Tag: psychedelics

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Two Reasons I’m Sceptical About Psychedelic Science

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Photo by Marek Piwnicki

Michiel van Elk, Leiden University

Since I was young, I have been intrigued by altered states of consciousness, such as out-of-body experiences, paranormal phenomena and religious visions. I studied psychology and neuroscience to gain a better understanding of how these experiences come about. And in my scientific career, I have focused on the question of why some people are more prone to having these experiences than others.

Naturally, when I came across psychedelic science a couple of years ago, this field also sparked my academic interest. Here was an opportunity to study people who had a psychedelic experience and who claimed to have had a glimpse of ultimate reality. I started to research psychedelic experiences at Leiden University and founded the PRSM lab – a group of scientists from different academic backgrounds who study psychedelic, religious, spiritual and mystical experiences.

Initially, I was enthusiastic about the mind-transforming potential of psychedelics. These substances, when administered correctly, appear to be capable of enhancing people’s mental and physical wellbeing. They also increase feelings of connectedness to and concern for the environment.

Psychedelic therapy appeared to offer great potential for treating a wide variety of disorders, including depression, anxiety, addiction and post-traumatic stress disorder. This enthusiasm about the potentially transformative effects of psychedelics was reflected in positive media attention on this topic over the past few years. Michael Pollan, an American author and journalist, has brought psychedelics to an audience of millions with his book and Netflix documentary.

However, my initial optimism about psychedelics and their potential has changed into scepticism about the science behind much of the media hype. This is due to a closer scrutiny of the empirical evidence. Yes, at face value it seems as if psychedelic therapy can cure mental disease. But on closer inspection, the story is not that straightforward.

The main reason? The empirical evidence for the efficacy of and the working mechanisms underlying psychedelic therapy is far from clear.

Two issues

I wrote a critical review paper with my colleague Eiko Fried in which we listed the problems with the current clinical trials on psychedelic therapy. The main concern is called the “breaking blind problem”. In psychedelic studies, patients easily figure out if they have been randomly assigned to the psychedelic or the placebo group, simply because of the profound mind-altering effects of psychedelic substances.

This breaking-of-the-blind can actually result in placebo effect in patients in the psychedelic group: they finally get the treatment they’d been hoping for and they start feeling better. But it can also result in frustration and disappointment in patients assigned to the control group. They were hoping to get a miracle cure but now find out they will have to spend six hours on a placebo pill with their therapist.

As a consequence, any difference in therapeutic outcomes between the psychedelic and the placebo group is largely driven by these placebo and nocebo effects. (A nocebo effect is when a harmless treatment causes side-effects or worsening of symptoms because the person believes they may occur or expects them to occur.)

Knowing who received what also affects the therapists, who may be motivated to get more out of the therapy session if their patient got the “real deal”. And this problem is impossible to control for in so-called randomised controlled trials – still the gold standard in evaluating the effectiveness of drugs and treatments.

Also, non-clinical research on psychedelics faces problems. You may recall the graphic of a brain on psilocybin compared to one on a placebo (see below). Psilocybin increases the connections between different brain areas, which is represented in a colourful array of connecting lines.

This has become known as the “entropic brain hypothesis”. Psychedelics make your brain more flexible such that it returns to a child-like state of openness, novelty and surprise. This mechanism in turn has been hypothesised to underlie psychedelic therapy’s efficacy: by “liberating your brain” psychedelics can change entrenched and maladaptive patterns and behaviour. However, it turns out the picture is much more complicated than that.

Psychedelics constrict the blood vessels in your body and brain and this causes problems in the measurement of brain signals with MRI machines.

The graphic of the entropic brain may simply reflect the fact that the blood flow in the brain is dramatically altered under psilocybin. Also, it is far from clear what entropy exactly means – let alone how it can be measured in the brain.

A recent psilocybin study, which is yet to be peer-reviewed, found that only four out of 12 entropy measures could be replicated, casting further doubt on how applicable this mechanism of action is.

Although the story about psychedelics freeing your mind is compelling, it does not yet square well with the available empirical evidence.

These are just two examples that illustrate why it is important to be really cautious when you evaluate empirical studies in psychedelic science. Don’t trust findings at face value, but ask yourself the question: is the story too good or too simple to be true?

Personally, I have developed a healthy dose of scepticism when it comes to psychedelic science. I am still intrigued by psychedelics’ potential. They offer great tools for studying changes in consciousness. However, it is too early to conclude anything definite about their working mechanisms or their therapeutic potential. For this, we need more research. And I’m excited to contribute to that endeavour.

Michiel van Elk, Associate Professor, Cognitive Psychology, Leiden University

This article is republished from The Conversation under a Creative Commons license.

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Receptor Location is Key when Rebuilding Neural Connections with Psychedelic Drugs

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When using psychedelic drugs to treat mental illness, it’s all down to location when rapidly rebuilding connections between nerve cells. In their paper published in Science, scientists show that engaging serotonin 2A receptors inside neurons promotes growth of new connections – but engaging the same receptor on the surface of nerve cells does not.

The findings will help guide efforts to discover new drugs for depression, PTSD and other disorders, according to senior author David E. Olson, associate professor at the University of California, Davis.

Drugs such as LSD, MDMA and psilocybin show great promise for treating a wide range of mental disorders that are characterised by a loss of neural connections. In laboratory studies, a single dose of these drugs can cause rapid growth of new dendrites from nerve cells, and formation of new spines on those dendrites.

Olson calls this group of drugs “psychoplastogens” because of their ability to regrow and remodel connections in the brain.

Earlier work from Olson’s and other labs showed that psychedelic drugs work by engaging the serotonin 2A receptor (5-HT2AR). But other drugs that engage the same receptor, including serotonin, do not have the same growth effects.

Maxemiliano Vargas, a graduate student in Olson’s lab, Olson and colleagues experimented with chemically tweaking drugs and using transporters to make it easier or harder for compounds to slip across cell membranes. Serotonin itself is polar, meaning it dissolves well in water but does not easily cross the lipid membranes that surround cells. The psychedelics, on the other hand, are much less polar and can easily enter the interior of a cell.

They found that the growth-promoting ability of compounds was correlated with the ability to cross cell membranes.

Drug receptors are usually thought of as being located on the cell membrane, facing out. But the researchers found that in nerve cells, serotonin 2A receptors were concentrated inside cells, mostly around a structure called the Golgi body, with some receptors on the cell surface. Other types of signalling receptors in the same class were on the surface.

The results show that there is a location bias in how these drugs work, Olson said. Engaging the serotonin 2A receptor when it is inside a cell produces a different effect from triggering it when it is on the outside.

“It gives us deeper mechanistic insight into how the receptor promotes plasticity, and allows us to design better drugs,” Olson said.

Source: University of California – Davis

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Psychedelic Experiences and Near-death Experiences Reduce Fear

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Researchers comparing psychedelic experiences with near-death experiences that were not drug related found notable similarities in people’s attitudes toward death. In a survey-based study published in the journal PLOS ONE, participants in both groups reported having less fear of death and dying after the experience. They also reported that the experience had a lasting positive effect, providing personal meaning, spiritual significance and psychological insight.

The results are in line with a number of previous trials showing that a single treatment with the psychedelic psilocybin produced sustained decreases in anxiety and depression among patients with a life-threatening cancer diagnosis. The largest of these trials was conducted at Johns Hopkins Medicine by the researchers, and involved 51 patients with cancer with anxiety or depressive symptoms. It demonstrated that psilocybin with supportive psychotherapy resulted in significant increases in ratings of death acceptance, as well as decreases in anxiety about death.

For the present study, the researchers analysed data gathered from 3192 people who answered an online survey between December 2015 and April 2018. Of these, 933 individuals had non-drug near-death experiences, and the rest of the participants had psychedelic experiences due to either lysergic acid diethylamide (LSD) (904), psilocybin (766), ayahuasca (282) or N,N-dimethyltryptamine (DMT) (307). Compared with the non-drug group, there were more men in the psychedelic group (78% versus 32%), and they tended to be younger (32 versus 55 years of age) at the time of the experience.

Similarities between the groups include:

  • About 90% of participants in both groups reported a decrease in fear of death when considering changes in their views from before to after the experience.
  • Most participants in both groups (non-drug group, 85%; psychedelics group, 75%) rated the experience to be among the top five most personally meaningful and spiritually significant of their life.
  • Participants in both groups reported moderate to strong persisting positive changes in personal well-being and life purpose and meaning.

Differences between the groups include:

  • The non-drug group was more likely to report that their life was in danger (47% versus the psychedelics group, 3%), being medically unconscious (36% versus the psychedelics group, 10%), or being clinically dead (21% versus the psychedelics group, less than 1%).
  • The non-drug group was more likely to report that their experience was very brief, lasting five minutes or less (40% versus the psychedelics group, 7%).

The researchers say that future studies are needed to better understand the potential clinical use of psychedelics in alleviating suffering related to fear of death.

Source: John Hopkins Medicine

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Psychedelic Treatments for Mental Illness a Step Closer

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To find better solutions to mental illness, a Virginia Tech researcher has found that long-banned psychedelic drugs can treat several forms of mental illness and, in mice, have achieved long-lasting results from just one dose.

Using a process his lab developed in 2015, Professor Chang Lu is helping his collaborators study the epigenomic effects of serotonergic hallucinogens, commonly known as psychedelics.

Their findings, published in Cell Reports, give insight into how psychedelic substances like psilocybin, mescaline, LSD, and similar drugs may relieve symptoms of addiction, anxiety, depression, and post-traumatic stress disorder. The drugs seem to work faster and last longer than current medications, all with fewer side effects.

Prof Lu’s genomic analysis allows researchers to use very small samples of tissue, down to hundreds to thousands of cells, and draw meaningful conclusions from them. Older processes require much larger sample sizes, so Prof Lu’s approach enables the studies using just a small quantity of material from a specific region of a mouse brain.

And looking at the effects of psychedelics on brain tissues is especially important.

While researchers can do human clinical trials with them, taking blood and urine samples and observing behaviours, Prof Lu said. “But the thing is, the behavioural data will tell you the result, but it doesn’t tell you why it works in a certain way,” he said.

But looking at molecular changes in animal models, such as the brains of mice, allows scientists to peer into what Prof Lu calls the black box of neuroscience to understand the biological processes at work. While the brains of mice are very different from human brains, Prof Lu said there are enough similarities to make valid comparisons between the two.

VCU pharmacologist Javier González-Maeso has made a career of studying psychedelics, which had previously been banned since the 1960s.
Other research, primarily on psilocybin, a substance found in more than 200 species of fungi, González-Maeso said psychedelics have shown promise in alleviating major depression and anxiety disorders. “They induce profound effects in perception,” he said. “But I was interested in how these drugs actually induce behavioral effects in mice.”

To explore the genomic basis of those effects, he teamed up with Prof Lu.

In the joint study, González-Maeso’s team used 2,5-dimethoxy-4-iodoamphetamine, or DOI, a drug similar to LSD, administering it to mice that had been trained to fear certain triggers. Prof Lu’s lab then analysed brain samples. They discovered that the epigenomic variations were generally more long-lasting than the changes in gene expression, thus more likely to link with the long-term effects of a psychedelic.

After one dose of DOI, the mice that had reacted to fear triggers no longer responded to them with anxious behaviours. Their brains also showed effects, even after the substance was no longer detectable in the tissues, Prof Lu said.

As well as the science, it’s personal for him too, saying: “My older brother has had schizophrenia for the last 30 years, basically. So I’ve always been intrigued by mental health,” Lu said. “And then once I found that our approach can be applied to look at processes like that – that’s why I decided to do research in the field of brain neuroscience.”

González-Maeso said research on psychedelics is still in its early stages, and there’s much work to be done before treatments derived from them could be widely available.

Source: Virginia Tech