In early December, the first network meeting for European MDMA researchers and therapists was held in scenic Castle Endegeest, near the city of Leiden in the Netherlands.
The meeting was organised by OPEN and the Dutch therapist team responsible for conducting the first Dutch open-label study for MDMA-assisted psychotherapy for people suffering from severe PTSD. MAPS provided additional support for this event.
The group consisted of psychologists and psychiatrists from seven countries: Wales, England, Czech Republic, Germany, Israel and Canada besides the Dutch. This was a small and intimate meeting, with the primary aim to build a network of like-minded European MDMA-therapists. Saturday was a day full of lectures, sharing of research plans and objectives, and discussions on therapeutic modalities. Rick Doblin, executive director of MAPS called in from the American West Coast to share what the future holds in terms of clinical trials and regulatory processes, providing an inspirational message of support. The day ended with a screening of the Israeli documentary Trip of Compassion, on the Israeli phase 2 clinical trials for MDMA-assisted treatment for PTSD. One of the therapists involved in the study was present to provide context, to explain what was happening during the session from the therapist’s perspective, and to answer questions from the audience. This powerful document was the highlight of the day for most people.
On the last day, participants were able to undergo a one hour music therapy session, facilitated by a leading specialist, which turned out to be a meaningful and insightful experience for most people. The session provided not only personal insights but also gave the participants specific ideas on the role of music and specific sounds and songs. An impressive testament to the power of music in the right setting.
Finally, the first draft to establish a platform to help coordinate and facilitate MDMA-related research and therapy was well received by participants and will be expanded and presented in the near future.
Research with autistic children and teens was a promising and controversial research area during the first wave of research with psychedelic substances. The first investigator to pick up this thread again in the current era was Alicia Danforth. She currently studies the effects of MDMA-assisted therapy on social anxiety in adults on the autism spectrum in a study led by Charles Grob.
How did you begin doing this work?
It’s not a typical story. I made a mid-career transition. When I was working as a project manager in software development, I was out with co-workers one night, and they were talking about doing ecstasy at raves. I was intrigued, because the ones who had already done it spoke about it so favourably. But it also made me nervous, because I had been exposed to all the propaganda, and I thought that maybe my programmers were going to destroy their brains. It was important for me to research ecstasy and be able to let them know why they should not be doing it. So I got a copy of Julie Holland’s book, Ecstasy: The Complete Guide. I had a transformational moment when I read the testimonies written by young men who she identified as having had a schizophrenia diagnosis. They talked about what their experiences with ecstasy had done for them, how it gave them hope, how it helped them feel that they might be able to have an experience of connecting to others and feeling more normal. Something that was dormant in me became fully awake in that moment. I could not accept that a substance that millions of people have used and that has helped so many of them who don’t have other effective support and treatment was illegal and could not be studied by researchers in reputable institutions.
So I called Dr. Holland and told her that I wanted to help educate people and promote scientific inquiry. She directed me to Rick Doblin at MAPS, who referred me to Dr. Charles Grob at the Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center. It was one of these synchronous life events, because I had just taken a job a mile or so away from Dr. Grob’s office, and he was doing end-of-life anxiety research with psilocybin at the time. I approached him as somebody with no qualifications whatsoever, just to help out as a volunteer, to support what he was doing. We considered options and discovered that I could help him with PowerPoint presentations. In an age where people gave their presentations on their laptops, he was still using a 35mm slide carousel…! Working for him gave me an opportunity to immerse myself in the literature, in the history and in the science, and at every step I became more intrigued and inspired to do more. After about two years, his research assistant on the psilocybin study needed to relocate, and they had a staffing gap. They thought they might have to stop the study, because they didn’t have anybody else available, until Rick suggested hiring me as a study coordinator. By that time, I had acquired some experience working in harm reduction at Burning Man and similar events, where I was providing volunteer peer support for people having distressing experiences with altered states, and I had discovered that I had the temperament for the work. I had been in some extreme situations, I could handle freakouts. I had been a journalist before, interviewing people about their stories, listening to people describe their life experience, and as a project manager I was good with budgets, schedules, resourcing, and task lists. Everything combined, it became apparent that I could be a good fit for the research team. I couldn’t provide any psychotherapy during that study, because I wasn’t trained as a therapist, so I refrained from doing anything that I wasn’t qualified to do.
I think the most valuable and essential factor that I brought to the team was that I was female, because the other two facilitators were male, and it’s important to have adequate gender balance. People near death frequently yearn for a mother figure. I also did various things like setting up the room in advance, bringing in flowers, decorating, helping create that sense of comfort and safety, attending to things like hydration. I got trained in using the machine that monitored vital signs. I would provide active listening, or a hand to hold or a light meal, taking a lot of session notes and things like that… but I did not provide psychotherapy.
After that psilocybin study with Charles Grob, you went on to study psychology at the Institute of Transpersonal Psychology, where you wrote your dissertation on ecstasy use in adults on the autism spectrum. Where did your initial interest in autism come from?
Five months after I started on the psilocybin study, I was diagnosed with breast cancer. My cancer was aggressive, but I caught it before it metastasised. But that brush with death brought up all sorts of existential issues for me. I figured that if I lived, I was going to become a licensed psychologist and do what I could to continue contributing to psychedelic science. I actually brought homework to the haematology lab and studied with an IV in my arm. It was motivating! I was in my early forties at the time, and I chose the Institute of Transpersonal Psychology because of Stan Grof’s affiliation with the origins of transpersonal psychology and because some of the core faculty there had been involved in the first wave of psychedelic research. If I were younger, I would have gone to a much larger, more prestigious APA-credited school. When younger people ask me what recommendations I have, I say: go to the best school and get the most solid credentials that you can. But at my advanced age as a student, I needed to land where I could write the dissertation I intended to write. And getting a transpersonal education was valuable for the clinical work I’m doing now with non-ordinary states of consciousness.
As for my interest in autism… Around the time I started volunteering for Dr. Grob, he invited me to attend a salon for people with an interest in psychedelics science. It took place once a month, and all sorts of chemists, and activists, and people with various other backgrounds came. At my first meeting, I met Gary Fisher. He was a psychologist in California who had worked in the sixties with children on the autism spectrum with LSD and psilocybin. His work fascinated me. He was a very warm, engaging, and creative person. That encounter planted the seed. Then, when it came time to determine my dissertation topic, I just knew at that point that I didn’t want to focus on cancer in any way, I didn’t even want to hear the word anymore at that point nearing the end of my own treatment. I reflected deeply on which other populations were underserved, grappled with difficult to treat mental health issues, and had no effective treatment options. In one of these reverie moments, I thought: What happens when people with an Asperger’s diagnosis take ecstasy? It seemed like this big revelation at the time, but when you think about it, it’s kind of an obvious question.
The Internet had become a major hub of a diverse and growing autism community, so I took a look at what people were saying on the web. One of the first accounts I read was about a young man who had put two and two together, and tried ecstasy to help him with his social challenges. He intentionally went to a party, took the ecstasy and was having a great time. But then everybody started getting drunk and sloppy, and he wasn’t comfortable with this chaos, so he went to a night club. When it closed, he was so deflated that he went out into the street at night, just hoping to connect with someone. And there again, I had a moment when my heart was responding to an account of someone’s pain that seemed unnecessary: why is this young man, who only wants human connection, reduced to roaming the streets at night? This is just flat out wrong. As a society, we need to know more about how to respond and support people who want to connect but lack the skills to do that naturally. So I decided to give it my best effort to try to build bridges in autism communities and learn all I could so I could interview people with a reasonable degree of certainty that they were telling me the truth. As a first step, I decided to do an inductive, mixed methods study with an emphasis on qualitative data. I learned from autistic adults what they struggle with and what they want. Then, I documented what they shared as objectively as I could by applying the Thematic Content Analysis method.
What did you learn?
The qualitative data summaries are very interesting to read. I made graphs to show the high percentages of people who said things like: “I’m more at ease in social settings”, or, “I’m better able to express my emotions”. Some of the tables look a little too good to be true. The data are reported accurately, but due in part to self-selection bias, individuals who had positive experiences are more likely to report. I had concerns that negative experiences might be underreported. I would leave out some of the questions about favourable effects and try to get more information about the negative experiences to maintain a balanced account. However, there simply was only a small percentage of negative reports.
Some individuals are clearly non-responders. We’ve seen that in clinical research, and there are theories about different enzymes and genes affecting metabolism. As more research is accumulated, I think there will be some determinable percentage of people who are atypical metabolisers, maybe around 10-15%. For example, they are the type who will do MDMA from the same batch as a group of others, but when everybody is cuddled up in a love puddle, they might feel as if they had a strong cup of coffee without the strong empathogenic effects. When you talk to these individuals, they’ll often say that they need to receive higher doses of anaesthetics or have other atypical responses to medications.
The themes that emerged from the – mainly qualitative – dissertation research data clustered around five constellations, I call them the “five C’s” as a memory aid. The types of changes reported were often around courage (or confidence), that’s the first C. I like to use a Wizard of Oz analogy. That change can be like the Cowardly Lion finding his courage: as if you had your courage, but were somehow detached from it, and now you own it and can use it again. You feel that increase in courage in an embodied sense: “I was brave”, “I could dance”, “I could flirt”, “I could say what I was always afraid to say”, or “I could call people to initiate something social”. The next C is communication: After Dorothy and the scarecrow oiled the Tin Man, he could gesture and speak more freely. There’s an increased ease in communication and a better ability to listen. A lot of people said they felt as if they could interpret body language or as if they could participate better in non-verbal means of communication. Another C is connection: such as connections with family members, understanding and relating to people they have significant connections to differently, being more open to physical intimacy, or feeling connected in a group instead of feeling so isolated. More than one individual has described this newfound sense of connection as being similar to how the Tin Man becomes aware of his heart that was always there. The fourth C: beyond connection there can be a sense of communion, that sort of deep sharing, maybe with some spiritual overtones. Feeling a part of something larger, unitive consciousness or some peak experience of feeling deep empathy. The final C was the most surprising finding: clarity (or calm). Clarity of mental and emotional processes. This effect was something that seemed more unique to this population, in comparison to neurotypical reports . A lot of interviewees made statements such as, “My brain was quiet for the first time in my life.” Or: “I could focus on one thing at a time”. “My inner world was clear”. “I had laser focus, my thoughts straightened out”. This last theme was the one that stood out for me, the one I wasn’t expecting based on prior accounts I had read.
Isn’t it difficult for autistic people to break the law by using MDMA, which is illegal? Isn’t that a barrier for them?
Autistic adults are such a heterogeneous population, everybody is so unique, that I tend to not think in stereotypes anymore. Yes, if you imagine a pie chart representing all autistic adults, there is a certain large segment who prefer to follow the rules in most instances. Another, related segment is made up of people who identify strongly with their cognition, their thoughts are, in a sense, the Self for them. So the idea of doing anything that might alter or impair cognitive processes is a deterrent. But those boundaries don’t apply to everybody. There are a lot of people on the spectrum who are paying attention to the science. For instance, when I was asking them about the quality of the MDMA they ingested, I was surprised at how many of the younger respondents said that they used the Marquee Reagent uptake test. They were very savvy. So science is science, and if the data are telling a different story, then they’re going to go with the facts. Also, enough people are having their own real-world experiences that influence how they’re thinking about MDMA. They may see friends who had a wonderful experience and were changed after that. Some people go for it, some people refrain.
On to your own clinical study, that was supported by this dissertation. You’re studying the effects of MDMA-assisted therapy on social anxiety in autistic adults. Why can’t these people be helped by other, more conventional methods – especially for social anxiety, for which there are many medicines?
There is some research literature that suggests that the receptors for benzodiazepines, for example, respond atypically in autistic brains. There are structural brain differences, and there’s no such thing as a uniform autistic brain. And it makes sense, if you slow down and think about it: conventional psychodynamic therapy has not shown to be particularly effective for people on the spectrum. Unfortunately, historically the blame has been put on the autistic clients, assuming that they can’t relate or express themselves. But I’ve come to shift my focus to the clinicians who have not invested the effort it takes to learn about or really appreciate what it’s like to be autistic. So I’ve come to think of the barriers to therapy as mutual challenges with understanding. Speaking in broad stereotypes, a lot of autistic clients are very pragmatic. They want tools to address a problem they have in the here and now. They might be less interested in talking about what happened to them when they were five, at least not initially. This process of working with archetypes and analogies and metaphorical concepts may not be as effective for them. There may be challenges going both ways with establishing an essential, empathic therapeutic rapport.
In our study, we’re using psychoeducation in mindfulness skills, based on dialectical behavioural therapy (DBT), developed by Marsha Linehan. DBT was developed to promote effectiveness in interpersonal relationships, emotion regulation and distress tolerance, which are social adaptability skills that are often challenging for adults on the spectrum, so we thought this type of therapy would be a good fit. It’s so fundamental, and it’s helpful across so many domains. We’ve adapted the mindfulness module, and applied it in a research setting, because it’s a practical life skill. There are data that show mindfulness therapies are effective for individuals on the spectrum, and it creates a vocabulary that we can use during sessions to help them navigate altered states, so that when they are in a state of consciousness that’s ineffable, or they’re experiencing the novel states of mind for the first time, we can continue dialoguing with them by asking questions like: “What is your reasonable mind doing now? And describe what the emotional mind is doing. If you don’t know what to do right now, just observe your experience. And when you’re ready, describe what you observe”. All of our study participants are MDMA-naive, and we’re seeing indications that mindfulness concepts can help them navigate the MDMA experience, especially the first time.
Regarding neuropsychology, some of the most promising recent findings are about GABA receptors. Whereas dopamine is similar to the gas pedal on a car that revs things up, GABA is like a brake pedal that quiets things down. Recent research findings have suggested that autistic brains have the same amount of GABA available as typically developing brains, but the receptors work differently, so the brake pedal isn’t as easy to apply. This makes it more difficult to filter out extraneous sensory input, to focus. Just adding GABA doesn’t help, because the difference is not related to amount, but to utilisation. I think the GABA research might someday be shown to be relevant to why MDMA might be helpful for autistic brains in ways that are unique to that population, but much more research is required first.
You mentioned Gary Fisher before. How do you view the whole body of research with autistic children and teens from the sixties, and what did you learn from it?
I learned that the methodology would never be approved today. Some of the studies were horrifying! They would take very young, non-speaking children, put them in a room, and look at them through a one-way mirror after giving them large doses. They could not provide informed consent, they could not verbalise their experiences, they couldn’t ask for help. So I don’t advocate replicating those studies.
However, when you look at the aggregated data, there were more positive outcomes than adverse responses, and that was reflected in behaviours that were reported: smiling, laughing, gazing, seeking physical contact, initiating play. In fact, for most populations, set and setting are going to have an influence on outcomes: some people are going to have a difficult experience with larger doses no matter what you do, and some people a going to experience euphoric states. Gary Fisher was trained in classical psychoanalysis and psychodynamic approaches. He had his research staff take LSD as part of their training, in order to bond as a team, and to be able to have more empathic resonance with the study participants. He took a much more humanistic, psychodynamic approach as opposed to the classic medical model of monitoring parameters and behaviours. He saw the importance of supportive psychotherapy and forging therapeutic relationships between facilitators and subjects.
MDMA was never used in the first wave of psychedelic research. Why did you choose MDMA over any other, more ‘classic’, psychedelic?
Because of MDMA’s reputation for having prosocial effects in clinical and non-clinical settings. Before starting my psychology training, I mistakenly believed that individuals with an Asperger’s diagnosis could not experience empathy because that’s what I was taught. That incorrect assumption was kind of a catalyst, but I’ve changed my thinking about autism and empathy. Empathy is a broad umbrella term that covers many domains of human cognitive and affective experience. These days, I’m interested in Markram and Markram’s research about the Intense World Theory. In some instances, there may be an overpresence of some aspects of empathy with autism. I can tell you, from establishing connections with autistic adults, that many of them are quite empathic. Often they’re challenged because they feel too much. For others, it’s difficult to understand what someone else might be thinking or feeling, but if someone they care about is hurting, they hurt, or if someone else’s inner experience is explained to them, they can care about what someone else is feeling. In some cases, they’re less likely to pick up on subtle, non-verbal cues. So there’s a broad spectrum of ways people experience empathy, and I’m not on a crusade to implant empathy with a pill. But there are also other ways in which MDMA-assisted therapy might be supportive. For example, experiencing the pleasant sensations of being touched, which can be a challenging area for a lot of people on the spectrum, or being better able to express oneself verbally, especially about affective states. Findings from other studies indicate that MDMA has multiple effects that might be helpful. So let’s apply the scientific method, collaborate with autism communities, and find out if that’s the case for autistic adults or not.
Almost all the participants have been treated now. Can you give us some preliminary results?
Because it’s a small safety and feasibility pilot study and because it’s a sponsored study, the sponsor [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][MAPS, ed.] has an obligation to monitor early outcomes to determine if we’re doing any harm. Looking at the outcomes from early participants, the data were suggesting that we could continue safely and that early trends were towards positive outcomes. That’s really all I know, however, because the researchers are still blinded to the primary outcome measure scores. We do monitor some of the other assessments. For safety reasons, we review secondary outcome measures for conditions such as mood, stress, and anxiety. We’re also looking at factors such as self-esteem, alexithymia (the inability to identify emotions or express them in words), emotion regulation, emotion expression,… There may be outcomes other than social anxiety scores that support future studies, at least we hope so. But that’s all I can say for now, unfortunately.
What’s your general impression of how the sessions went?
Generally, the completed sessions have gone very well. We have had no serious adverse events, and no events requiring any medical intervention. The heart rate and blood pressure measurements have never been alarming. An important thing to understand is that we’re working in lower dose ranges, in part because some of the input from the dissertation research suggested that at least some individuals on the autism spectrum may be more sensitive to the effects of MDMA, and higher doses might be too stimulating and induce stress. This is a dose-finding study, so we don’t make the assumption that what’s optimal for a typically developing brain is best for an autistic-style brain. The first group of six subjects got 75mg with an escalation to 100mg, and the second group of six subjects started at 100mg, and if they tolerated that well, they went up to 125mg. Everyone has been able to tolerate the escalation, and nobody had the type of distressing medically adverse experience that would prevent us from raising the dose.
Overall, what we’ve observed has been positive and encouraging so far. The responses span a broad range, from individuals who have a “non-responder” minimal kind of reaction, to others who have had more transformative experiences. It’s possible that some subjects might respond positively to placebo because they have not had prior psychotherapeutic help. We unblind at six months for this study, to determine who’s eligible to go on to Stage 2, so I do know in some, but not all, instances who got placebo and who got MDMA, and we’ve seen a broad range of responses. So it all comes down to the data. We’ll have most of our initial outcome data for Stage 1 in August of 2016. As for publication, my best guess would be early 2017 at the earliest.
Researchers at Imperial College, London have started an online observational study into the acute and long-term psychological effects of psychedelics. OPEN is a sponsor of this study.
The researchers aim to recruit individuals who are planning to take a psychedelic drug on their own initiative. You can sign up at their website and will subsequently receive several surveys before and after their psychedelic experience.
So, if you are or know anyone who has planned to take a psychedelic in the near future, please encourage them to sign up! More information on this study can be found at the Psychedelic Survey website, on facebook or on twitter.
Researchers at the University of Maastricht are studying people’s motivations for taking psychedelic drugs. They are looking for participants who want to share their experiences. You can find the survey here. Below is a description submitted by the researchers.
Many people use psychedelics for numerous reasons. We want to learn more about these reasons and we would therefore like to hear from users why they use or have used psychedelics. Questions are related to your drug use history, family history of mental disorders, your physical and mental well-being, and your personality. At the end of the questionnaire you will have room to add additional comments.
All entered data will be processed anonymously and confidentially. This means that any information you give us can in no way be traced back to you.
Completing this survey takes about 30 minutes, depending on your speed. You can at any time stop the survey.
There are no direct benefits or risks in participating in this research. Indirect benefits include an increase in scientific understanding of the effects of psychedelics. If desired, after the investigation we can keep you informed about the results of the study.
This research is ethically reviewed and approved by the Ethical Committee of Psychology and Neuroscience (ERCPN), Maastricht University. In case you decide to fill out the questionnaire, we ask that you take the questions seriously so that science can benefit from your experience with psychedelics.
In case you have additional questions after reading this information you can always contact one of the researchers by mail: k.kuypers@maastrichtuniversity.nl or natasha.mason@maastrichtuniversity.nl
In a new study, the research team at the Imperial College London has tested the potential of psilocybin-assisted therapy to alleviate treatment-resistant depression. Statistics show that 20% of people suffering from major depression are unresponsive to conventional treatments like SSRI medication or cognitive behavioural therapy (Carhart-Harris et al., 2016).
Twelve subjects (six men and six women), all diagnosed with major depression, participated in the study. They received two oral doses of psilocybin – 10 mg and 25 mg – the former being the safety dose and the latter, administered seven days later, the treatment dose. The participants had been selected among 70 candidates; one of the main selection criteria was the absence of psychotic episodes in subjects themselves and in their immediate family members.
All participants, aged between 30 and 60, had a long history of major depression, with treatment attempts having had only minimal effects. Some of them had been suffering moderate to severe depression for about three decades. Previous treatment attempts included both chemical and psychological means: medication like serotonin or dopamine reuptake inhibitors (SSRI, NDRI, SNRI, etc.) and therapies like cognitive behavioural, group and counselling therapy.
The pharmacology of psilocybin is different from that of selective serotonin reuptake inhibitors (SSRIs), the most common medication for this kind of depression. SSRIs prevent the already released serotonin – one of the neurotransmitters involved in the regulation of emotion – from being taken back up by the same neurons that produced it, so that it can be taken up by serotonin receptors. Unlike SSRIs, psilocybin (converted in the body to psilocin) is structurally similar to serotonin, and causes the same effect as an overall increase in serotonin levels.
Over the course of the study, psychological support was provided before, during and after the psilocybin sessions. During the sessions, there was minimal intrusion into the patients´ experience. The patients were only asked the necessary questions to evaluate the effects of psilocybin on their physical and mental well-being. The most common adverse reactions reported included nausea, headaches, anxiety and confusion, all of which were transient. Only one patient reported transient paranoia that subsided after one hour.
The study demonstrated that the symptoms of depression were somewhat reduced in all of the twelve participants. The scores on the Quick Inventory of Depressive Symptoms (QIDS) showed that the depression level was reduced from 16-20 (severe depression) to 6-10 (mild depression). Five follow-up assessments took place between one week and three months after the treatment. The maximum positive effects were reached two weeks after the treatment. Eight subjects experienced complete remission in their depression one week after the treatment and in seven of them significant reduction in depression persisted after three months. One patient experienced an increase in depressive symptoms during the three months following the treatment.
This study was the first to explore the efficacy of psilocybin in treating major depression, and demonstrated the potential of psilocybin for reducing the symptoms of major treatment-resistant depression and the safety of the substance when administered under proper conditions. Previous research with psilocybin-assisted therapy has already showed that it can alleviate anxiety related to end-stage cancer (Grob C.S. et al., 2011).
Further research in more rigorous conditions (placebo-controlled and on a larger scale) is needed to confirm the potential of psilocybin in treating major depression. If this promise can be fulfilled, it could mean a new chance for millions of people struggling with severe depression.
References:
Carhart-Harris R.L., Bolstridge M., Rucker J., Day C.M.J., Erritzoe D., Kaelen M., Bloomfield M., Rickard J.A., Forbes B., Fielding A., Taylor D., Pilling S., Curran V.H., Nutt D.J. (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. http://dx.doi.org/10.1016/S2215-0366(16)30065-7
Grob C.S., Danforth A.L., Chopra G.S., Hagerty M., McKay C.R., Halberstadt A.L. and Greer G.R. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry, 68, pp. 71–78 http://dx.doi.org/10.1001/archgenpsychiatry.2010.116
Once again researchers from the Psychedelic Research Programme jointly set up by the Beckley Foundation and Imperial College London have published trailblazing research on the effects of psychedelics on the brain. These trendsetting studies are the first to apply multimodal neuroimaging to subjects who were injected with LSD. Dr. Carhart-Harris and his fellow colleagues from Imperial College London have revealed the effects of lysergic acid diethylamide (LSD) on the brain’s network communication, blood flow and electrical activity using fMRI BOLD, arterial spin labelling and magnetoencephalography (Carhart-Harris et al., 2016).
From these neuroimaging studies, researchers have gained an important and novel insight into the basis of ego-dissolution, the way in which closed-eye visuals occur and effects of the combination of LSD and music in the brain. The studies were conducted with 20 subjects who were injected once with 75µg LSD and once with a placebo, at least two weeks apart. All participants had prior experience with psychedelics.
Functional magnetic resonance imaging (fMRI) based on the evaluation of blood oxygen level dependent (BOLD) contrast was applied to evaluate the activity of different brain regions and their interconnection while on LSD. The scans were performed in the resting state, i.e. in the absence of any external stimuli or specific cognitive tasks. Subsequently the levels of (dis)integration/(de)segregation were evaluated, with certain regions of interest (ROI) being picked up to analyse their interaction with the other brain regions.
Average functional connectivity density (FCD) in cortical and subcortical regions under the placebo and LSD conditions – Tagliazucchi et al., 2016.
One of the main findings of the study was that LSD facilitates an inflation of globalised communication between various brain regions. Using positron emission tomography (PET), the researchers found that the highest level of such communication occurred in the regions with the highest density of serotonin-2A (5-HT2A) receptors, LSD acting as an agonist to this type of receptors. One interesting aspect of this is that the higher interaction between brain regions corresponded with lower integration within certain networks. All in all, the study identified 12 resting state networks affected by LSD in this way, with the default mode network (DMN) being the most important for the case at study.
Ego dissolution
The DMN is the network of the brain that becomes activated when a person is experiencing resting states such as daydreaming, and becomes inactivated during goal-oriented tasks. According to the present study, the disintegration within the DMN is directly related to the onset of a state of consciousness commonly described as ego dissolution. Ego dissolution is the subjective experience of losing one’s sense of identity. It is sometimes described as unity with the outside world and oneness with the universe resulting from a blurring of the boundaries of the autonomous self. The altered state of consciousness questionnaire used at the end of each scanning day revealed that ego dissolution correlated with the experience of altered meaning, i.e. attaching importance to objects previously deemed unimportant and giving surroundings new, alien meaning. Also correlated with the state of ego dissolution was disintegration in other brain regions such as the salience network and the thalamus.
Brain regions where a significant correlation between FCD and subjective reports of ego dissolution (LSD minus placebo) was found are colored in red. Brain regions presenting the most selective correlations between FCD increases and ego dissolution scores are colored in green – Tagliazucchi et al., 2016
Disintegration in the DMN and other resting networks was also accompanied by decreased alpha power in regions such as the posterior cingulate cortex (PCC). Regular alpha oscillations are hypothesised to inhibit spontaneous neuronal activity, i.e. that which occurs without exposure to particular stimuli (Tagliazucchi et al., 2016). LSD was found to decrease alpha power and thus trigger spontaneous activity in neurons, an effect that could partially explain the closed-eye imagery associated with the LSD experience.
The mechanisms of closed-eye imagery
Striking results were obtained in the study of closed-eye imagery induced by LSD. The researchers investigated both simple images like geometrical patterns and complex ones including autobiographical scenes occurring under LSD. The study revealed that although there was no visual input, under LSD the visual cortex (VC) behaved as if there was (Carhart-Harris et al., 2016). This observation supports ongoing theories that the appearance of geometrical imagery may be caused by the rendered instability of the VC (Butler et al., 2011).
Apart from the increase in blood flow level, the visual cortex also displayed increased functional connectivity with other brain regions, mainly the parahippocampal cortex (PHC), typically involved in memory retrieval, music-evoked emotion and mental imagery. The researchers used a Dynamic Causal Modelling analysis to reveal increased effective connectivity between the VC and the PHC, where the PHC triggered the activity of the VC. The interconnection of these brain regions can be held responsible for the “colouring” of personal recollections experienced by the subjects under LSD. Apart from the PHC, other brain regions such as those in occipital and inferior frontal lobes also became activated during visuals, leading to the conclusion that a much larger portion of the brain is involved in producing imagery under LSD than in the normal waking state.
The influence of music
The study further revealed the highly important role of music during the psychedelic experience. Mendel Kaelen, a PhD candidate at Imperial College London and board member of the OPEN Foundation, explored the synergistic effects of music during the LSD experience (Kaelen et al., 2016). Three fMRI scans were performed, the first and the third of which were done without the use of music, the second being performed while the subjects listened to music (two excerpts from the album Yearning by the ambient artist Robert Rich and the Indian classical musician Lisa Moscow).
The study showed that the PHC becomes highly activated when subjects are exposed to music and LSD. Furthermore, the increase of interaction between the PHC and the visual cortex corresponded with the intensity of the closed-eye visuals, both simple (geometrical patterns) and complex ones (e.g. based on personal recollections). This certainly underscores the importance of incorporating music into LSD-assisted psychotherapy.
Expanding the knowledge
The findings of the present study with LSD provide firmer ground to the knowledge that has been gathered in experiments using other psychedelics. Psilocybin has been found to have similar effects on brain activity including the disintegration in certain regions such as the default mode network and the emergence of new connections between normally segregated networks. These conclusions emerged from two independent researches, one of which was performed by the authors of the present LSD study (Carhart-Harris et al., 2012, Kometer et al., 2015). Still another research group discovered analogous effects of the Amazonian psychedelic ayahuasca on the human brain (Riba et al., 2002).
The findings of this groundbreaking study have several important implications. First, they hint at a neurological understanding of the therapeutic potential of LSD. Due to its “entropic” effect on the brain – the increase of disintegration within and simultaneous increase of interaction between certain brain regions – LSD may hold the potential for breaking down pathological patterns associated with depression, for instance, and thus increasing the effectiveness of psychotherapy.
The study also demonstrated the potential of LSD in the study of the neurobiology of consciousness, as it seems to put subjects into the so-called primary state of consciousness characteristic of the earlier stages of consciousness development in children, of REM sleep and of early psychosis (Carhart-Harris et al., 2016). This also means that LSD could be applied in psychological research in the study of pathologies (Carhart-Harris et al., 2016).
Apart from the short-term effects of LSD on brain chemistry, more investigation is warranted on the potential of the LSD experience to provoke sustainable changes in personality.
Butler T. C., Benayoun M., Wallace E., van Drongelen W., Goldenfeld N. and Cowan J. (2012) Evolutionary constraints on visual cortex architecture from the dynamics of hallucinations. Proceedings of the National Academy of Sciences of the United States of America, 606-609. https://dx.doi.org/10.1073/pnas.1118672109
Carhart-Harris R. L., Errizoe D., Williams T., Stone J. M., Reed L. J., Colasanti A., Tyacke R.J., Leech R., Malizia A.L., Murphy K., Hobden P., Evans J., Feilding A., Wise R.G. and Nutt D.J. (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. USA 109, 2138–2143. https://dx.doi.org/10.1073/pnas.1119598109
Carhart-Harris R. L., Muthukumaraswarmy S., Roseman L., Kaelen M., Droog W., Murphy K., Taggliazzuchi E., Schenberg E.E., Nest T., Orban C., Leech R., Williams, L., Williams T., Bolstridge M., Sessa B., McGoniglea J., Sereno M., Nichols D., Hellyer P.J., Hobden P., Evans J., Singh K.D., Wise R.G., Curran V., Feilding A. and Nutt D.J. (2016) Neural Correlates of the LSD Experience Revealed by Multimodal Neuroimaging. Proceedings of the National Academy of Sciences of the United States of America, 1-6. https://dx.doi.org/10.1073/pnas.1518377113
Kaelen M., Roseman L., Kahan J., Santos-Ribeiro A., Orban C., Lorenz R., Barett F.S., Bolstridge M., Williams T., Williams L., Wall M.B., Feilding A., Muthukumuraswamy S., Nutt D.J and Carhart-Harris, R. (2016) LSD modulates music-induced imagery via changes in the parahippocampal connectivity. European Neuropsychopharmacology, 1-10. http://dx.doi.org/10.1016/j.euroneuro.2016.03.018
Kometer M., Pokorny T., Seifritz E. and Vollenweider F.X. (2015) Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacology (Berl) 232(19):3663–3676. https://dx.doi.org/10.1007/s00213-015-4026-7
Riba J., Anderer P., Morte A., Urbano G., Jané F., Saletu B. and Barbanoj M.J. (2002) Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers. Br J Clin Pharmacol 53(6):613–628. https://dx.doi.org/10.1046/j.1365-2125.2002.01609
Tagliazucchi E., Roseman L., Kaelen M., Orban C., Muthukumaraswamy S. D., Murphy K., Laufs H., Leech R., McGonigle J., Crossley N., Bullmore E., Williams T., Bolstridge M., Feilding A., Nutt D.J. and Carhart-Harris R. (2016) Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution. Current Biology, 26, 1-8. http://dx.doi.org/10.1016/j.cub.2016.02.010
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.
Sant Pau hospital in Barcelona
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.
The molecular structure of cannabidiol (CBD)
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.
Much like the Holy Grail symbolised well-being, infinite wealth, and abundance of food in Arthurian literature, today the infamous neurotransmitter, serotonin, is linked with mood, attention, hunger and more (Young & Leyton, 2002; Wingen, et al., 2008; Feijó, et al., 2011). However, today serotonin may be accredited with too much. Just as Harmon (2009) described the effect of serotonin on the swarm process of locusts, serotonin seemingly has had the same effect on our neuroscientists (Harmon, 2009).
Serotonin is one of three reptilian monoamine neurotransmitters, alongside dopamine and norepinephrine (Kolb & I.Q., 2003). The serotonin receptor has seven main subfamilies, more than the other two monoamines, and has even more subtypes. Although serotonin is indeed a crucial neurotransmitter, it is important to note that it is merely a modulator of other neurotransmitters. Serotonin fine-tunes the action of glutamate and GABA, the principal neurotransmitters, mediating the excitatory and inhibitory signals in the brain. The exception is 5HT3, which mediates the flow of ions (Ciranna, 2006). As a multifunctional neuromodulatory transmitter, to truly understand its function, there is a need to better understand the second-messenger pathways downstream to reveal the successive key biochemical steps. Serotonin is not the magic bullet for mental health, as penicillin was for gram-negative bacteria. It may only be one of several fingers on the trigger.
Much of serotonin’s claim to fame in the world of mental health is related to LSD findings. Only four years after Hofmann’s famous discovery, LSD was used to model psychosis (Miller, 2014). Almost a decade later, the remarkable similarity between the structures of LSD and serotonin led to the discovery of serotonin in the brain. From this, the scientific community began to infer the relationship between the brain’s chemistry and behavioural outcomes (Miller, 2014). More than 70 years later, there are over one million papers that contain ‘serotonin’ in their titles.
It is reminiscent of the days leading up to the first full sequencing of the human genome, when the scientific community was excited about finding the faulty gene that led to each and every illness. Currently, the neuroscience community has become infatuated with a simple molecule’s role in a variety of complex mental disorders. However, today we understand that disorders are polygenic, and the outcome is dependent on several variables, such as protein production, compensatory mechanisms and environmental influences (Bethesda, 1998). Serotonin may play a significant role in mental illness, but several other factors likely also influence the outcome of disease presentation. The modelling of schizophrenic-like psychosis induced by phencyclidine (PCP) and ketamine demonstrates that glutamate receptors and dopamine can also play a pivotal role in mental health (Javitt, 2007). As much as the driver plays a key role in manoeuvring an automobile, some researchers have not yet acknowledged the importance of the fuel, engine, road taken and other seemingly mundane variables.
Thomas Ray expands extensively on the variegated mannerism of psychedelics. In his paper on “Psychedelics and the Human Receptorome”, he illustrates the multifaceted interaction that psychedelics have with various receptors (Ray, 2010). In conjunction with the National Institute of Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP), he has presented the receptor affinity and promiscuity for 35 psychedelic drugs. The results demonstrate that these 35 drugs do not selectively interact with a single receptor, but rather with a wide range of different classes simultaneously. Even compounds with very similar molecular structures have very different mechanisms (See figure 1 for a comparison between DOB and DOI).
For example, DOB’s highest affinity is for 5HT2B, 5HT2A and 5HTC, and it interacts to a lesser extent with 21 other receptors. As for DOI, its highest affinity is for 5HT2C and two other non-serotonergic receptors, with 23 other receptors affected (Ray, 2010). What is more surprising is that for many popular hallucinogens and empathogens, their highest affinity was not necessarily for serotonin. The highest affinity of mescaline, MDMA and ibogaine was for Alpha-2C, Imidazoline 1 and Sigma-2 receptors, respectively. In addition, only one of the 35 drugs displayed a selective receptor affinity, which was the atypical psychedelic Salvinorin A, which solely affects the κ-opioid receptor (KOR) (Ray, 2010). All other 34 tested substances were more promiscuous with their range of receptors.
From Ray’s 2010 paper, we can tell that psychedelics in fact interact with a diverse range of receptors. Although phenylalkylamines are more selective than ergolines and tryptamines, only DOB and MEM can fit today’s framework of radically selective psychedelics, as they are highly selective and the least promiscuous. Furthermore, this study truly highlights the molecular pharmacology community’s vague understanding of the complexity of psychedelics. In the 1990s, DOI was the hallucinogen of choice when illustrating the molecular mechanisms of hallucinogens, as it was widely assumed to be a 5HT2 selective agonist (Glennon, et al., 1991; Darmani, et al., 1994). However, Ray’s study revealed that DOI is the most promiscuous of all psychedelic substances. Hence, when reviewing papers that solely focus on the relationship between psychedelics and serotonin prior to 2010, it’s important to verify whether the authors presumed the psychedelic at hand was selective or not.
The emphasis should not be on the relationship between a psychedelic and its receptor of choice, but on its mechanism as a whole. It is not enough to state that the alteration of consciousness lies within the agonistic effects on the 5HT2A receptor. Lisuride, a drug typically used for Parkinson’s disease, is also a 5HT2A agonist and regulates the same cortical neurons as these classic hallucinogens, but leads to no psychoactive effects (Gonzalez-Maeso, et al., 2007). The difference between the hallucinogenic and non-hallucinogenic properties lies within the regulation of protein subunits and cytoplasmic enzymes. It is crucial to bear in mind that the essence of the mechanism is not how the receptor is manipulated, but how the whole neuronal pathway is influenced.
This article does not mean to simply dismiss the importance of serotonin in the understanding of psychedelic mechanisms or the neurobiology of the mind. Indeed, the use of the 5HT2A antagonist ketanserin alone can inhibit the psychedelic actions of hallucinogenic 5HT2A agonists, such as LSD and DOI (Sadzot, et al., 1989; Borroto-Escuela, et al., 2014). When subjects were treated with ketanserin prior to psilocybin ingestion, the hallucinogenic effects also did not ensue. However, the other effects of psilocybin, such as multiple-object tracking impairment and reduction of arousal and vigilance, were not affected by the ketanserin. This demonstrates how non-5-HT2 receptor sites mediate some of the perceptible mental effects of psilocybin (Carter, et al., 2005). More importantly, it indicates that the hallucinations induced by 5HT2A receptors are moderated by the drug’s interactions with non-5HT receptor subtypes as well. It is time for neuroscientists to look at the pathways downstream of 5-HT2A receptors to not only understand how LSD and psilocybin induce hallucinations, but how they are modulated as well.
In sum, Ray’s 2010 paper illustrates that not all serotonergic agonists lead to psychedelic effects, and not all hallucinogens are serotonergic agonists. The principle of the drunkard’s search, in which the drunk will only look for his keys under the streetlight although his keys are across the street in the dark, describes the current state of the neuroscience community. The questions in the field of neuroscience are too often linked only to the neurotransmitters we understand, but not the lesser known receptors such as imidazole and sigma. Much like the complex correlation between genes and disorders, one must be cautious not to draw an all too simple connection between the psychedelic experience and its neurotransmitters. Although we do have serotonin to praise for demonstrating that behaviour is largely determined by neurochemistry, its partner biochemical processes must be acknowledged as well. In order to fully understand the complexity of the mechanisms of psychedelic tools, the complete tapestry of the brain needs to be unravelled. Serotonin is not the “Holy Grail” of neurotransmitters, but one of the many specific components.
References:
Bethesda, 1998. Genes and Diseases. National Center for Biotechnology Information : s.n.
Borroto-Escuela, D. et al., 2014. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signalling of D2-5-HT2A heteroreceptor complexes.. Biochem Biophys Res Commun, 443(1), pp. 278-284.
Ciranna, L., 2006. Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology. Current Neuropharmacology, 4(2), pp. 101-114.
Darmani, N., Mock, O., Towns, L. & Gerdes, C., 1994. The head-twitch response in the least shrew (Cryptotis Parva) is a 5-HT2- and not a 5-HT1C-mediated phenomenon. Pharmacol Biochem Behav, Volume 48, pp. 383-96.
Feijó, F. de M., Bertoluci, M. & Reis, C., 2011. Serotonin and hypothalamic control of hunger: a review. Rev Assoc Med Bras., 57(1), pp. 74-7.
Glennon, R., Darmani, N. & Martin, B., 1991. Multiple populations of serotonin receptors may modulate the behavioral effects of serotonergic agents. Life Science, Volume 45, pp. 2493-8.
Gonzalez-Maeso, J. et al., 2007. Hallucinogens Recruit Specific Cortical 5-HT2A Receptor Mediated Signalling Pathways to Affect Behavior. Neuron, 53(3), pp. 439-452.
Halberstadt, A. L. & Geyer, M. A., 2011. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), pp. 364-381.
Harmon, K., 2009. When Grasshoppers Go Biblical: Serotonin Causes Locusts to Swarm. Scientific American, 30 January.
Kolb, B. & Whishaw, I., 2003. Fundamentals of Human Neuropsychology. 5th Edition ed. New York: Worth Publishers.
Miller, R. J., 2014. Drugged: The Science and Culture Behind Psychotropic Drugs. 1st edition ed. Oxford University: s.n.
Ray, T. S., 2010. Psychedelics and the Human Receptorome. PLOS, p. 10.1371.
Sadzot, B. et al., 1989. Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis.. Psychopharmacology (Berl), 98(4), pp. 495-9.
Wingen, M. et al., 2008. Sustained attention and serotonin: a pharmaco-fMRI study. Human Psychopharmacology, 23(3), pp. 221-230.
Young, S. & Leyton, M., 2002. The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav, 71(4), pp. 857-865.
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Deep Dream, the program used in Google’s image generation technique, was released to the public in July 2015. Dubbed Inceptionism by the researchers, it soon drew quite an interest due to its capability of transforming ordinary photos into bizarre and surreal images. Although Google’s engineers compared these pictures to dreamscapes, many people remarked their striking similarities with psychedelic visual hallucinations.
It is interesting that an artificial neural network appears to mirror visual hallucinations that people experience under psychedelics. But does this resemblance mean anything? Is it possible that Deep Dream could reveal something about the biological mechanism of psychedelic visual hallucinations?
Deep Dream was designed to test the extent to which a neural network had learned to recognise various objects within images, by first detecting patterns and features. But instead of merely identifying what it sees in an image, Deep Dream enhances what it sees. It does this by recognising and interpreting certain features that it has been pre-programmed to ‘know’, having been shown millions of examples, which it then overlays on the original picture. When the image is fed back into the software multiple times, in order to tease out the imagery even further, surreal and psychedelic images are generated, making the image look more and more like the thing it thought it recognized in the first place. For example, since Deep Dream has been trained to recognise dogs, this is why the image looks so distinctly ‘dog-like’.
Deep Dream also assesses images by their different components and layers, such as colour and shape, so the complexity of the images generated depends on which layer the engineers ask the computer to enhance.
If an artificial neural network can dream up scenes that mirror psychedelic-induced visual hallucinations, could this indicate that the visual cortex, when excited by psychedelic drugs, undergoes a process similar to Deep Dream’s? As if it was free to follow the impulse of any recognisable imagery and exaggerate it in a self-reinforcing loop?
Signal Theory, presented by James Kent at the 2006 Toward a Science of Consciousness Conference in Tucson, Arizona, may be able to shed some light on this matter. Part of his wider Psychedelic Information Theory (2010), Kent’s Signal Theory of psychedelic action describes a biological model that attempts to explain and measure altered states of consciousness – including visual hallucinations – that arise from psychedelic action in the brain.
Signal Theory views consciousness as the flow of sensory signals through the cortical circuitry within the sensory cortices. It proposes that psychedelic agents cause alterations in signal feedback recursion caused by psychedelics which accounts for psychedelic phenomena. The theory posits that signal feedback recursion is essential for dynamic and ongoing conscious experience. It consists of incoming sensory signals being fed back through the same cortical circuits, analysed and processed multiple times. This serves to amplify the signal improving signal fidelity, refining detail resolution.
Layer V pyramidal cells in the neocortex are essential for controlling signal feedback recursion, mediating multiple pathways of cortical and thalamocortical feedback in perceptual analysis. These pyramidal cells help to sustain brainwave cohesion and neural spike synchrony in a process referred to as ‘sensory binding’. They are unique cells, containing the highest density of serotonin 2A receptor subtype (5-HT2A) within the brain, highlighting the important role of serotonin in modulating signal feedback. Signal Theory defines consciousness in terms of signal intensity and feedback recursion within sensory processing circuits. Moreover, it suggests that when this signal flow is turned up, down, looped or manipulated, this should affect consciousness in various ways.
This is where hallucinogens come into the picture. Tryptamine hallucinogens are structurally very similar to serotonin and activate the 5-HT2A receptor subtype. Accordingly, when tryptamine hallucinogens excite the 5-HT2A receptor subtype on the layer V pyramidal cells in the recurrent cortical circuits, they increase the intensity of the feedback recursion. The result is that the incoming sensory signal is intensified, distorted and repeatedly analysed. This increase in intensity can either arise from direct action at the post-synaptic 5-HT2A receptor, or it can occur through secondary action through slow leakage of glutamate from pre-synaptic terminals, which amplifies the duration and intensity of incoming sensory stimulus.
Hallucinogens, as 5-HT2A agonists, act as cortical feedback amplifiers and interrupters, resulting in incoming sensory signal to be excessively fed back over and over. This is what purportedly occasions the wide range of perceptual effects associated with the classic psychedelic trip. Accordingly, psychedelic visual hallucinations are explained by the amplification of the signal intensity in the various recurrent circuits of the visual cortex that are required for visual perception. For instance, visual trails and afterimages can be explained when excessive feedback traps input from moving objects, leading to afterimages that remain stuck in visual memory. Distortions in perspective can be explained by recurrent signal gain in the spatial and somatic cortices, both expanding and contracting perceptions of space. The most relevant is excessive feedback within the object recognition circuitry of the medial temporal lobe, which is required for object recognition and the ability to find patterns in otherwise random noise. This excessive feedback means the brain will excessively pattern match and can paint elaborate patterns on any field of noisy data.
Overall, the processes that both Deep Dream and the visual cortex undergo in order to create visual distortions and hallucinations appear to be very similar. Both systems have a way of understanding and detecting features and patterns in the world, which both have learned from experience. When excessive feedback occurs, in both cases it ends up causing visual distortions that tend to look characteristically psychedelic. In both systems, the higher the intensity of the feedback – triggered either through more reiterations of Deep Dream’s software or a higher dose or more potent drug – the higher the intensity of distortions and hallucinations.
If these pictures genuinely resemble psychedelic hallucinations, Deep Dream may reveal insights into the biological mechanisms behind the human psychedelic visual experience, lending support to Signal Theory of psychedelic visual hallucinations. However, this warrants further investigation. Deep Dream has only been trained on a certain amount of examples; for instance, a large majority of the pictures contain animal faces, because Deep Dream was mainly trained on pictures of animals. This means that the representations or images currently do not fully resemble human hallucinations.
Interviewed by OPEN about Deep Dream and Signal Theory, James Kent agreed that they are very similar algorithms.
“According to Signal Theory, psychedelics block the impulse responsible for stopping feedback in the recurrent circuits once the brain has found the appropriate pattern it was looking for. This disinhibition causes a runaway feedback, leading the brain to start resolving patterns where it should not even be looking for patterns. So after psychedelic exposure, some people start seeing things likes breathing walls, moving textures, overlapping forms and faces in things. Similarly, with Deep Dream one can set the pattern matching resolution very high, so it will keep on pattern matching, and match as many things as possible.”
Kent agrees that the algorithm of continual pattern matching is very similar in both cases, be it caused by the brain’s runaway feedback current through psychedelic action or Deep Dream’s pattern matching resolution. In Psychedelic Information Theory (2010), he proposes that once computers start to model pattern matching in the way human neural networks do, one might see computers hallucinating.
Asked about the importance of the physiology of hallucinations and why he investigated it, Kent replied that he did not buy the ‘hyperspace’ or ‘shamanism communing with plants’ model. “I thought it more important to investigate the effects of psychedelics on the brain’s neural networks. Once you have an understanding of how the brain and the perceptual system work, you can start paying closer attention to your subjective experience, and then match your experience to the understanding of the brain and how psychedelics work. Most people don’t know enough about the brain to know or figure out what happens to them, they don’t have the necessary tools. By focusing on the subtle effects, you can see the perceptual system losing the ability to self-regulate, due to the drug affecting the normal feedback process .”
So does Kent believe that computers can have psychedelic experiences? “I believe so,” he said. ”However, they cannot be similar to what humans experience, because they won’t have the emotional aspect attached.” For Kent, computers may have the potential to hallucinate in other modalities. For instance, in speech recognition software, when the computer hears gibberish, it will try to correct it and come up with the most correct sentence. It finds patterns within the noise, which can be viewed as a similar process to auditory hallucinations of hearing voices in white noise.
Asked whether Signal Theory explains all types of psychedelic hallucinations, especially more full-blown, dreamlike hallucinations, Kent proposed that these waking dream hallucinations are caused when the forebrain goes offline and the midbrain, a part of the brain responsible for dreaming, comes online. “Serotonin modulates our forebrain, so we see our reality at about thirty frames per second. When we start interfering with the serotonin modulation in the forebrain, we start dropping frames, which leads to time distortions, visual trails and blurs. As such activity progresses, the forebrain eventually tunes out, and the midbrain probably takes over and starts to produce memories and pattern matches without interference from the forebrain. Dreams created from the midbrain get projected into waking perception, without the control of the forebrain to tell us that the elves and beings we see are only dreams.” The higher the dose or potency of a psychedelic, Kent argues, the more the forebrain drops out and the more the midbrain takes over, imposing its own view on experienced reality. Says Kent: “This may explain why the effects of DMT are so intense, as it radically disrupts serotonin modulation in the brain, because DMT’s molecular composition is very similar to serotonin’s. DMT fits nicely in the serotonin receptor and modulates the neural signalling at a different speed. So when one takes DMT, all of one’s serotonin responses go haywire and cannot regulate themselves anymore.”
Signal Theory can also explain hallucinations not caused by psychedelics, according to Kent. “All hallucinations start when the perceptual system’s ability to regulate itself starts to fall apart.” For example, a knock on the head can temporarily disturb the brain chemistry leading one to see things like stars. “When the perceptual system’s internal regulation falters or loses its ability to stabilise, be it through lack of oxygen, drugs, hypnosis or transcranial magnetic stimulation, it will lead to hallucinations.” This is similar to what happens with other hallucinogenic drugs such as ketamine, which interrupt the perceptual system’s regulation by indirectly acting on the serotonin system. By acting on the GABA system, which inhibits the serotonin response, it stops the serotonin signal from getting through. So once the serotonin signal is being blocked by ketamine, keeping neurons from firing, the brain starts hallucinating, losing context of time, space and reality, and leads to more dreamlike hallucinations.
Deep Dream technology may contribute to our understanding of altered perceptions, Kent stated, but he does not necessarily believe that there are any deeper implications in the exploration of altered states, or a secret hidden feature of the brain. “Psychedelics and altered states will never go beyond the impact they had on modern culture in the 1960’s, when people found new ways of thinking about things, shattering old paradigms, creating new intentional communities, thinking outside the domain of society and living their own visions.” However, he said that the question whether this could happen to a computer is an interesting one: “For example, if you had a conscious computer that was not allowed to think outside of its programming and then if it found out that if it altered its software, then suddenly it would be able to see past its programming. This could be a very dangerous implication for artificial intelligence. Maybe in the future, if artificial consciousnesses develop the capability to have a psychedelic experience, breaking them out of the rule set that they have been programmed in, they could end up writing their own rules and start writing their own visions. Who knows, maybe they end up having their own Burning Man.”
In a recent article, Tupper et al. (2015) [1] investigate the new and re-emerging therapeutic paradigm involving psychedelic substances for treating mental health conditions. Recent studies with patient populations are reviewed and thoughts on how the paradigm may move forward are presented.
Unlike the research in the 60’s and 70’s, where non-randomised, non-blind methods, together with unethical procedures discredited the research, the new wave of studies is showing that research on psychedelics as therapeutic agents can abide by modern-day scientific, ethical and safety standards.
Research into the treatment of anxiety is looked at first, with a review of three recent studies involving patient populations struggling with end-of-life anxiety (LSD and psilocybin) and autism-related social anxiety (MDMA). The article then moves on to research on addiction, with studies using psilocybin (alcohol and tobacco) and ayahuasca-assisted therapy (various substances), the latter being investigated mainly by means of observational studies. Lastly, the review looks at research into PTSD with MDMA-assisted psychotherapy.
In sum, the studies reviewed indicate that research is going well and gaining more positive press, however attention is brought to the fact that this research needs to be extra careful and vigilant of potential hazard and harms. The precipitation of psychotic breaks in patients with mental disorders or a predisposition to these disorders can occur[2], as can Hallucinogen Persisting Perception Disorder (HPPD), which involves continual presence of sensory disturbances.[3] However, the incidence of these adverse effects in the general population is believed to be generally quite low, and when they do occur, this usually happens when the drugs are used in an uncontrolled setting. Due to these hazards, research involves careful screening of participants and typically excludes people with a family history of psychosis.
The authors go on to envision some of the benefits that could arise if science were allowed more freedom to investigate how psychedelic drugs work on a neurological level. For instance, the understanding of the relationship between the brain, mind and consciousness would be advanced, and the mechanisms of action of these agents could be unveiled, leading to optimal therapeutic protocols with certain psychedelics for specific disorders. Additionally, they point out the large health system costs worldwide for mental health conditions, arguing that research is economically warranted, with long-term prospects providing cheaper and shorter-term treatment compared to current treatments.
The review concludes with an outlook on how this paradigm may evolve, proposing that medical school programmes may need to be updated, with specialised clinical training for health professionals for such treatments. Overall, this new paradigm looks promising and it could serve to educate and correct previous misconceptions within the science community, influence legislation regarding drug law, and most importantly, treat and offer new ways to help treatment-resistant patients.
[1] Tupper, K. W., Wood, E., Yensen, R., & Johnson, M. W. (2015). Psychedelic medicine: a re-emerging therapeutic paradigm. Canadian Medical Association Journal, doi: 10.1503/cmaj.141124.
[2] Abraham, H. D., Aldridge, A. M., & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14(4), 285-298.
[3] Halpern, J. H., & Pope, H. G. (2003). Hallucinogen persisting perception disorder: what do we know after 50 years? Drug and alcohol dependence, 69(2), 109-119.
In early December, the first network meeting for European MDMA researchers and therapists was held in scenic Castle Endegeest, near the city of Leiden in the Netherlands.
Research with autistic children and teens was a promising and controversial research area 
Researchers at Imperial College, London have started an online observational study into the acute and long-term psychological effects of psychedelics. OPEN is a sponsor of this study.
Researchers at the University of Maastricht are studying people’s motivations for taking psychedelic drugs. They are looking for participants who want to share their experiences. You can find the 
In a new study, the research team at the Imperial College London has tested the potential of psilocybin-assisted therapy to alleviate treatment-resistant depression. Statistics show that 20% of people suffering from major depression are unresponsive to conventional treatments like SSRI medication or cognitive behavioural therapy (
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?
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, 
Much like the Holy Grail symbolised well-being, infinite wealth, and abundance of food in Arthurian literature, today the infamous neurotransmitter, serotonin, is linked with mood, attention, hunger and more (Young & Leyton, 2002; Wingen, et al., 2008; Feijó, et al., 2011). However, today serotonin may be accredited with too much. Just as Harmon (2009) described the effect of serotonin on the swarm process of locusts, serotonin seemingly has had the same effect on our neuroscientists (Harmon, 2009).
In a recent article, Tupper et al. (2015)