Have you ever really looked at your hands?

I mean, like, really looked at them? [voice pitch dropping] First of all, they are huge, and your fingers only bend one way! [normal voice] At Woodstock in 1969, people made these kinds of revolutionary discoveries and more… aided by the psychedelic drugs they were taking, like LSD. But—seriously—drugs like LSD have also been the basis of some more rigorous research, too.

After some initial research into the drug, it was banned in the 1960s. But today, under careful regulation, some scientists have been trying to figure out how it works and whether it might have a medical benefit. [INTRO♪]. A Swiss chemist named Albert Hofmann created lysergic acid diethylamide, or LSD, in 1938.

He had been reacting different chemicals with lysergic acid, a derivative of a family of fungus called ergot. He hoped to find a compound that could be a heart and respiration stimulant. What he discovered in 1943, after getting some LSD on his fingertips by accident, is that it makes you hallucinate... [voice pitch dropping:] a lot.

He described a dream-like state in which he saw fantastic images and colors. And, today, we can kind of explain what was going on. Mostly, LSD was interacting with several kinds of serotonin receptors in Hofmann's brain.

Serotonin is one of the feel-good neurotransmitters involved in regulation of sleep and wakefulness, so it might have been responsible for the relaxed, dream-like state he described. The 5-HT2A receptor specifically seems to be associated with the psychedelic effects. We think LSD also interacts with a bunch of other receptors in the brain, including dopamine receptors.

Dopamine is thought of as a feel-good neurotransmitter, too, and it's involved in processes of reward and addiction, among lots of other things. Specifically, LSD interacts with D2 dopamine receptors, which are found in different parts of the brain and serve different functions than you might expect. Too little stimulation of these receptors and people have mobility problems, like in Parkinson's disease.

And too much stimulation of these receptors is linked with hallucinations, like in patients with schizophrenia... and, well, people taking LSD. Despite interacting with a lot of different parts of the brain,. LSD doesn't seem to cause symptoms of addiction, although we haven't entirely figured out why.

So after its discovery, researchers were looking into whether LSD could treat mild mental illnesses and addiction to alcohol. Oh! [opening of Star Spangled Banner on electric guitar] And lots of people started taking it at music festivals and stuff for fun. Even though some scientists were optimistic that it could be useful as a medical treatment, and it was widely studied in the the 1950s and 60s, research didn't really pan out.

Some people suffered anxiety, stress, or panic attacks after taking LSD. And other scientists feared it could be toxic, leading to coma or bleeding, particularly at high doses. So for a lot of reasons, in the US and most of the world,.

LSD was made illegal in the 1960s. And since then, very little research has been done. Lately, because we have a deeper understanding of neuroscience, some researchers have ventured back into testing LSD— to figure out possible harms or benefits.

But not without some clear safeguards. For example, scientists testing psychedelic drugs in the US need to be licensed by the DEA, which can require them to measure the stored drugs daily, by two people, to prevent theft. And their experiments have to be carefully designed and reviewed by committees.

Through these experiments, we've found some evidence that LSD could potentially be a useful treatment. One of the most promising areas is for alcohol addiction. In a meta-analysis published in 2012, 6 randomized trials had been done on a total of 536 alcoholic patients.

These experiments tested whether a dose of about 500 micrograms of LSD would improve their symptoms. And across all the studies, the LSD treatment reduced the reported misuse of alcohol, often up to months later. It definitely wasn't a cure-all— the researchers estimated that for every 6 patients treated, 1 would see the benefit.

But that isn't nothing. Another study, published in 2014, tested to see if the drug could benefit patients with anxiety. Specifically, people seeking therapy for anxiety because they had a life-threatening disease.

It was a very small sample of only 12 patients, but those who received a dose of about 200 micrograms of LSD wound up reporting much less anxiety 2 months later than those in the control group. And that tentative positive effect for mood disorders was also supported by findings from a 2016 meta-analysis. These researchers reviewed 151 clinical trials on LSD and other hallucinogenic drugs, and honed in on 6 studies.

It's worth noting that the control groups in most of these studies got LSD too— just a smaller dose of around 20-50 micrograms, which is less noticeable. And this was to make the studies double-blind. Like, if you sign up for a study of LSD, you'll probably notice if you take a treatment and don't feel anything.

So, this way, researchers can try to make sure any effects are because of the difference in dose size, and not because someone could tell they were in a placebo group. There's also very new research into an idea called microdosing— taking an even smaller dose of about 10 micrograms. That's about a tenth of what you'd find on a recreational paper tab of LSD— although, those doses can vary too.

Very little research has been done on microdosing. A paper published in February 2018 said they didn't find other research on the subject. Those scientists interviewed 21 people who reported that when they take microdoses of LSD, they feel things like improved mood, energy, and creativity, or reduced anxiety or depression— all without the hallucinations or other side effects.

Of course, it's important to note that those are just personal stories— there was no controlled experiments, no placebo control group, and no randomization. So it's also possible that taking too little to hallucinate might also be taking too little to... really do anything. Other experiments have used fMRIs to understand more about how the drug affects our brains.

In one 2016 study, 20 participants were injected with either 75 micrograms of LSD or saline as a control, and then had their functional connectivity measured. Basically, that's looking at the brain and seeing which regions activate at the same time. For example, one network you often see in this kind of analysis is called the default mode network.

It seems to be active when people are daydreaming, or accessing autobiographical memories. But in the subjects that got LSD, researchers didn't see this network emerge clearly in fMRI data. Instead, they saw more global connectivity across the brain.

The scientists predicted that this effect might be related to the experience of ego dissolution that reportedly comes with taking the drug. Basically, this is someone feeling less like they're a separate individual from everyone and everything else. And in fact, that change in functional connectivity was correlated with whether the subjects reported feeling more ego dissolution.

A similar 2016 study looked at 20 subjects who also were given an injection of 75 micrograms of LSD or a placebo and hopped in an fMRI machine. But in this one, they did multiple types of imaging and subjects filled out a questionnaire about hallucinating during the experience. Like the other experiment, researchers found more functional connectivity between the primary visual cortex and other brain regions— and that was also correlated with how much participants reported hallucinating.

Besides giving insight into how LSD affects us, these studies can also reveal how hallucinations generally work in the brain— for instance, to help scientists better understand patients with schizophrenia. So nowadays we know a little bit more about this drug, but there is a long way to go before we can say whether or not it's a useful treatment for things like anxiety or alcohol addiction. But with more careful, regulated experiments, we'll hopefully keep learning more.

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