Miracles and medication The new science of psychedelic drugs
There is a renaissance in psychedelic drug use, but for science, not recreation,
Ascientist stands before a crowd in an Auckland pub with a microphone in his hand and asks them all a question. “Who’s had something to drink?” he asks. “Hands up. And who’s tripping? It’s a serious question.”
The scientist is Suresh Muthukumaraswamy, an associate professor in psychopharmacology at the University of Auckland. The event is called Raising the Bar, when the university sends some of its experts out into the world for a night.
This particular one was at the Birdcage Tavern in April. More than a few people would have had a drink or two. But tripping? No-one put their hands up.
It was an attentiongetting opening, but Muthukumaraswamy, who describes himself as someone who “gives people drugs and studies their brains”, was making a serious point about his controversial subject, the mind-altering substance
LSD.
The point is this. Having one or two social drinks is fine, but being blackout drunk is not so good. Perhaps LSD could be understood the same way. Perhaps a full-blown psychedelic trip is like being blind drunk. Perhaps we should be thinking about smaller amounts.
The word for this is microdosing, which became trendy first in Silicon Valley, based on a notion that a small amount of LSD can inspire creativity and original thinking.
Muthukumaraswamy has estimated that around 1000 people in New Zealand microdose regularly. But those people are conducting experiments on themselves. Muthukumaraswamy, who is running what he believes to be New Zealand’s first Class A psychedelic study, is doing it responsibly and legally.
The trial involves 80 participants. Those who are given LSD rather than a placebo get small amounts, just 10mg of the drug 14 times over six weeks, or on every third day. That amount would be about a tenth of a recreational LSD trip.
Rather than fullblown phantasmagoria, they would get barely a ripple. It’s called a sub-perceptual level.
The trial started in 2021 and, due to lockdowns, won’t be complete until 2022. The first dose was given in the lab, to check there weren’t unusual reactions, and then the volunteers were given the remaining doses to take home with them and use like any other medication.
Unlike some LSD research overseas, this is not about therapeutic use.
“This is looking at their wellbeing, their creativity, cognitive function and just how well they tolerate doing this.”
The trial is a first step, before he would try it on people with mood disorders and anxiety.
Was it hard to find participants? “People are volunteering,” Muthukumaraswamy says. “People are really generous with their time. We ask quite a lot of them, actually.”
A conversation with Muthukumaraswamy is surprisingly sober and straightforward, given the potentially lurid nature of the subject. Those three capital letters bring up all sorts of horror stories and past controversies, whether it’s images of 1960s LSD evangelists like Timothy Leary and Ken Kesey, or the CIA’s mind-control experiments.
There has been an enormous amount of interest globally over the past decade in what some see as the promise of previously stigmatised psychedelic and related substances. Not just LSD, but also psilocybin, which is the active compound in socalled magic mushrooms, ketamine and MDMA. Research demonstrates that, in controlled situations, these substances might cure depression, anxiety, post-traumatic stress disorder (PTSD), addiction and even the fear of death in terminal cancer patients.
But illegal drugs are also a hotbutton topic, which means that a lot of media hype accompanies these findings. Miracles are promised. It was only last month that Newsweek magazine put some wizened mushrooms on the cover and announced that psilocybin was the biggest thing since Prozac.
A new age of psychedelic evangelism could be imminent, and that worries scientists like Muthukumaraswamy.
“I’m not an evangelist at all,” he says. “I’m a data person. I think the field is in a dangerous position, where there’s a lot of people who want things to work. That shouldn’t be our job as scientists.
‘‘Our job should be to describe reality and to conduct experiments that test hypotheses. We are humans, so we are naturally biased, but we should try to minimise that as much as we possibly can.”
This is the renaissance of LSD research. Between 1943, when Swiss chemist Albert Hofmann first tried 250mg of the chemical he synthesised five years earlier, and around 1970, more than 1000 scientific papers were published on LSD. More than 20,000 patients sampled it.
Some of this research was promising. Senator Robert Kennedy defended it, reportedly because LSD helped treat his wife Ethel’s alcoholism. But the drug’s strong links to the civil unrest of the 1960s made legitimate research impossible.
That early research might provide some hints and pathways, Muthukumaraswamy says, but it lacks the rigour we expect now. And then the following 40 years of potential research was lost, “for political reasons”.
While in the UK, after getting his PhD at Auckland University, Muthukumaraswamy was working with David Nutt, a giant in the field. He initially worked “on some of the boring drugs that no-one cares about”, before moving on to one of the early psilocybin studies.
When he came back to New Zealand, he started working on ketamine, “because I could. It was relatively easy to get off the ground.”
The problematic history of LSD is a bigger hurdle to overcome. Was it easy to get this approved?
“The university has been pretty supportive,” Muthukumaraswamy says. “It takes a bit of time. You just have to work the right levers. The Ministry of Health is allowing us to do it.
“There was a little bit of resistance, I would say, at the start. I’ll be honest, it was really hard getting this study started, because it was the first one. I’m hopeful that if we do more studies, follow-up studies, that will be less hard.”
There will be a MDMA trial in collaboration with the University of Otago, and more to come on LSD microdosing.
“We’re hoping 2022 will be a real breakthrough year for us in terms of having maybe four or five different trials running.”
There will come a point when you think you’re going to die, but by then you really won’t care.
That is how a person who must remain anonymous was briefed about a ketamine trip. That user describes what follows as “the most powerful psychedelic experience I’ve ever had in my life”, and this person has tried almost everything. There were hallucinations, there was powerful imagery and a feeling that one was losing one’s mind. But as the trip adviser said, you have to just go with it. Here is another vivid account of a ketamine experience.
“The world’s frame rate dropped. I thought very hard about moving my hand, but it lagged behind; it looked grotesque and waxy, like the skin on cheese. I closed my eyes. That was a bad idea. I fell through my entire life and out the other side into death.
‘‘It must have looked horrible, because a doctor tried to console me by
reading a passage from her book: Prehistoric wombats were over six feet tall. This was too much. I threw up everywhere.’’
That second experience, written by Asia Martusia King in Otago University student magazine Critic in 2020, was under the supervision of Dr Paul Glue, who has spent roughly a decade researching ketamine’s potential as a cure for treatment-resistant depression.
‘‘I thought her description was hilarious,’’ Glue says.
King had responded to a call for volunteers. She reported that once the lurid effects wore off, she enjoyed a week of feeling good.
While resistant to talking about miracles, Muthukumaraswamy has been impressed by the effect.
‘‘It’s fascinating, if someone has had depression for so long, and they can be given something that flicks the switch, and they feel better. It’s not that they’re high. They feel better the next day. We know the ketamine has left their body, but they’re still undepressed over the course of the next week, which means it’s done something in their brain to modify their brain circuits to make their moods better.
‘‘That suggests there’s a switch in there that can be flicked. That’s the interesting question.’’
Many people are looking for answers to that question. One of the details is that ketamine appears to work on depression within a week, whereas the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, that are dispensed to around 9 per cent of adults in New Zealand, take four to six weeks.
‘‘Compared with regular antidepressants, this is blazingly fast,’’ Glue says.
Ketamine is used as an anaesthetic in New Zealand. There is also a nasal spray available, but it is expensive and rarely used. Otherwise, ketamine is a Class C drug here.
It has found recreational users, who called it ‘‘Special K’’ and talked about the dissociative, death-like experience as ‘‘going through the K-hole’’.
The question that preoccupied Glue is how to use it to treat depression while avoiding its terrible effects. In about 2015, he had a fateful meeting with Peter Surman, chief scientific officer with Auckland company Douglas Pharmaceuticals. Glue had previously worked with Surman on a liquid form of the schizophrenia treatment Clozapine.
‘‘That went really well,’’ Surman says. ‘‘It’s now globally available. Paul’s got a very good understanding of industry as well as academia.’’
An idea was hatched. You could produce a ketamine tablet for the depressed patients who don’t respond to SSRIs. And it could be a slow-release drug, so that 120mg could leak out gradually rather than all at once.
To cut a long story short, the pill, which is dubbed R107, has just had very promising results from a phase two trial on patients in New Zealand and Australia, plus a handful in Singapore and Taiwan, and a phase three trial starts next year.
‘‘What we’ve seen is on day eight, when they get their scoring done for level of depression, 75 per cent of them are well,’’ Surman says.
On the Montgomery-Asberg Depression Rating Scale (MADRS), they now have scores below 12, ‘‘which is really good’’. Zero to 6 is normal and 7 to 19 is mild depression. Many started with scores in the 30s, which is severe depression.
‘‘So all the hallmarks are there that this drug is actually working and is providing a response in patients,’’ Surman says. ‘‘Many of them have been sick for years or decades. It’s a really positive feeling for us when the investigators or the primary care physicians say, ‘Look, I don’t want to take the patients off this’.’’
What happens now? The likely timeframe is to submit the drug to the Food and Drug Administration (FDA) in the US for approval in 2025. The whole world watches what the FDA does, and ‘‘to recover the cost of the development, which is significant, you need to have the US a party to it’’.
And then, ‘‘hopefully the first launch will be 2026 in treatmentresistant depression’’, Surman says. ‘‘It has huge potential. It’s going to be too deep for our pockets to do the US launch and the distribution, but we’ll be working with a commercial partner, and that partner may see sales of US$2 billion or more on that product line. That’s what the forecast need is. It could be a blockbuster with the right partner.’’
Depression and anxiety, which Glue’s ketamine research has also tackled, are growing mental health epidemics. ‘‘There have been literally hundreds of groups around the world who have shown it works in depression,’’ Glue says. ‘‘The bit we’ve added is to show it works in anxiety as well. People with bad generalised anxiety, social anxiety, about an hour after dosing, about 70-80 per cent of them will say, ‘My symptoms have gone’.’’
Of those with anxiety, around a quarter remained well and half had lessened anxiety. Is that a good result?
‘‘It’s a spectacular result. The natural history of anxiety disorders is you get them as a child or an adolescent, and they’re with you pretty much for the rest of your life. It tends to be a neglected disease. It’s one of the big highprevalence disorders and there are very few novel treatments for it. So that a quarter of people after three months didn’t get their anxiety back is striking.’’
Surman adds: ‘‘The FDA is on the lookout for safe products that are going to help with people who are really suffering.’’
Of course, the psychedelic goldrush means that Douglas Pharmaceuticals is not the only company with a bright idea.
‘‘Absolutely,’’ Surman says. ‘‘Any idea that’s a good idea, people soon pick up on it, and we know there’s a few companies looking at ketamine at the moment.
‘‘I think we’re in a good position. But we can’t take our foot off the gas. We have to get an application into the United States. That’s really critical. As quickly as possible.’’
Paul Glue had just received good news on the day Stuff rang. He learned that the collaboration with the University of Auckland on an MDMA study had won ethics approval. They hope to start in about six months. ‘‘It’s taken two years to get to this stage.’’
The notion is to use MDMA to help treat anxiety and depression in people who have terminal cancer. It follows one of the most celebrated studies from the psychedelic renaissance, conducted by Roland Griffiths of Johns Hopkins University in the US, using psilocybin.
Griffiths found that in those patients, high doses of psilocybin increased their quality of life, their sense of meaning and optimism, and lowered their death anxiety.
An earlier paper by Griffiths showed that psilocybin can ‘‘occasion mystical-type experiences’’ that have ‘‘substantial and sustained personal meaning and spiritual significance’’.
But words like ‘‘mystical’’ and ‘‘spiritual’’ make some people worried. It’s not just that it harks back to the 1960s, and the utopian free-for-all of Leary and Kesey. It also moves beyond treatment, as surely we could all benefit from mystical, meaningful experiences, not just those who are unwell.
This is the dilemma writer Michael Pollan arrived at in his book How to Change Your Mind: The New Science of Psychedelics, when Griffiths told him that these drugs ‘‘will be far too valuable to limit to sick people’’.
The difference can be illustrated on the Otago campus. Geoff Noller works at the same university as Paul Glue, but is an anthropologist by training, with an understanding of how drugs are used culturally, not just medically.
‘‘I’m fascinated by consciousness,’’ Noller explains. ‘‘I would say that one of the most important elements of treating people with these drugs is that journey people go on. Paul is a psychiatrist. He’s interested in the brain and not the mind.’’
Griffiths’ paper about the ‘‘mystical’’ properties of psilocybin followed a reconstruction of what was called the Good Friday experiment of 1962, when divinity students in Boston were dosed with the drug and had spiritual experiences in a church.
It said much about what they call ‘‘set and setting’’, the importance of the mindset and the environment, and therefore about suggestibility. As Noller says about Griffiths’ experiment, many reported a peak experience, and still felt that way 18 months later. ‘‘That is an example of the power of these substances to have an effect that is not just ephemeral, but lasting.’’
As an anthropologist, Noller is aware this is a near-universal impulse. Every society he knows about, except Ma¯ ori, has a substance that alters consciousness. Ma¯ ori knowledge may have been hidden by the Tohunga Suppression Act, he thinks. ‘‘Presumably Ma¯ ori living very close to the land would have been familiar with the effects of psychedelic mushrooms.’’
Noller is especially knowledgeable about Ibogaine, a powerful but dangerous drug that is used in west African religion. ‘‘They call it ‘breaking the head’. The idea is to crack open one’s consciousness and engage with issues within oneself. Not in a drug treatment sense but just in a general sense of exploration, I suppose.’’
The drug treatment part is that Ibogaine is used by some to cure opioid addiction. The downside is that it can also produce a fatal arrhythmia, and there was a death during treatment in Kaitaia in 2013.
It is said to produce a dream-like state that is far from pleasant, in which patients’ lives appear before them, forcing them to confront the trauma or physical injury that caused their addiction. ‘‘Not exactly a great Saturday night out,’’ Glue quips.
‘‘You really do need to know what you’re doing in terms of treating someone,’’ Noller agrees. He is also an enthusiast of cannabis law reform who wrote, somewhat presciently, in 2017 that cannabis policy was too important to leave to politicians. Yes, he was disappointed about how it went in
2020, but also not surprised.
A crude moralistic division exists between good and bad drugtaking, expressed in public views about medicinal cannabis versus weed smoking. You can see similar divisions in the psychedelic world now.
The binary opposition between recreational and therapeutic use seems flawed to Noller. ‘‘I don’t like using the word recreational. It sounds like we’re playing soccer.’’
People who use cannabis to relax or destress are using it therapeutically, even if they don’t see it that way, Noller argues. It’s the same with those who might take LSD every so often for a personal reset. ‘‘There is a whole swath of people who have a meaningful relationship with the substance.’’
But despite the differences in nuance, there is collegiality across the wider scene. When Muthukumaraswamy had a psychedelics meeting at the end of
2021, around 150 people attended, Glue says. The sense of some kind of movement was obvious.
‘‘It’s a huge mix of disciplines,’’ Glue says. ‘‘I’m a psychiatrist. We had palliative care specialists, lots of nurses and psychologists, a lot of super keen students from different disciplines. There’s a huge groundswell of support from an academic perspective and a clinical perspective. Watch this space.’’