Dr Suresh Muthukumaraswamy was quite prepared for his proposed trial of LSD microdosing to show … nothing much.
At the time, five years ago, there was plenty of cultural chatter about the potential benefits of “subperceptual” doses of LSD and other psychedelic drugs. Some Silicon Valley start-ups even ordained “microdosing Fridays” to boost their employees’ creativity and intellectual vigour. But there was no robust evidence the effect was real. “It could,” he mused back then, “just be homeopathy.”
The microdosing trial at the University of Auckland School of Pharmacy, where Muthukumaraswamy is an associate professor, has now published its first academic article (there are seven more to come) in the journal Biological Psychiatry.
So, was it homeopathy? “We can certainly say that microdosing LSD is not homeopathy,” he says. “We can be sure of that now.”
He adds, “To some extent, the science has borne out the anecdotal wisdom.” The journal article reports the trial showed “improved ratings of creativity, connectedness, energy, happiness, irritability and wellness on dose days” for the LSD group. The effects were sufficient to “suggest the potential for microdosing to counteract anhedonic states in clinical populations by restoring enjoyment in creative and social activities”. That translates as there was evidence microdosing could help address a key symptom of clinical depression: the inability to enjoy life.
The finding could have important implications for the management and treatment of depression. The official wellbeing indicators show 11% of New Zealanders experienced “high or very high levels of psychological distress” in the 2021-22 year, nearly three times the number reported a decade ago. Increasingly, the default health intervention is to prescribe antidepressants, usually SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine. According to Pharmac, 673,155 people were prescribed some form of antidepressant in 2022, at a cost to the agency’s budget of $10.7 million.
On one level, it’s a good thing that people are seeking help – and not all of those prescriptions are actually for anxiety or depression. But SSRIs are not risk-free, and even those who find the side effects intolerable may experience real difficulty withdrawing from them.
The promise of psychedelic therapy is long-term benefits from only one or two doses. But the “therapy” part is expensive. In the US, the Multidisciplinary Association for Psychedelic Studies is approaching approval for a protocol to treat post-traumatic stress patients with the controlled drug MDMA. More than 90% of the treatment cost is the time of human therapists. It could cost about $20,000 to deliver to one patient here – in which case, Pharmac’s 2022 bill for antidepressants for 670,000 people would fund 535 psychedelic therapy interventions.
Making microdosing work could help solve that problem. In the Auckland trial, half of a group of 80 healthy volunteers took 10 micrograms of LSD – about a 10th of the dose at which someone would experience appreciable psychedelic effects – and half took a placebo every three days for six weeks. After an initial microdose in the lab, the volunteers took their doses at home and went about their usual lives (though they weren’t allowed to drive cars).
In interview responses provided to the Listener, one participant reported feeling “renewed appreciation for more simple things like catching sunrises and sunsets”, and another felt “a bit more in tune with the kids and what was important for them”. In general, they liked doing the things they already liked, just more.
Not everyone felt the same way. Seven of the LSD group reported mild anxiety and four were consequently withdrawn from the trial. “In each discontinuation case,” the authors of the paper wrote, “participants had a feeling of overstimulation that led to experiences of anxiety when combined with stressful life events.”
The dropouts were offered counselling for two weeks and none suffered any lasting adverse effects. The other three had their doses reduced to levels not previously suspected to be psychoactive and happily carried on.
“There are other microdosing studies out there that have just microdosed people in the lab, and they haven’t seen huge effects,” says Muthukumaraswamy. “We think it’s probably just because there’s no stimulation to drive you either way. That’s probably not a great ecological test of what is actually happening when people are microdosing in the community. I think our paper starts to get into that.”
Robin Murphy, who is working on the trial as a PhD candidate, admits they came into it as a sceptic after reading the existing literature. “Really, not a lot had been found that you could hang your hat on. I think what’s exciting about our study is that we were able to show very strong statistics that people do feel differently on [dosing] day. We did quite robust statistics, we really had a high threshold to say that there was something there – and it survived those really high thresholds.”
Was microdosing LSD the productivity panacea hailed by some in Silicon Valley? Yes and no. “It seemed that if people were enjoying what they did, then for some people, they could just drop into a bit of focus and flow and get really absorbed in that task,” says Murphy. “But if it was a boring task, or a difficult task that was not interesting, those kinds of things could become harder. It threw a bit of cold water on this tech industry idea that it’s going to make everyone productive super-workers.”
Murphy is still compiling data from other tests, including blood-based biomarkers and creativity tasks set before, during and after the trial. Auckland’s Covid lockdown meant planned MRI imaging was too difficult to organise, but the team did conduct electroencephalograph (EEG) tests, which measure electrical activity in the brain.
“We’re definitely seeing effects in the brain that indicate that not only is it in the blood, but also we can actually see measurable effects in people’s EEG – consistent, measurable effects,” says Muthukumara-swamy. “So again, that’s not consistent with the homeopathy effect – it might be a placebo, but it’s not homeopathy.”
Brain ‘reset’ effect
The Auckland study comes amid a global renaissance of interest in psychedelic medicine in which Muthukumaraswamy himself has played a role. After earning his PhD in psychology in Auckland in 2014, he joined the newly established Cardiff University Brain Research Imaging Centre as a post-doctoral fellow. That brought him into the orbit of Professor Robin Carhart-Harris, head of the Centre for Psychedelic Research at Imperial College London and one of the key figures of the new science of psychedelics.
Muthukumaraswamy did the MRI imaging for the Imperial College studies that helped establish that the full psychedelic experience is reflected in dramatic changes in brain activity. Neuroplasticity – the ability of the brain to change and adapt in response to experiences – is increased. Parts of the brain that don’t usually communicate with each other engage in “crosstalk” at the same time as activity in a set of structures in the brain called the default mode network significantly decreases.
This network can be thought of as the repository of assumptions about the self and the world that establish order and let adults get through their day (it’s much less active in young children). But it’s also associated with excess rumination (associated with depression) and repetitive behaviours( addiction). It may be that psychedelics allow this network to reset and correct its functional abnormalities. (Meditation and even electroconvulsive therapy may have similar effects.)
Some of the clinical research since has been spectacular. In 2020, for example, a randomised clinical trial at Johns Hopkins Medical Hospital reported “large, rapid, and sustained antidepressant effects in patients with major depressive disorder” who had been given psilocybin, the active ingredient in magic mushrooms. But nearly all of it has focused on full doses and consequent full psychedelic experiences.
Less attention has been paid to microdosing, in part because no one, until now, has been able to make it work. The Auckland researchers have not only been able to demonstrate potentially beneficial effects, but also they’ve established a good safety profile, which is the primary purpose of a phase-one trial.
While the phase-one data is compiled, Muthukumaraswamy is preparing the next step – a phase-two trial with a clinical population. “We’re recruiting patients with major depressive disorder, but not treatment-resistant depression or ones with complex comorbidities; [we’re seeking] patients who are less likely to be in psychiatric care.”
The first round with healthy volunteers offered a key lesson about incorporating feedback from participants. “In setting up this next phase, we actually convened a patient panel. We had about 100 people come in for an open community night. We asked them some questions, we told them what we were planning and they asked us questions. And then we actually had a panel of about 10 patients coming in and helping us make some design decisions. So, we’ve been talking to the patients about what they would like and how they think the trial should run.”
That process will continue through a pilot phase that will probably begin next month and could last as long as a year.
Benefits on mood
There are caveats. Notwithstanding the benefits recorded on dosing days in phase one, the microdosing team did not find significant cognitive improvements after the six weeks had ended.
“They’re really well-functioning people, so they are at a ceiling, right?”, Muthukumaraswamy says. “The chances you can get lasting cognitive improvements from almost any intervention in these people are just vanishingly small. But we observed effects that are consistent with an anti-anhedonic profile – having more energy, more motivation, feeling good, feeling connected to things. Those are the things that are lacking in anhedonic depression. If you have depression, you might have more room to move in those scales.”
His hope is that the lighter touch of microdosing might mean more accessible therapy. “We’re not going to do [the depression trial] completely unguided. We’re using a mobile phone app for volunteers and light psychotherapeutic intervention will be delivered via their phones. That might not work, but that would mean that intervention itself will be very low cost, because it’s just the drug substance and installing a phone app.
“The ideal scenario is people come in, they do a microdosing course, they stop taking it, they’re not depressed any more and life goes on.”
There are both ethical and scientific questions to be worked through. Many overseas trials have required participants to go off their conventional depression medication –something most depression patients don’t want to do, says Muthukumaraswamy.
“It’s actually a really difficult design decision. You might think on the surface, oh well, we just withdraw everybody. But actually, all the evidence is that it takes maybe three months to withdraw from an antidepressant properly. And even then, you might be destabilised.”
Like the first phase, the second trial will be placebo-controlled. Which is one thing for healthy volunteers, another for people with clinical depression. No one who needs help wants the placebo. One option, says Muthukumaraswamy, is to run an open-label extension after the trial concludes, where the drug is available to everyone.
The microdosing research is being funded by the Health Research Council, wealthy American podcaster Tim Ferriss, and MindBio Therapeutics, an Australian start-up that has an agreement with the university to develop medicines for approval and run the hugely expensive phase-three trials required for that to happen. MindBio is already touting the results of the Auckland trial on its website.
At the end of it all, there are, potentially, medicines. How and to whom they would be delivered isn’t clear yet. Muthukumaraswamy says the safety profile of psychedelics, especially in microdoses, appears to be better than that of conventional antidepressants. Good enough, potentially, to let them be sold over the counter.
“Maybe in 10 years, you can get microdoses as a medicine – or maybe just as a substance that you can buy in a more regulated environment.
“That’s what should be happening in liberal and democratic societies. Because we know that these substances come with risks, but they’re not that harmful. They’re not more harmful than alcohol.”
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