only taken intermittently (not every day)
Legislative efforts in VT and NY
- Vermont "state of the state" speech 2014
Lotsof and Wachtel 2003 – manual for ibogaine treatment
Ibogaine death rate of 1 in 300 uses. Is that clinical or street?
- Clinical, probably
- But there are ibogaine centers that have administered thousands of treatments w/o having any poor outcomes
- Brown doesn't see ibogaine as a last resort. Many people on methadone treatment want to get off it
Longterm abstinence from ibogaine treatment?
- Standard detox treatments have abysmal longterm followup rates
- Brown's study is best evidence of longterm outcomes
- No indication of adverse longterm effects
What accounts for the withdrawal interruption caused by ibogaine?
- Something pharmacological going on here
Ibogaine distinct from other psychedelics for addiction in that it causes an immediate cessation of craving and withdrawal symptoms. Not understood what's going on here
- Ken Alpert: ibogaine is not an opioid agonist; effective in animals, so presumably not entirely psychologically mediated
Other applications?
- Helpful for reducing depression, maybe. Shown in the New Zealand study but not in Brown and Alpert
- Anecdotal evidence that it's helpful for Parkinsons, not studied yet
What's being done re: legal advocacy for ibogaine?
- Vermonters for Ibogaine Treatment, Molly Scott (?)
- Activists in New York
- Global Ibogaine Alliance
No research into the efficacy of ritual coupled with ibogaine treatment (illegal in US)
- Brown suspects there is an additive benefit to the ritual aspect
- Clinics aren't incorporating any of the indigenous ritual understanding
Ibogaine mostly for opioid addiction. Some people have tried it for alcoholism and smoking cessation. Anecdotal success there
- Some evidence that ibogaine can reduce cravings for cocaine
- The best treatment providers think it doesn't work for alcohol, doesn't work well for benzodiazepines

Horizons 2017: Notes on Dr. Phil Wolfson's ketamine talk

2017-10-07T20:00:00-07:00

Rough notes from Dr. Phil Wolfson's ketamine talk at Horizons 2017:

Ketamine given under a intermittent treatment regimen; can produce trance states and psychedelic experiences
- Patients refrain from stimulants on the day of treatment
- Can stay on antidepressant regimen while undergoing Ketamine treatment; they have different mechanisms of action
Ketamine experiences catalogued in Dr. Wolfson's book, the Ketamine Papers; diverse experiences had on Ketamine
Wolfson's psychedelic toolkit: psilocybin, MDMA, Ketamine, Ayahuasca
- LSD trips last too long
Toxicity profile of Ketamine: main concerning side effect is hypertension. Very little other than nausea, hypertension, people growing agitated. Day-after effects are minimal, fast recovery.
- Bladder toxicity – 1 out of 200 in clinical practice have bladder issues
- Most irreversible damage occurs only at high (street) doses

Upcoming conferences

2017-10-02T17:00:00-07:00

Two relevant conferences coming up this October –

Horizons: New York, October 6th to 8th
Reform: Atlanta, October 11th to 14th

Conferences are an effective way to quickly gather a lot of context about a topic. If drug policy reform or psychedelic liberalization interest you, but you don't know very much about the current state of things, we recommend attending!

We'll be at both Horizons and Reform, and would love to connect at either. If you're interested in chatting, shoot us a note at info@enthea.net

Cost-effectiveness model published

2017-09-14T20:00:00-07:00

We recently published our cost-effectiveness analysis of drug liberalization as a mental health intervention.

Guide to the model here.

September 2017 update

2017-09-09T21:34:00-07:00

Recommended reading list just published, check it out here.

A first-cut cost-effectiveness analysis is in the works and should be published later this month.

There's now an atom feed for Enthea (feed here, also linked at bottom left). Most major updates will be published non-chronologically as pages, whereas blog posts will record news & changes to the site.