Imperial College London



Under the influence of LSD, the brain's visual cortex has increased connectivity with other brain regions (right) than when imaged under placebo (left).
Researchers have published the first images showing the effects of LSD on the human brain, as part of a series of studies that are examining how the drug causes its characteristic hallucinogenic effects1.
David Nutt, a neuropsychopharmacologist at Imperial College London who has previously examined the neural effects of mind-altering drugs such as the hallucinogen psilocybin — an active ingredient in magic mushrooms — was one of the study's leaders. He tells Nature what the research revealed, and how LSD (lysergic acid diethylamide) might ultimately be useful in therapies.

Why study the effects of LSD on the brain?

For brain researchers, studying how psychedelic drugs such as LSD alter the ‘normal’ brain state is a way to study the biological phenomenon that is consciousness.

No link found between psychedelics and psychosis
We ultimately would also like to see LSD deployed as a therapeutic tool. The idea has old roots. In the 1950s and 1960s, thousands of people took LSD for alcoholism; in 2012, a retrospective analysis of some of these studies2 suggested that it helped to cut down on drinking. Since the 1970s, there have been lots of studies with LSD on animals, but not on the human brain. We need that data to validate the trial of this drug as a potential therapy for addiction or depression.

Why hasn’t anyone done brain scans before?

Before the 1960s, LSD was studied for its potential therapeutic uses, as were other hallucinogens. But the drug was heavily restricted in the United Kingdom, the United States and around the world after 1967 — in my view, due to unfounded hysteria over its potential dangers. The restrictions vary worldwide, but in general, countries have insisted that LSD has ‘no medical value’, making it tremendously difficult to work with.

Suzanne Plunkett/REUTERS
David Nutt.

How did you get approval to give volunteers LSD?

United Nations conventions and national laws do permit academic research on heavily restricted drugs such as LSD. In the United Kingdom, this sort of study is legal as long as the drug is not being used as a therapeutic. This was not a clinical trial: we gave LSD to volunteers who were already experienced with the drugs and took their brain scans over eight hours in the lab in Cardiff, UK, in 2014. It took us nine months to get approval from a UK ethics committee for the work: the research was funded by the Safra Foundation [a philanthropic foundation based in Geneva, Switzerland] and the Beckley Foundation [a charity near Oxford, UK, that promotes drug-policy reform], although we needed to crowdfund through Walacea.com for the resources to analyse the data.

What were the results of the study?

To take advantage of the “long trip” produced by LSD — an eight-hour experience, as compared to, say, four on psilocybin — we put our participants through a huge range of tests.
In one study in the Proceedings of the National Academy of Sciences, we looked at blood flow in different parts of the brain using functional magnetic resonance imaging (fMRI), and at electrical activity using magnetoencephalography1. We found that under LSD, as compared to placebo, disparate regions in the brain communicate with each other when they don’t normally do so. In particular, the visual cortex increases its communication with other areas of the brain, which helps to explain the vivid and complex hallucinations experienced under LSD, and the emotional flavour they can take.

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On the other hand, within some important brain networks, such as the neuronal networks that normally fire together when the brain is at rest, which is sometimes called the ‘default mode’ network, we saw reduced blood flow — something we’ve also seen with psilocybin — and that neurons that normally fire together lost synchronization. That correlated with our volunteers reporting a disintegration of their sense of self, or ego. This known effect is called ‘ego dissolution’: the sense that you are less a singular entity, and more melded with people and things around you. We showed that this could be experienced independently of the hallucinatory effects — the two don’t necessarily go together.

What else?

Among other studies, one of our team, Mendel Kaelen, a PhD student at Imperial College London, has a paper which will appear next week in European Neuropsychopharmacology3 looking at how listening to music affects the experience of taking LSD. He found that communication between the parahippocampus [a brain region important in memory storage] and the visual cortex [which processes information input from the eyes] is reduced when you take LSD. But when you hear music as well, the visual cortex receives more information from the parahippocampus, and this is associated with increases in ‘eyes-closed’ imagery and personal memories. So music enhances the LSD experience and might be important in therapeutic settings.
Another study, to be published in Current Biology4 and led by Robin Carhart-Harris of Imperial, looks at how ego dissolution correlates with an increase in global connectivity — all the parts of the brain communicating with each other to a greater degree.

With only 20 participants — and only 15 quality data points because 5 people moved too much inside the brain scanner — how confident can you be in your findings?

We got very clear and significant effects — and they were consistent with the data from previous studies with psilocybin4, although the effects with LSD were much stronger.

Are other scientists working with LSD?

We think there is only one other group in the world currently working with LSD in humans. They are based at the University of Zurich in Switzerland, led by Franz Vollenweider. They seem to be focusing on using antagonists [which block LSD and its effects] to clarify the pharmacological targets of LSD. They have done their own fMRI scans, but taken during psychological tasks, rather than when the brain is at rest, as we did. Their results haven’t been published yet, so I can’t comment on their findings.

What studies will you do next?

We have plans to do separate experiments to look at how LSD can influence creativity, and how the LSD state mimics the dream state.

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More importantly, we have already completed a trial on psilocybin as a therapy for treatment-resistant depression funded by the UK Medical Research Council: not as a daily drug, but in targeted psychotherapeutic sessions. Results will be presented next month. The basic argument for this is that we know that the default-mode network is overactive in people who are depressed, and we know from our earlier study5 that psilocybin reduces how integrated that network is — at least during the ‘trip’ itself.
Our latest brain-imaging study suggests that LSD has similar effects — suggesting that it could be trialled therapeutically, too.