If taking microdoses of LSD enables more sleep while improving your mood and energy, could it transform the market for treating depression?
This is the key question researchers are diving into following a phase-one trial by Auckland University’s Faculty of Medical and Health Sciences that showed people who had taken microdoses of the substance slept 24 minutes longer than those who didn’t.
This followed earlier findings where those who had microdosed for a period of six weeks reported improved mood, less irritability, and increased energy, creativity and connectedness, with minimal safety issues.
The implications are potentially huge: more than half a million New Zealanders take some form of antidepressant, many of which are not conducive to good sleep.
The hypothesis, which further trials will test, is that these changes placed a heavier burden on the mind and body, leading to a need to sleep for longer.
“We can’t say that with any certainty, but it’s very suggestive,” project lead Associate Professor Dr Suresh Muthukumaraswamy told the Herald.
“It was also totally unexpected, and nothing had ever been reported in the literature. The participants weren’t expecting to sleep more.”
Those participants in phase one didn’t have any health issues, but for the phase-two trial - pending Medsafe approval - Muthukumaraswamy’s team will study the effect microdosing LSD has on people with moderate depression.
This is hoped to be the next step into the big-picture question of whether microdosing could be an effective, safe and relatively cheap antidepressant - as well as one that doesn’t hinder sleep, which is vital for restoring connections in the brain.
“It’s a period of time in your daily cycle where you consolidate information, and your brain kind of sorts through the junk,” Muthukumaraswamy says.
“Sleep problems are really common in patients with depression, and ironically enough, a lot of antidepressants on the market disrupt sleep even more. Our results suggest that they’re getting a bit more of an opportunity to sleep, so here we have something that is maybe working quite differently.”
Microdosing LSD as a viable and legal antidepressant is still at least five years away, he says, if all the hurdles are cleared.
Those include getting approval for the phase-two trial, having effective results including a good safety profile, and then replicating those results again for a much larger phase-three trial - the final step before approval as a medicine.
But results so far have been encouraging.
Phase two is also hoped to shed light on an unsolved mystery from phase one: why did the additional sleep happen not on the night after taking the dose, but on the following night?
The sleep factor has emerged from crunching the data from the phase-one randomised-control trial in Auckland, one of the first of its kind in the world, which finished in April last year.
There were 80 healthy participants, all men aged 25 to 56. Half of them took 10 micrograms of LSD - about a tenth of what is considered a full dose - every third morning for six weeks, while the other half took a placebo. After an initial dose in the lab, they spent the rest of the time going about their normal lives while also doing a daily questionnaire about how they felt, and wearing Fitbits to track physical activity and sleep.
According to the first academic paper, published in the Biological Psychiatry journal, the microdose was “associated with improvements in ratings of connectedness, creativity, energy, happiness, irritability and wellness on dosing days”.
These improvements were transient, however, rather than enduring beyond the trial period. Muthukumaraswamy says the healthy participants might be closer to a ceiling, whereas those with moderate depression might have more room for lasting cognitive improvements.
They also weren’t universal. Four people reported feelings of overstimulation that “led to experiences of anxiety when combined with stressful life events” and withdrew from the trial. Three others had mild anxiety, but continued the trial with a lower dose.
The paper’s conclusion: “Microdosing LSD appears relatively safe in a healthy male volunteer population and may be a viable mental health treatment, but caution should be applied to untested claims of its benefits and safety in clinical populations.”
The mood improvements were self-reported, however, which Muthukumaraswamy concedes isn’t the most reliable measurement. This is where the extra sleep potentially becomes an important factor.
“Just asking people on a scale what the difference feels like is not the most objective measure,” he says. “But sleep is a very objective biomarker, which makes us more confident that it’s not some sort of placebo response.”
The researchers’ second paper, yet to be peer-reviewed, says those who were microdosing went to bed earlier on the following night, and then rose in the morning at the same time they usually did - sleeping an extra 24.3 minutes in total, including extra eight minutes of REM sleep.
Muthukumaraswamy says this is not only statistically significant, but “clinically meaningful”.
“Very often when you do a study, you might find a statistically significant result where ‘this’ didn’t happen by chance, but the size of the effect is quite small - like 1000 people in a study and a two-minute difference in sleep time.
“So that’s not necessarily clinically significant. But if you were trialling a sleeping pill and the results showed a 24-minute difference, that’s enough to say that it’s showing you something.”
The Fitbits across the groups didn’t show any “detectable differences” in physical activity, though the microdosers mentioned that they felt “marginally more tired” the day after dosing.
“Definitely post-dosage, I could definitely feel a low, and I just felt more tired, as if the dosing consumed a higher level of energy than normal,” says one anonymous participant quoted in the researchers’ paper. “I definitely noticed extra fatigue for sure ... I would notice it the next morning.”
Says another: “I had like huge rushes of energy ... I found myself staying up later than I kind of wanted to. But equally, I didn’t feel overly unrested the next day ... I didn’t feel overly tired.”
But there was no explicit mention of needing more sleep or going to bed earlier. Whatever was happening appeared to be happening subconsciously.
“Modifications to sleep may be a factor that contributes to that effect [of improvements in symptoms of depression],” the paper continues. “Speculatively, a candidate therapeutic mechanism by which microdosing LSD might improve mood is by restoring sleep and promoting accompanying synaptic plasticity.”
What Muthukumaraswamy hopes to examine further in phase two is why the extra sleep happened on the following night, not the night after they’d taken the microdose that morning.
“It’s puzzling. You might think the extra sleep requirement is because of a busy day, but that’s not what’s happened. It seems to be the next day, and we’re not really sure why.”
He speculates the participants woke up at set times every morning, without which they might have woken up later on the morning after dosing.
“And then on the next night, they still need a bit more sleep so they go to bed earlier, and then still wake up at the same set time the following morning when the alarm goes off. That might be what’s going on. We just didn’t collect the data to know about that.”
It will be something they want to collect data on for phase two, now that they know it’s something to monitor.
Why LSD can improve mood and increase energy and connectedness is still unclear, but it is thought to do with an increase in neural plasticity. A brain that’s more changeable, with different networks talking to each other more, might more easily free someone from deeply entrenched and habitual ways of thinking - such as the kind of rumination trough that can lead to depression.
Muthukumaraswamy’s team is still processing data from phase one, including blood-based biomarkers and the results of electroencephalograph (EEG) tests, which measure electrical activity in the brain.
“We’ve got some initial results starting to come out, and it looks like it’s definitely doing something in the brain, making changes in there,” he says. “But I don’t have the full story on that yet.”
The potential for psychedelic medicine has been investigated for decades, but came to a screeching halt with the moral panic that saw the substance made illegal in the late 1960s.
There has since been a revival, with Australia leading the way. As of this month, psychiatrists can prescribe MDMA (also known as party drug Ecstasy) for post-traumatic stress disorder and psilocybin (the active ingredient in magic mushrooms) for some types of depression.
Clinical trials are also well under way in parts of the US and Canada, but the bulk of research into LSD has involved taking a full dose in a prescribed setting with a therapist. The cost of such treatments is estimated in the tens of thousands, most of which would be for the therapist.
Microdosing, though, would cost a fraction of that.
“That’s what we’re aiming for,” says Muthukumaraswamy. “The financial implications aren’t entirely clear to me, but the drug can be manufactured at scale relatively cheaply. There’ll be the recovery of research costs and profits and that sort of stuff, but you’re talking far, far less money.”
There would also be the costs of a mobile phone app, which aims to maximise whatever therapeutic properties microdosing has.
“In phase one, people reported that they got more enjoyment out of things, like playing with their children or going for a walk in the park, or doing some hobby. So we developed this app where they’re asked to do particular things that might be psychotherapeutically beneficial,” Muthukumaraswamy says.
“One of the problems in depression is often what we call anhedonia, where people just don’t enjoy things as much, and they don’t get as much fulfilment out of things that they might otherwise enjoy. Potentially, what we’re trying to do is to stimulate breaking out of some of that anhedonia.”
It’s still a big ‘if’, but if the treatment ends up being cheap enough, it could benefit hundreds of thousands of New Zealanders; according to Pharmac, more than half a million people were prescribed some form of antidepressant in 2020.
Why could LSD microdoses be a more appealing alternative?
Antidepressants have side effects which are often experienced every day because they typically need to be taken every day; LSD microdoses can also have side effects, but usually only on dose days, though there remains very little research about any long-term adverse health effects - if any.
And then there’s the sleep factor.
“Most antidepressants actually suppress REM sleep, and first-line treatments for depression such as SSRIs [selective serotonin reuptake inhibitors] can actually decrease sleep continuity, leading to increased levels of insomnia,” the researchers’ paper says.
“The potential use of microdosed LSD as an antidepressant may have very different effects on sleep and therapeutic effects in patients with depression than standard antidepressants.”
There’s still a long way to go, five to 10 years according to Muthukumaraswamy, before LSD could be signed off as an antidepressant.
“We were thrilled by the results from phase one,” he says. “It was more than we were expecting to happen.”
“Pending approval, we might be finishing this phase-two trial at the end of 2024 or the start of 2025. Then we’ll kind of know whether this has got legs. Of course, it might not work at all. That’s why we do the trial.”
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Derek Cheng is a senior journalist who first started at the Herald in 2004. He has worked several stints in the press gallery and is a former deputy political editor.
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