7 May 2020

Turning on to psychedelics: fear and loathing no more

Drugs Mental Health

Drugs such as LSD and psilocybin, that for half a century have been demonised as criminal, counterculture and dangerous, are suddenly undergoing a facelift, with scientists busily studying their effects on a range of hard-to-treat psychological problems.

It’s a development which Dr Stephen Bright, a senior lecturer in Edith Cowan University, describes as “an international psychedelic science renaissance in the 21st century”.

A major driver of this re-evaluation is the stark reality that barely any new pharmacotherapies for depression and other mental health conditions have entered the market in decades.

Take depression, for example. An estimated 123,000 Australians experience an episode of major depression each year. Across a lifetime, around one in three men and almost one in two women will experience major depressive disorder.

Yet agomelatine is arguably the only novel antidepressant to have reached the market in many years, according to Professor David Castle, chair of psychiatry at St Vincent’s Mental Health.

Instead, “we have been flogging the monoamine reuptake inhibition horse for decades now”, he writes in a recent article in the Australian & New Zealand Journal of Psychiatry.

Professor Castle is a member of the steering committee for Mind Medicine Australia, a not-for-profit organisation which aims to “establish safe and effective psychedelics” for mental illness.

While traditional antidepressant drugs will probably continue to play a role in the treatment of this condition, proponents of psychedelic research are quick to point out the limitations of these therapies.

Many adults with major depression have to try multiple antidepressants to find one that helps, and even then around one in three won’t achieve remission. Those that do benefit may still have to deal with side-effects such as weight gain, sexual dysfunction and digestive issues.

This rethink has resulting in older drugs, such as ketamine, being approved to treat depression in some parts of the world, with research suggesting the drug may also reduce suicidality.

And MDMA, commonly known as ecstasy, has now been classified as a “breakthrough” therapy for post traumatic stress disorder (PTSD) by the FDA in the US. Such a designation will speed up how the drug is developed and reviewed by the administration, sparking hopes that the therapy will be approved shortly after phase 3 trials conclude in 2021.

And, of course, cannabis may be the most successful drug yet to shuck off its past associations with crime, violence and madness.

When it comes to psychedelics, the compound found in magic mushrooms, called psilocybin, has the best modern evidence base, says Professor Castle. Psilocybin is being trialled for everything from treatment-resistant depression and anxiety, to palliative care, PTSD, anorexia and obsessive compulsive disorder.

PYSCHEDELICS

So firstly, what is, and what is not, a psychedelic drug?

While some lump MDMA, ketamine and cannabis together under the psychedelic umbrella, many researchers exclude these drugs.

Instead, researchers are often talking about serotonergic hallucinogens. That is,  drugs that have a profound effect on the perception, mood and cognition of those who take them.

Perhaps the most well-known of these is lysergic acid diethylamide, commonly known as LSD or acid. It was first synthesised in 1938, and by the 1950s and 1960s, tens of thousands of people had participated in scientific studies on the drug.

Psilocybin, the compound found in a number of mushroom species, has a similar structure to LSD, and has similar effects on the mind. Drug maker Sandoz even supplied psilocybin once as an experimental medicine called Indocybin.

The other drug of interest to researchers is N,N-Dimethyltryptamine, or DMT, which is found naturally in plants such as ayahuasca and also in some animals.

Some of these drugs have been used for hundreds or even thousands of years for ceremonial, spiritual and recreational reasons, and one in 10 Australians say they have tried a hallucinogen.

While their illegality has made it difficult for researchers to test their benefits as a therapy, signficant strides have been made in recent years, culminating in several hubs dedicated to psychedelic research, including at the Imperial College London in the UK and Johns Hopkins University in the US.

Last year, the FDA also classified psilocybin as a breakthrough therapy for severe depression, following promising research.

At the Imperial College London, researchers gave two doses of psilocybin to 20 people with treatment-resistant depression, spaced one week apart. Immediately after the first session, the participants reported a reduction in depressive symptoms and improvements to their mood and stress levels.

“Several of our patients described feeling ‘reset’ after the treatment and often used computer analogies. For example, one said he felt like his brain had been ‘defragged’ like a computer hard drive, and another said he felt ‘rebooted’,” lead author Dr Robin Carhart-Harris said at the time.

Functional MRI imaging done after the sessions showed lower blood flow to the amygdala, the area linked with fear and emotional responses.

The benefits remained for five weeks in half of the participants and up to six months for some others.

“Psilocybin may be giving these individuals the temporary ‘kick start’ they need to break out of their depressive states and these imaging results do tentatively support a ‘reset’ analogy,” said Dr Carhart-Harris.

There is also promising research into the drug for people who are faced with their own imminent mortality and are struggling to cope with that situation.

Brave New World author Aldous Huxley notably used psychedelics in the later stage of his life, asking his wife to inject him with LSD as he lay dying from cancer.

He told The Paris Review in 1960 that taking LSD led to “penetrating insights” into his life and the people around him.“Many people get tremendous recalls of buried material,” he said. “A process which may take six years of psychoanalysis happens in an hour, and [is] considerably cheaper!”

Given that, according to a 2011 meta analysis, at least one in three cancer patients have mood and anxiety disorders, research into the effeciveness of treatment with a drug such as LSD seems worth pursuing.

In 2016, New York University researchers randomly assigned 29 cancer patients with end-of-life depression and anxiety to either psilocybin or a niacin placebo, before swapping the treatments.

Creating a proper placebo for psychedelics is tough, because the effects are so obvious but the researchers chose niacin because it causes some facial flushing and other physiological effects.

The participants had two-hour sessions with a male and female psychotherapist team to prepare. In these sessions they discussed the type of existential distress the patients were experiencing and worked on management plans.

Participants then took the psilocybin or niacin in a room designed to feel like a lounge-room, where they could sit or lay in comfort, listening to music chosen by the researchers with headphones and eye masks on.

They were accompanied by both therapists for the entire sessions, and towards the end they were guided to discuss the experience to reinforce the memory and start to integrate that into their normal experience. This was backed up by follow-up sessions over the next few weeks that were designed to consolidate the memory further and integrate the experience into their normal lives.

The researchers found that 83% of those taking psilocybin experienced antidepressant effects within the day, compared with 14% of the control group. These benefits continued for six months for 60 to 80% of the participants.

The fact that people had such a profound psychological shift when faced with such a significant change such as cancer and their possible death could “only be a good news story”, says Professor Castle.

“That’s the opportunity which is afforded by this integration of the psychological and biological. People can have psychotherapy for years and years and years, and of course some get benefit from that, but other people don’t,” he says.

To improve the benefits of psychotherapy, and do so in a truncated way, makes it an appealing prospect, he says.

ADDICTION

Early studies on LSD have indicated that the drug might be helpful in the treatment of alcohol use disorder.

For example, a 1959 study of 16 people with severe alcohol dependence looked at the effects of LSD-assisted psychotherapy and found that 15 had lower alcohol use half a year later, and 10 had stopped drinking altogether.

Similar benefits have been found with psilocybin. A 2017 study of 15 people with tobacco addiction found that two out of three were confirmed abstinent one year after the study. Benefits have also been found with alcohol use disorder, and bigger studies are now under way.

Observational studies indicate that ayahuasca, a shamanic brew used in South America, may also help people reduce their use and dependence on substances such as alcohol, tobacco or cocaine.

PRACTICALITIES

The psychedelic revival has led to more of an interest in psilocybin than LSD, largely for practical reasons. Because patients are given the substance under the care of trained therapists, the more practical and cheaper option is to use something like psilocybin.

An entire psilocybin trip may last anywhere from three to eight hours, whereas LSD can be up to 12 hours, with some mild effects lingering even longer. Given that psychiatrists charge hundreds of dollars an hour, this is an expensive solution.

“On the other hand, you’re talking about potentially one or two dosing sessions and that’s it, rather than having to pay ongoing costs for medication and follow-ups,” says Professor Castle.

Dr Bright calls this a “paradigm shift” in how we treat complex mental illness.

“For one, people aren’t taking drugs home to take them,” he says. “They are doing it in the context of psychotherapy, with trained psychological staff who provide psychological support during it.”

This approach requires preparation and integration in a broader context of several months of psychotherapy, he says. And they are only administered on two or three occasions.

“Whereas if you’re prescribing someone with an SSRI, then you’re prescribing that treatment on an ongoing basis, potentially with no clear indication for when that would be ceased,” he says.

But even if an economic case could be made, it could be a challenge to find enough clinicians willing and able to provide this type of therapy.

This is why Ian McDonald, CEO of Bright Minds Biosciences, is trying to develop a quicker-acting version of psilocybin. His goal is to tweak the psilocybin molecule to find a “superior compound” that gives comparable effects with a shorter trip. This would reduce clinician and room costs, enabling more widespread uptake.

“Ideally we’d have it at around 45 mins to an hour,” says Mr McDonald. “It remains to be seen what we can accomplish, but any reduction is highly material.”

Whether patients will benefit as much from a shorter burst is contested because it’s unclear how much of the effect is due to the psychological experience and how much is due to the biological changes these drugs provoke.

UNDER THE BONNET

Psychedelic drugs work by activating serotonin receptors in the frontal parts of the brain, such as the cortex.

“This leads to lots of firing of the neurons, and those particular neurons that the psychedelics work on organise how different parts of the brain integrate,” says Dr Chandni Hindocha, of the clinical psycho-pharmacology unit at University College, London.

“So when you get huge amounts of firing it leads to real changes in that integration and the signalling across the brain,” she says.

For example, when somebody takes psilocybin it is converted into psilocin in the body. This is a partial agonist at serotonin 5HT2A and 5HT2C receptors, which are found in higher levels in the “thinking parts of the brain”.

“This area is active during thought processes like daydreaming, recalling memories, and thinking about the future, when the mind is wandering, essentially,” neuropharmacologist Professor David Nutt explained in a recent Cell commentary. “It’s also an area that is overactive in people with disorders like depression and anxiety.”

But it’s not yet clear why the effects of psychedelic treatments last so long, either psychologically or anatomically.

Research suggests that some psychedelics increase the level of brain derived neurotrophic factor (BDNF), a protein thought to play an important role in neural plasticity. Conventional antidepressants also have an effect on BDNF, although at a much more gradual rate than psychedelics.

Work out of Imperial College London shows that people taking psilocybin have a quick drop in functional connectivity in a system in the brain linked with introspection, self-reference and autobiographical memory, called the default mode network (DMN). But this is followed by an uptick in DMN connectivity.

“Taken together, these findings have been interpreted as a potential ‘reset’ mechanism,” Professor Castle wrote in his 2019 Australian and New Zealand Journal of Psychiatry viewpoint.

Psychedelics have a host of other strange effects on the brain that increase synchrony between modules of the brain that usually don’t operate in tandem, and reverse normal hierarchical dynamics.

“These changes may correspond to a rebalancing of predictive processing, a reduction in excessive top-down processing leading to a reduction in cognitive and affective biases,” Professor Castle wrote.

This might explain how taking psychedelics decreases the extent to which people focus on their own thoughts, feelings and desires, and how it may break the cycle of rumination that plagues depressive thinking.

Which means that they may help people by allowing them to see themselves and the world around them in a new way. Brain imaging of people with treatment-refractory depression found that the ones most likely to still be in remission three months after treatment were those who had the largest deactivation of DMN during their session.

All of these changes may make patients more open to suggestion from psychotherapists.

A clear difference between this and conventional antidepressants is that the psychedelics don’t, by themselves, address the underlying biological, psychological or social causes of depression.

“In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain via the effects of the drugs to facilitate insight and emotional release and, with psychotherapeutic support, a subsequent healthy revision of outlook and lifestyle,” Dr Nutt wrote.

Regardless, properly understanding exactly how psilocybin creates these beneficial effects, and that will be vital to convincing people that the drug is more than jst a powerful placebo.

AYAHUASCA

The other serotonergic psychedelics generating research interest is ayahuasca, which is a tea containing DMT and monoamine oxidase inhibitors (MAOI). Like psilocybin, DMT also acts on serotonin transmission through the 5-HT2A receptors and MAOI.

In 2015, researchers from Brazil and Spain gave a single dose of the drug to six participants with severe depression. On average, depression scores dropped 62% within the first day, dropping further to 72% one week later, only to bounce back somewhat by day 14. The scores still remained 45% lower than baseline three weeks after the treatment.

A systematic review conducted by some of the same researchers concluded that studies “consistently” found reductions in depression and anxiety among people treated with the drug.

In the 1990s, researchers studied the brains of members of a Brazilian church that uses ayahuasca. They found that individuals had more serotonin platelet binding sites than their peers. In contrast, depression and suicidality are linked with a low density of these receptors.

MDMA

MDMA, or methylenedioxymethamphetamine, is sometimes referred to as an empathogen or entactogen, rather than a psychedelic, because it heightens feelings of connection and of touch.

The most promising way MDMA is being used is in combination with psychotherapy for PTSD.

Around one in 100 Australians are estimated to have PTSD in any year. Exposure-based psychotherapies are effective in those it works for, but around one in three don’t benefit from it.

A 2011 randomised controlled pilot study of 20 patients with treatment-refractory PTSD found that 12 sessions of psychotherapy in conjunction with two MDMA sessions led to 83% of the participants no longer meeting the criteria for the condition two months later. Of these, only 10% had relapsed 3.5 years later.

These took a similar form to the psilocybin experiments, in which the MDMA sessions took place in a comfortable room with a program of music and a male and female therapist team to accompany them through it.

If the participant did not bring up the trauma organically then the therapists were directed to at some point during the session, and engaged in cognitive restructuring if the opportunity arose.

“Though remarkably, [the lead researcher] notes that the effects of MDMA alone often led the client to have profound insights about cognitive distortions spontaneously,” Dr Bright wrote in a review for Australian Psychologist.

The participant then stayed the night and there was another session in the morning to further integrate the insights they had into their regular consciousness.

Several phase 3 clinical trials on treatment refractory PTSD found that 60% no longer met the criteria of PTSD at a 12 month follow up.

WHAT ABOUT THE HARMS?

After decades of being illegal, it’s understandable that clinicians may have reservations about facilitating the use of such apparently powerful drugs.

Nevertheless, the studies so far indicate these drugs are relatively safe. A 2015 study of 130,000 adults in the US found that mental health problems were the same regardless of whether the participants had used LSD, psilocybin or mescaline.

The side-effects are typically mild and short term, such as feelings of anxiety or a bad trip, but these usually resolve after a few hours and can be helped with experienced clinicians on hand.

“These are not addictive drugs,” says Professor Castle. Nor do they have worrying physiological effects, particularly in a controlled, therapeutic context.

A recent Australian paper by Professor Castle and colleagues ranked drugs of abuse in terms of how harmful they are, showing that psilocybin was low on the totem pole of harmful substances.

Alcohol, one of the most commonly used drugs in Australia, was the most harmful. Prescription opioids and benzodiazepines also ranked higher than psychedelics when it came to deaths, hospitalisations and emergency department presentations.

However, there are important limitations to the research.

Professor Castle cautions that current studies have been relatively small, and that it is “very difficult” to truly blind the participants and researchers from what condition they are in.

Many people participating in trials have previous experience with psychedelics, which muddies the waters in evaluating the placebo effect and how well these substances would work for people who are drug-naive.

Studies often exclude those who might have problems with such substances, such as those with family or personal history of psychotic illness and those with bipolar disorder.

But aside from helping those who are struggling, there may be even broader benefits for society at large. Researchers at the Imperial College of London undertook a randomised controlled trial of 20 healthy participants and found that one dose of LSD led to more optimism, improved mood and openness for a fortnight.

Much work is still to be done before psychedelics and psychotherapy take their space alongside SSRIs and the other incumbent treatments. But now that the shackles of the War on Drugs have been lifted, research is moving quickly.

You never know, in a year or two you might be writing referrals to the local trip clinic.

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