Day: 29 January 2016

The research conducted by Jordi Riba, a Spanish pharmacologist working at Sant Pau hospital in Barcelona, revolves mostly around ayahuasca. He has a background in botany, chemistry, pharmacology and neuroscience. In an interview with the OPEN Foundation, he summarises the main findings of his work on the Amazonian psychedelic brew. In the second part, he refutes some of the controversy stirred up by a recent article about cannabis he co-authored. Jordi Riba will be among the speakers at our ICPR 2016 conference on psychedelics research.

How did you wind up in the psychedelic field?

I was always interested in the biochemistry of the brain, so any substances that interacted with the central nervous system had an interest for me. I did a lot of research into alkaloids, and one day while I was in college I came across Gordon Wasson’s account of his experiences with psilocybin mushrooms. I was quite impressed that there might be these alkaloids that could induce such profound effects on the psyche. I also thought it raised some interesting philosophical questions, since it was at the verge between religion and science. However, there were virtually no studies at the time, in the 1980s or early 1990s. A few years later I got to know Josep Maria Fericgla, an anthropologist who had been doing research in the Amazon on the ritual use of ayahuasca by the Shuar. He suggested that I translate Jonathan Ott’s Pharmacotheon into Spanish, so that gave me a lot of information about this field. He also introduced me to some ayahuasca-using groups in Spain, and I decided I was going to do my thesis on ayahuasca research.

Why did you choose to study ayahuasca rather than any other psychedelic?

For me it was important that it had a cultural use, that it was not merely a recreational substance. I thought the fact that there might be a religion around the use of a psychoactive plant, that cultures had evolved around the use of these plants for many centuries, gave an added interest. When I got to know people who were attending these rituals, I was very impressed by what they told me about the effects they were experiencing: insight in personal life matters, autobiographical memories, intense emotional feelings,… It was like nothing else I had heard about.

What’s the legal status of ayahuasca in Spain, and how easy was it for you to start doing the research, from a legal point of view?

Of course, there’s this international list of prohibited psychotropic substances, but authorities always leave the door open for legitimate research. I also happened to meet Manel Barbanoj, who became my thesis director. He was a pharmacologist at Sant Pau hospital in Barcelona, where I still work now. He had a very good reputation, having conducted many clinical studies in healthy volunteers and in patients. He was also very passionate about centrally acting drugs. So when I said: there’s this drug, ayahuasca, with an interesting interaction between alkaloids, it’s being taken ritually and these are the effects that people are reporting, he said: OK, I’m in, let’s start working on this. So we wrote a protocol and sent it to the internal review board. Years later, the head of this board told me that they had been shocked at first when they received this proposal, but they trusted my supervisor because he had such a good reputation, so they had decided to allow it. We then had to submit the protocol to the Spanish ministry of health, and they also approved it. So we’ve never encountered any opposition from the medical establishment or from the regulatory authorities against this kind of research.

Do you think it would have been as easy for you to start conducting research on psilocybin or LSD?

LSD, for sure, has a bad name. Maybe I could have tried studying psilocybin, but I think LSD would have been more difficult. Another difficulty we had at the time was that I wouldn’t have known where to obtain psilocybin, whereas I knew where I could get ayahuasca. That’s also a reason why I went for ayahuasca despite the fact that it’s a very complex mixture of substances.

Yes, ‘ayahuasca’ is such a vague thing. These two plants are supposed to be mixed in, but if you go to the Amazon, everyone who prepares ayahuasca has their own recipe. So how do you standardise it?

Of course, in every tradition, there are different plants that are being added, but we decided to focus on what had become popular in the urban areas of South America, and had also come to Europe and North America. This was basically the combination of Banisteriopsis caapi and Psychotria viridis, as the ayahuasca churches were using it. At the start of our research, we had a debate whether we should study synthetic compounds: just DMT, or a combination of synthetic DMT plus synthetic harmine. However, we really wanted to have a general view of the effects of ayahuasca as a whole in human physiology, because this was what people were taking in these ayahuasca rituals, at least the ones that were reaching Europe. So we decided to go for ayahuasca, and what we did was freeze-dry it. Basically, this only removes the water, but everything else is still there. It took us about three years to get this encapsulated freeze-dried ayahuasca ready before we could start our first trial. Maybe we could have progressed faster if we had used pure compounds, but then we would have gotten the criticism that what we studied was not ayahuasca.

Moreover, the encapsulated form solved the problem of placebo administration, because you can give placebo capsules, whereas it would be difficult to make a brew that resembles ayahuasca but is an inactive placebo.

Some researchers have tried to make a fake brew, with varying degrees of success. I think Rafael Guimarães dos Santos, a former PhD student of mine who is now working in Brazil, had prepared a placebo brew which he used in one of his studies. But of course, we wanted our results to be acceptable for mainstream pharmacological journals, and we knew that we would be required to compare ayahuasca with an inactive placebo, and also to control for subjects’ and investigators’ expectations. This is why I took all the trouble to do that. Later, some people have said that after a while, if you take ayahuasca, you will immediately notice that there’s something going on and there’s no more placebo effect…

That’s the classic placebo problem with psychedelics.

Yes, and it’s a legitimate criticism, but this problem is perhaps more obvious if you’re comparing a high ayahuasca dose versus a pure placebo. In several of our studies, we administered ayahuasca doses of different potencies, and some volunteers claimed to have had visions on placebo, while other people had no effect after a low ayahuasca dose.

Another aspect that we wanted to address was that it’s very common among ayahuasca users to say that sometimes they took a small amount and the effects were huge, and other times they took larger amounts and nothing happened. Once we standardised the ayahuasca in this freeze-dried form, we found that you get very nice dose-response effects in terms of intensity when you analyse the results as a whole, among groups. So there’s nothing ‘abnormal’ there, nothing that I wouldn’t expect.

This is a mean measure, derived from groups of subjects. But are there any individual differences? Ayahuasca seems much less linear than, say, psilocybin or LSD: the come-up time, the dose-effect ratio, duration of effects,… This is something your findings don’t seem to confirm.

Liquid ayahuasca has so much variability. From one batch to the next, the amounts of alkaloids can vary enormously. Maybe you think you’ve taken the same kind of ayahuasca, but the concentrations were totally different.

Sometimes two people drink from the same bottle, and one doesn’t feel anything, while the other one is floored.

Of course, there may be differences between subjects. But if you take the same person, and you give them carefully controlled doses, you’ll see an increase in the effect if you raise the dosage. In general terms, we saw the normal behaviour of effects induced by pharmacological substances, there was nothing magical about it. The magic was in the content of the visions, in the access to autobiographical memories, the insights and revelations; all of that was really magical.

There’s also the problem of purging. Do you have buckets in the lab, or how does this work?

I know that the shamanic tradition emphasises cleansing, but in most of our studies, we needed the people not to vomit. We didn’t want them to throw up part of the active compounds they had ingested, because we intended to measure blood and plasma levels of alkaloids. I think in this respect the formulation we used helped us a lot, because people were not nauseated right from the start, they didn’t feel the taste or the smell. Nausea was common at some point, but very few people have vomited in the lab using this formulation.

Doesn’t this introduce some differences between lab and field conditions?

Yes, of course. Whenever you want to obtain measures, you have to standardise. So it’s always going to be different if you take it in the lab or at home alone, or with friends, or in the Amazon with someone you trust or someone you distrust. What we do in the lab is to always try to reproduce the same conditions, but we try to make it as comfortable as possible for the subject. Usually, the experience is so introspective they completely forget about their surroundings. Sometimes it’s harder for participants to stand all the procedures when they get the placebo than when they get the active ayahuasca dose, because on ayahuasca they focus their attention on their inner experience, and they can completely forget about their surroundings.

What do you ascribe the near absence of purging to? I remember reading that the purging came from some kind of serotonergic process in the digestive system, not just from the vile taste or the amount of liquid. So how would you explain this absence of purging from a pharmacological point of view?

Purging is a very complex mechanism. You get information that goes from many different sources to the centre in the brain that controls vomiting. Vision can be a source: you can watch something unpleasant and have an inclination to vomit. Smell and taste also play a role. So can irritation of the stomach and the gastro-intestinal tract, as well as the activation of the vagus nerve, which occurs when you stimulate serotonergic neurotransmission. But there are many other neurochemical mechanisms that play a role there. The nausea is not as intense as when you take the liquid ayahuasca, perhaps because instead of getting stimulation from five different channels, you’re only getting stimulation from one channel, and this is usually not enough to trigger the purging response. This is my educated guess of what’s going on there.

Could you summarise the main findings of all these years of research?

Our initial goal was to see whether we could administer ayahuasca safely, and we were able to demonstrate this. This is important, because every now and then we get a news report in the media about people becoming aggressive or even dying during ayahuasca sessions in the Amazon. We don’t know why that is, but what we do know is that if you’re careful when selecting people, and with the dosages you administer, and you provide a safe and controlled environment, it can be done in the lab and people have good experiences.

You never observed any serious adverse effects?

In our first pilot study, we had a person who experienced a transient disorientation state, which caused him anxiety. It was quite unpleasant for him, he didn’t know who he was for a while. But it only lasted about 20 minutes, and then it was over. This person subsequently decided to withdraw from the study. That was perhaps the most serious adverse consequence I’ve ever observed in these controlled settings.

All the studies we have conducted have allowed us to gather a lot of data: we have learned what happens to the ayahuasca alkaloids when they are ingested. For instance, there were worries that harmine, a monoamine oxydase inhibitor (MAOI) that’s present in the tea, might interact with certain foodstuffs or other drugs, resulting in hypertensive reactions. We found that harmine is very rapidly eliminated from the organism, though. So ayahuasca is quite safe also from this point of view, the physiological effects can easily be tolerated by a healthy person. We don’t get very intense increases in blood pressure or in heart rate.

Regarding harmine, doesn’t it turn out to be safer than people very often suppose it to be? People tend to start dieting several days in advance before an ayahuasca session, abstaining from foods high in tyramine in order to avoid hypertensive crisis. Your studies don’t seem to confirm this risk.

We were surprised to find that in many subjects, we couldn’t even find any harmine, so it didn’t even cross the barrier between the gastro-intestinal tract and systemic circulation, due to both gut and liver enzymes. There might also be individual differences there. Some people might be more effective at eliminating harmine than others, so people should be careful anyway and not try to combine harmine with certain medications. But I also have to say that I witnessed many ayahuasca rituals in which people, after having taken two or three doses of ayahuasca, later dined on cheese and ham and other foodstuffs that, in principle, one wouldn’t recommend people to take. It seems difficult to get a serious toxicity effect from a single ayahuasca dose if your health is OK and you’re not taking other medications.

Beside of that, what I was really interested in was the brain mechanisms by which ayahuasca elicits its effects. We’ve used different techniques to assess this. Initially, we studied spontaneous brain electrical activity before and after ayahuasca administration. This was interesting, because what we see here is that ayahuasca decreases the alpha rhythm, which is a very prominent EEG rhythm that you get in posterior brain areas, and this rhythm is inhibitory. So when ayahuasca suppresses this rhythm, it enhances the spontaneous activity of posterior, visual regions. This might explain all these dreamlike visions people are having. And with functional connectivity analysis between EEG signals recorded at different sites, we’ve also found that ayahuasca decreases ‘top-down control’ of information processing. Usually, incoming information – be it internal information from your memory storage or external, sensory information – is interpreted based on your prior experience with this information. Ayahuasca reduces the expectations you have, and you are re-experiencing stored memories, for instance, in a very different way. So it helps you to take some distance or have a new outlook on things that, in principle, you already know, you’ve already experienced. I think this is quite valuable, and this is what might give ayahuasca its therapeutic potential.

We’ve also done neuroimaging studies. We did a SPECT study, in which we showed that ayahuasca increases the activation of areas that process memory and emotion. It also increases activity in areas that are at the frontier between cognition and emotion. This also supports the claims of ayahuasca users who say that the experience is not recreational at all, that painful memories may come to the mind, and that they are able to re-experience very intense affective processes.

In line with this possibility of being able to detach yourself from your own thoughts and to observe your feelings, emotions and memories, we’ve done recent studies in which we have assessed ‘mindfulness facets’ and creativity following ayahuasca intake. There are some psychotherapeutic schools that try to teach people to be present-centred, non-reactive, accepting and non-judgemental of their own thoughts, and not to identify themselves with them. We’ve seen in a recent study that in the hours following an ayahuasca session, these mindfulness abilities are increased. Enhancing these skills is the goal of mindfulness therapies and may take a long time to achieve using more classical approaches, such as meditation. In our study, participants’ scores after a single ayahuasca dose were similar to those of experienced meditators with many years of training. We have also assessed creativity during ayahuasca sessions [paper under review for publication in Psychopharmacology – Ed.], and we’ve seen that ayahuasca decreases conventional thinking and promotes creative ‘divergent thinking’, finding new ways of looking at things.

All these effects that we’ve been able to measure doing these experiments might explain why ayahuasca is showing promise to treat some medical conditions. I’ve also been able to get psychiatrists in my own institution interested in ayahuasca now, and some initial therapeutic studies have been conducted. I’ve collaborated with studies in Brazil, in which we’ve shown that ayahuasca can exert very rapid antidepressant effects, which are seen after a single dose and can be maintained for three weeks. Classic antidepressants take weeks before they induce any observable and beneficial effects on the patients. I’m really satisfied to see that ayahuasca can be put to good use.

Now, with my colleagues from the psychiatry department, we’re exploring the possibility of investigating whether ayahuasca could be useful to treat other conditions. Some well-designed studies on people with drug dependence, people with post-traumatic stress disorder,… This is what I’m looking forward to now, to start getting data on new potential applications. But I think it was essential to get these safety data first, and to determine a biological basis for the benefits people are reporting. If you only report these flowery stories that people might give you, perhaps my colleagues would not be so easily convinced.

You’ve monitored the acute effects of ayahuasca using brain imagery techniques. The same has been done at Imperial College in London with psilocybin. Have you found any correlation between the effects of both substances? For instance, they determined that psilocybin inhibits the functioning of the default mode network (DMN). Are these conclusions you’ve been able to verify or confirm?

The study Robin Carhart-Harris conducted was done with magnetic resonance imaging, and the study I did with ayahuasca used a nuclear medicine technique called SPECT. Depending on the technique you’re using, you’re getting access to part of the whole picture, but not of everything that’s going on there. So I think it’s good that research has been done with other techniques, and it also helps us if we combine all this information to get a picture of what’s going on there.

Since you mention the default mode network, we did a study of changes in brain structure in long-term ayahuasca users, and what we saw was a decrease in cortical thickness in the posterior cingulate cortex, in this key hub of the DMN. So that would fit with the results I had obtained with EEG, with results by Draulio de Araujo in Brazil, and with the results Robin has obtained with MRI and also with magnetoencephalography.

Have you been able to correlate these durable changes in brain structure with personality changes?

Yes, we administered a series of personality questionnaires, and the long-term ayahuasca users scored higher than the controls on a personality trait called self-transcendence, which has to do with spirituality, less materialistic life attitudes. There was also an interesting correlation there: the greater these cortical thickness decreases were, the higher they scored on this personality trait. In some psychiatric disorders, you see that there’s an inability to inhibit the DMN, and you get all these ruminations and depression. And then you see these long-term ayahuasca users that have a reduction in the brain structure around this area, and they seem to have a healthier approach to life. Even though we could not establish causation here, there was an obvious correlation that might contribute to explain the therapeutic potential ayahuasca may have.

Another interesting conclusion is that experienced ayahuasca users seem to perform better on some basic tasks in a number of ways. They perform better than naïve subjects, both sober and under the effects, but they also perform better under the effects than they do sober.

We did several studies in Brazil and here in Spain, assessing members of the ayahuasca churches. We administered a battery of questionnaires, but we also did a neuropsychological assessment: how their working memory is, their performance on different tasks. When we administered those neuropsychological tasks, ayahuasca users performed better than controls on some tasks. In a way, this came as a surprise because traditionally, regular use of psychoactives has been associated with certain deficits, at least for some addictive drugs. The pattern we’re seeing here with ayahuasca has nothing to do with the traditional patterns of addictive drugs.

As you said, we also assessed people before an ayahuasca session and during the ayahuasca session. In this experiment we saw that people could be divided in two groups. People who had taken ayahuasca just a few times – say, less than 30 – saw a decrease in their performance under ayahuasca. But those who were experienced users not only didn’t suffer these detrimental effects, but they performed better. How did we interpret this? In our study of the brain structure of long-term ayahuasca users, we had also observed an increase in cortical thickness in the frontal part of the brain, in an area which is a key hub of the ‘task-positive’ or ‘attentional’ network. It appears this might be helping people to perform better on certain neuropsychological tasks, because many of those are dependent on the correct functioning of the prefrontal cortex.

You often mention the experienced subjects that you use in your studies. Did these subjects come from a variety of backgrounds, including shamanic backgrounds, or only from established ayahuasca churches?

In most of the lab studies we have conducted where we administered ayahuasca, the participants did not have any religious background. They were experienced with psychedelics, and only some of them had had previous experience with ayahuasca. In the first pilot study, we did recruit six volunteers who had experience with ayahuasca. Then, when we saw that it was safe to administer, we also recruited people who had experience with psilocybin, mescaline or other similar substances. For the studies in the long-term users, the samples did come from the ayahuasca religions, mostly from the Santo Daime.

Do you think this might impact the results in any way? The membership of a religion can also have an impact on personality and – who knows? – maybe even on brain structure…

Yes, that’s a confounding factor, and we were worried that perhaps the beneficial effects we were seeing in the participants might be due to the combined effects of membership in a supportive group and ayahuasca intake. But in this last paper we have published on mindfulness facets, none of the people we assessed had any association with an ayahuasca religion, and they weren’t part of a group that was meeting on a regular basis. An important finding here is that we can see the same benefits in people that don’t have the confounding effect of religious beliefs or membership in a religious group. So I think ayahuasca has therapeutic potential of its own.

* * *

Now over to another type of research you did, about cannabis. The title of a recent article you co-authored, and which stirred up some controversy, was: “Cannabis users show increased susceptibility to false memories.” What struck me was the apparent lack of caution here, whereas usually you seem like a very cautious person. In the article, you state yourself that the results are “subtle”, but the wording, “false memories”, seems quite strong, while this is about lists of words, not images or personal memories. Also, some inferences are quite far-reaching, since you mention possible legal implications in the courtroom. Don’t you think this could lead to a situation where the word of chronic cannabis users would systematically be doubted?

Let me start with the term “false memory”. It’s a technical term used in psychology research and associated with the Roediger-McDermott paradigm we used in the study. In this sense, false memory is a kind of illusion that is common, it affects everyone in everyday life. Memory is constantly reprocessing information. Using this term was not a strategy to attract the reader’s attention, it’s just how this illusion is referred to in psychology.

If you want to assess this phenomenon in the lab, you have to standardise the way you’re doing this. One of the best approaches people have developed to do this, and that’s been used in different studies in different contexts, is this Roediger-McDermott paradigm, in which you use word lists. We had some experience with this paradigm, so we thought we could adapt it to be used in a magnetic resonance imaging setting. To my knowledge, this had not been done before, certainly not in the context of regular cannabis use. So we adapted it and looked at brain activation in two groups of subjects, and the methodology we used to compare these two populations was the same I had used to compare ayahuasca users and controls. We interviewed more than 60 long-term cannabis users, and we left some of them out of the study for various reasons, among which medical reasons: people who made it to the scanner were actually in good health, and in a situation in which we thought that any experience with other substances they might have, or any minor condition for which they could be taking medication would not interfere with the results.

What we found was that there was a difference in performance. We were assessing the users one month after having completely ceased cannabis use (as confirmed by negative urine samples), not during the acute effects of cannabis. They performed worse than the controls on the memory tests. The difference was not huge, but nevertheless around 50% more errors than controls. When you look at the brain activation patterns, you can clearly see that there’s a network which has been described by other scientists to be used in order to reject the false memory stimuli we were testing. To know that a certain word was not present in the initial list, you have to activate prefrontal regions, parietal regions and medial temporal lobe regions, which together act as a network. The controls performed better, they showed increased activation in all these regions that are needed to reject these lures, while in the cannabis users, there was a hypoactivation of this network. On top of that, when you look at the lifetime use of cannabis these people have, and you correlate this with brain regions where you see these hypoactivations, you see a clear negative correlation with the medial temporal cortex, an area that’s crucial for memory processing. We’re not the first team of researchers to have found such differences. There have been studies of hippocampal structure in which they have found decreases in hippocampal volume in cannabis users.

I know this study caused a lot of controversy, but I think the results show a good internal consistency because of these three facts: the behaviour results, the differences in brain activations, and this correlation. I’ve had some very negative reactions to this study, and unfortunately, some of them were quite hysterical, and not very rational. But I think one of the criticisms that were made was legitimate, namely the fact that the cannabis subjects might have been exposed to other substances as well over their lifetimes. This is possible, but not to an extent that was in the least comparable to their daily cannabis use for 20 years. To try to address this concern, we conducted another lab study in which we took healthy volunteers, people with no experience with cannabis, and this time we administered low doses of the active compound, tetrahydrocannabinol (THC). We were able to prove that the administration of 7.5 mg of THC could induce this false memory effect. So these deficits are present in long-term users one month after cessation of use, and the same false memory effect appears in healthy volunteers after acute administration. In a crime series, this would be called a smoking gun.

However, publishing these results doesn’t mean I think that cannabis has no therapeutic potential. And the good news from this second cannabis study is that we also assessed cannabidiol (CBD), this other compound that’s also present in the cannabis plant. CBD totally blocked the effect that THC was exerting on these memory processes when it was administered together with THC. And CBD on its own was actually able to improve performance on some neuropsychological tasks. So I think the cannabis plant has potential for therapeutic use, and I think CBD is a good candidate there. But I think what we should all think about is whether this trend that we’ve seen over the last 20 years or so, of selecting breeds of the cannabis plant with increasingly high THC levels, and increasingly low CBD levels, knowing they are somehow balancing out each other, is a good option. I’m not against personal choice regarding any drug, but if one decides to make this available to everyone over 18, I think people should be informed and they should know that THC and CBD exert very different effects. There are many other studies showing that acute cannabis administration causes memory troubles, that’s nothing new. The reason this paper got so much visibility and was published in a high-impact journal is that this specific false memory phenomenon had never been assessed in this group of users.

When it comes to ayahuasca, there’s a recurring criticism that I’m not studying ayahuasca in its ecological setting, that my studies may not have ecological validity. Here, one might argue that my study in cannabis users didn’t have ecological validity, because regular cannabis users use cannabis every day, and this study assessed effect after one month of abstinence. So perhaps I should have recruited stoned cannabis users. We would have seen they were even more affected, since we can induce these effects in the lab in non-chronic users with 7.5 mg of THC. So will a person, being a current daily cannabis user of a strain high in THC levels be a good witness in a trial? My educated guess is that more likely than not they won’t be.

But did you need to state this implication in the article?

You need to indicate why you’re calling people’s attention to this phenomenon. You have to put these things into context, you have to explain in which context this might be relevant. Moreover, we were asked by reviewers to contextualise our findings.

I think what also bothers people when you write about possible legal implications, is that they draw a line towards possible future discrimination against chronic cannabis users, be it in the courtroom, for job opportunities or whatever, some of which is already happening.

It was really not the intention to discriminate against anyone. If anyone thinks that’s what we intended, I apologise, this was not the case. I’m concerned about the users, and I think they should be informed, they should know that they might face these problems.

I think the problem with people who favour legalisation or decriminalisation, is that they interpret any bad news as an attack. Rafael Guimarães, my former PhD student, wrote an article describing a case study of someone who had suffered a psychotic break from ayahuasca, and he got a lot of criticism. Some people in the ayahuasca studies community told him that this was a war, so you shouldn’t show the enemy your weaknesses. But this is not a war, we’re trying to be scientists here. If we ask from society that we should be able to use these substances for legitimate purposes, medical or whatever, we should be aware of all their benefits, but also their risks. There’s no use in trying to sweep them under the carpet.

This also gave some people the impression that it’s easier to get public funding and a publication in renowned journals for studies that highlight the harms of cannabis rather than its benefits. People say there’s an imbalance between studies examining the benefits and the ones studying the harms of cannabis. Do you agree with this?

I’ve received public funds to study ayahuasca, salvinorin A and cannabis. Having received public funds has not interfered in any way in the way I’ve interpreted my findings. There was never a fear that, depending on what I might publish, I would get my funding cut. Review boards include scientists, who assess projects on their scientific merit and are usually driven by curiosity. It’s not the government who grants me these funds, it’s a panel of scientists. So there has not been any pressure from that side at all. I think I have a track record of saying positive and negative things, and we shouldn’t practice or encourage any kind of self-censorship.

And I don’t think it’s easier to get negative findings published than positive ones. Take for instance ketamine, which was demonised by the media. Some years ago, it was said that it was only used as an anaesthetic for horses by veterinarians, and by crazy young people in raves and clubs. Then some psychiatrists found out that ketamine had very potent antidepressant effects, and it worked very rapidly. This didn’t have to be published in underground magazines supporting free drugs for club users, just because it was about ketamine. It got published in Archives of General Psychiatry, and in many other top journals. The same goes for psilocybin. The study by Charles Grob in cancer patients, which was a pilot study with a very small sample, perhaps not with the best of designs, also got published in Archives of General Psychiatry. I don’t think we should succumb to this kind of paranoia.