Associate Professor Dr Suresh Muthukumaraswamy is the lead researcher for a phase two trial looking to treat people with moderate depression with microdoses of LSD. Photo / Supplied
It can supposedly jolt you into a spurt of productivity, or just improve your mood. But can taking tiny doses of LSD for a couple of months lead to depression melting away?
The answer, based so far on countless anecdotal reports, is possibly, or even probably. But there's a dearth of clinically robust data to support this.
That is now changing, and New Zealand is leading the charge.
The Health Research Council (HRC) has just approved a $1.44 million dollar grant, over three years, to Auckland University's Faculty of Medical and Health Sciences for a phase two trial treating depression with microdoses of LSD.
It follows a phase one trial, completed in April this year, where 80 healthy Auckland men aged between 25 and 60 took 10 micrograms of LSD - a 10th of what's considered a full dose - every three days over a six-week period.
Much of that data is still being crunched, but it showed that a trial was not only feasible, but also relatively safe, prompting an application for funding for the phase two trial.
Phase two is now scheduled to begin early next year and, according to project lead Associate Professor Dr Suresh Muthukumaraswamy, it will also be one of the first of its kind in the world.
His work is already garnering enough attention to have the support of a global venture capital start-up, MindBio Therapeutics, which could fund a far more expensive phase three trial off the back of strong phase two results. Phase three is the final step before approval as a medicine.
But let's not get ahead of ourselves, Muthukumaraswamy told the Weekend Herald.
"The main question to unpack is: Does this work, will people be less depressed? It's the patients who're really important. They want to know if it works, and that's still a five-year question."
He's asking for those with moderate depression to get in touch (deptrial@auckland.ac.nz) so he can convene a panel of patients to provide insights into how phase two should run.
And while there is plenty of scientific interest and curiosity into why LSD - an illegal substance that still carries the weight of decades of social stigma - might help with depression or anxiety, this is of secondary importance.
"If it does work, how might it work?" Muthukumaraswamy asks.
"Honestly, no one in the literature has really nailed down the answer to that question. We think it works by improving neuroplasticity, but it's not definitive, and no one's ever run the clinical trials, let alone made the biological measurements to try to confirm those mechanisms."
The phase two trial could include brain and blood measurements before and after treatment to try to shed some light on that question.
"But I'm not so grandiose to say I'm going to solve it. We still have to answer the fundamental question: 'Does it even work?'" Muthukumaraswamy says.
The wave of clinical research into taking microdoses of psychedelics in certain settings could see some of them being approved as medicines in the near future - as soon as next year in the US, for example.
Earlier this year, the Australian Government gave more than $16 million to support seven clinical trials into the potential efficacy of treating mental health issues with psilocybin (the active ingredient in magic mushrooms), MDMA, DMT, and CBD.
But such a research surge has been lacking in microdosing, which is far from an actual "trip" and is, for most people, thought to be barely perceptible.
There are, however, countless anecdotal studies that indicate an increase in general wellbeing and cognition.
"Microdosers exhibited lower levels of depression, anxiety, and stress across gender," reported a study of 8700 self-selected and self-reporting people across 84 nations, 4050 of whom were microdosing. Most were taking psilocybin, but 11 per cent were taking LSD. The study was approved by the University of British Columbia behavioural research ethics board.
The results align with the experience of a Wellingtonian who spoke to the Weekend Herald on condition of anonymity about his LSD microdosing.
"I didn't really have a name for what I now think is anxiety. It was just a horrible feeling, and it would often lead to depression and feelings of hopelessness.
"I'd often attributed the feelings to external things that were happening, but after a few months of microdosing, I started realising that probably my brain was just going a bit off track. Microdosing allowed me to just get on with things."
He has never tried antidepressants, and has been microdosing "irregularly" over a few years because sometimes he forgets, and sometimes he feels fine for months.
"I still have bad times. My mind can be really good at convincing me that everything is terrible. I think doses twice weekly or even less frequently would be good."
There have also been a handful of controlled research trials into microdosing.
A study in 2020 looked at different levels of microdoses, and found that between five and 20 micrograms "enhances sustained attention" and "affects mood states in positive directions", but also increased anxiety and, at 20mcg, confusion.
And a 2020 review of the science and medical literature found 14 controlled experimental studies for microdosing LSD or psilocybin - with mixed views of the impact on depression.
"Findings show that both LSD (10–20mcg) and psilocybin (<1–3mg) have subtle (positive) effects on cognitive processes (time perception, convergent and divergent thinking) and brain regions involved in affective processes," the review found, but it also noted "increased anxiety and a cycling pattern of depressive and euphoric mood".
"Some of the reviewed studies showed subtle positive effects on cognitive and affective processes that are dysfunctional in depressed patients," the review said, noting that clinical microdosing trials in depressed patients are yet to take place.
"Low doses of psychedelics could play a role in depression by inducing some kind of cognitive flexibility, which might lead to decreased rumination."
The review called for the kind of placebo-controlled clinical trial in depressed people for which Muthukumaraswamy has just successfully received funding.
Phase two will have the same clinical standards as phase one, which provides greater confidence about the size and composition of the dose, when it's taken, and what effect it might have on, for example, mood and temperance.
Phase one results are still being processed, but Muthukumaraswamy says there are already suggestions of a positive effect, with relatively few negative effects.
"There was a sub-population of about 10 to 20 per cent that experienced over-stimulation to the dose, and a few people for whom it did derail their day," he says.
"We had to drop them out of the study or reduce their dose. We switched to doing titration halfway through the trial, and that seems to work.
"So when we move to phase two, instead of doing a fixed dose, we'll start with a lower dose and build up the dose over a few weeks to avoid that kind of overstimulation."
It would be extremely uncommon to have no adverse health effects at all, he adds.
"All drugs have adverse events. That's just what drugs do. People who microdose - adverse events only happen on the dose day, so you've got two out of three days where you're not actually going to have any adverse events."
That could indicate microdosing had a better safety profile than standard antidepressants, he says, which can subject the user to side-effects every day they're taken - which is every day.
The caveat is that the phase one trial was only six weeks.
"We don't have long-term safety data. We don't know what happens when you do it for a year. But reading the literature, the intent here wouldn't be people microdosing for the rest of their lives. It might just be a six- or eight-week course and then you stop, or you go into a once-a-week thing.
"This is purely speculation, but people who are microdosing out in the wild don't seem to microdose continuously. They tend to do it for a bit, get the benefits they want, and then they stop."
Muthukumaraswamy says his team will take 18 months to go through the phase one data relating to changes in cognition, creativity and brain function.
"Very informally - we haven't quantified it - but we did get reports back from people that felt increased social connectedness. They seem to enjoy their interactions with people or children more than otherwise."
There were also signs of a positive impact when plans were made on microdosing days, he says.
"We've got to get into this data more, but people seemed to get more out of it when they had a planned structure with what they would do on those days. That suggests that you probably don't want to just microdose and forget about it, but you actually want to have some kind of intention and plan."
There might be lessons there for how phase two should run.
"One of the things we'll be developing is a light intervention, rather than a drug-only therapy. Why not go running, or play with your kids? Such things might be therapeutically beneficial."
But then if a person feels better, is it the drug or is it the intervention?
"It's really complicated, and it's a different model to antidepressants. We're not just giving people a drug and sending them on their way. It's harnessing psychotherapeutic principles. It's not been done before.
"If we think that drugs like LSD and psilocybin work by enhancing behavioural flexibility and neuroplasticity and the ability to learn, then what are you learning during that window of time?
"Maybe we should actually provide the learning material for that window, rather than just letting it float free and leaving it to the winds of chance."
He's still teasing out the idea, and there are still hurdles to clear - approval from Health NZ, MedSafe, and the Ministry of Health's ethics committee - before phase two can even run.
"But maybe we have a small piloting phase where we test it out. Maybe it will be therapeutically beneficial. It's complicated to work out how to do, but this is our aim, before we start the trial next year, to build a kind of structure into it."
The details of phase two are still open for discussion with the right patients.
"We're hoping to set up a participant panel with questions around how we design it, how we implement it, and how we present it to patients," Muthukumaraswamy says.
"They're the ones living with these problems, so we're hoping to ask them what they think would be best, rather than us telling them what we think is best."
He's looking for people with moderate rather than severe depression.
"These will be patients who are probably being dealt with by GPs, people who are just struggling."
He doesn't want people who are already self-medicating with microdosing, but what about people who are already on antidepressants?
"That's a really difficult question. We've gone in with the idea that people won't be on antidepressants, but we'd like to put that to patients and see what they think."
It will be the second microdosing phase two trial that the HRC has funded; the first was $250,000 over three and a half years for LSD microdosing-assisted psychotherapy to help depression and anxiety in those with advanced-stage cancer.
The Government has shown no interest so far in supporting psychedelic medical research, which has raised questions about whether we might be left behind in a rapidly-evolving field of medicine.
But the HRC makes independent decisions and saw merit in Muthukumaraswamy's application, who is "tremendously grateful" for the funding.
And although microdosing is held up by some as a potential game-changer in the mental health space, Muthukumaraswamy says he will patiently wait for the data.
"There's a very real scenario where we find no sign of efficacy at all. And then we'd say you probably shouldn't be microdosing to self-medicate your depression.
"I never feel it's my job to try to second-guess what the outcome might be. My job is just to run the most rigorous clinical trial I can - and run it hopefully safely."
* Patients interested in the phase two trial should email deptrial@auckland.ac.nz
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