The ultimate trip-up

In the 1970s, political and cultural stigma kneecapped decades of research on the use of psychedelic drugs to treat mental illness. Now scientists are returning for a second look.

 Illustration by Alexis Lee

Illustration by Alexis Lee

Medicine is on the brink of a ‘psychedelic revolution,’ at least if you take the word of mainstream media outlets like The Huffington Post. Drugs like psilocybin (the psychoactive ingredient in ‘magic mushrooms') and MDMA (the chemical compound in ecstasy) are now being studied as potential treatment options for various mental health issues, including depression, post-traumatic stress disorder and the anxiety associated with a terminal illness.

Aldous Huxley, author of the 1932 dystopian novel Brave New World, believed that psychedelics open the doors of perception. Dr Evan Wood, professor of medicine at the University of British Columbia, has said that psychedelic medicine may open a different kind of door, unlocking clinical and therapeutic gateways that have been long closed.

The re-emergence of this research has been called a paradigm shift in mental health, with one researcher going as far as saying that “this is to neuroscience what the Higgs boson was to particle physics”. But if we go beyond the hype, and look at the present state of the science, what do we find?

Research on psychedelics and mental health began in the 1950s and progressed until the early 1970s. While it may seem strange to us today, this research was quite mainstream. Some commentators even claim that such research was at the forefront of psychiatry, both exciting and cutting-edge.

 
  Author Aldous Huxley (left) detailed his experiences taking the drug mescaline in his 1954 book The Doors of Perception (right) .  Anonymous/Wikimedia Commons  (public domain);  Tradlands/Flickr  (CC BY 2.0)

Author Aldous Huxley (left) detailed his experiences taking the drug mescaline in his 1954 book The Doors of Perception (right). Anonymous/Wikimedia Commons (public domain); Tradlands/Flickr (CC BY 2.0)

 

However, research on psychedelic drugs was brought to a halt by legislation classifying them as Schedule 1 drugs, described as “drugs of abuse” with “no medical value”. This legal status, as well as their use as recreational drugs, has led to a stigma that is still present today. Some scientists argue that the ban on psychedelics was not due to any firm scientific or medical rationale, but was a result of societal and political reactions to the emerging counter-culture of the time.

Unfortunately, the stigma and legality of the drugs have been “significant obstacles and hurdles for scientific research using and investigating hallucinogens”. Yet as society continues to change, and as mental health concerns attract widespread awareness, research has once again begun on psychedelic substances, or ‘hallucinogens’. 

The term ‘hallucinogen’ is actually a misnomer. This is because the drugs don’t cause “true” hallucinations; rather, they create perpetual alterations and disturbances in the stimuli we experience. Researchers usually group classical hallucinogens into three categories: triptamines (such as psilocin, as found in ‘magic mushrooms'), lysergamines (such as LSD) and phenthylamines (found in mescaline, the psychoactive ingredient in the peyote cactus). Ketamine and MDMA have different effects and mechanisms of action, but in common usage they are often grouped together with the psychedelics.

These drugs all have several things in common: they are used recreationally, they have stigma attached to their use and research, and, aside from ketamine, they presently have no officially recognised medical use. 

Psychedelic compounds have been used by various cultures for millennia, long before they attracted the attention of scientists. Typically, this use was associated with religious or spiritual rituals. DMT and psilocybin have a long history of use in Latin America. DMT was first synthesised in 1931, but also occurs naturally in the plant Mimosa hostilis, used by northeastern indigenous Brazilians to prepare a 'sacred beverage'. Likewise, DMT occurs in ayahuasca, a drink consumed by native people in Brazil, Columbia, Peru and Ecuador for social, therapeutic and ritual purposes. The compound psilocybin, found in many species of mushrooms around the world, is used ritually in Mexico. LSD, a man-made chemical, has overlapping effects with naturally occurring psychedelic compounds: specifically, they all act on some of the same serotonin receptors in the brain. 

 
  Dr Timothy Leary was a vocal proponent of psychedelic drugs from the 1960s until his death in 1996.   Dr. Dennis Bogdan/Wikimedia Commons  (CC BY-SA 3.0)

Dr Timothy Leary was a vocal proponent of psychedelic drugs from the 1960s until his death in 1996. Dr. Dennis Bogdan/Wikimedia Commons (CC BY-SA 3.0)

 

Early clinical research on psychedelics was considered "promising”; however, much of these data need to be treated with caution due to methodological limitations and poor experimental design. Many of these studies were conducted without adequate control groups, as well as inconsistent standardisation, both in terms of how patients were treated and how outcomes were measured. In consequence, very little of the initial research is consistent with today's gold standard of medical or psychological research.

Nevertheless, there has been a resurgence in interest in these substances. Given the change, it is natural to ask, why? In many ways, the field of psychiatry is in a much better state than it was previously. The development of antidepressants, antipsychotics and mood stabilisers has increased quality of life for untold numbers of people. But, for many, the future state of psychiatry is disheartening. 

According to Jeffrey Lieberman, chairman of the Department of Psychiatry at Columbia University College of Physicians and Surgeons, the rate of innovations in major psychiatric drug classes has been “painfully slow”. Twenty-first century psychiatry, he argues, is still using drugs with the same mechanisms of action as those developed in the 1950s and 60s, something the New Yorker termed the "psychiatric drug crisis".

Cornell University clinical psychiatrist Richard Friedman lamented that "it is hard to think of a single truly novel psychotropic drug that has emerged in the last thirty years”. Spending has slowed down on psychiatric drug development, potentially due to the long-term financial risk, the breakdown of the chemical imbalance hypothesis and the fall in spending on psychiatric medication.

As recounted in Nature, many available therapies simply do not work for some people; up to 70% of patients with depression and 80% of patients with post-traumatic stress disorder (PTSD) don’t achieve full remission with first-line antidepressant treatment. By the early 1990s, the pharmaceutical industry had discovered the psychiatric drug classes that account for most prescriptions – but then “the pipeline ran dry.” Rather than looking to the future, some psychiatrists are looking to the past: towards the formerly neglected psychedelics and related compounds.

One disorder that may benefit from these new trials is PTSD, a severe mental health condition that can develop following a traumatic life event. PTSD can have a large impact on patients' everyday lives, resulting in symptoms such as hyperarousal, re-experiencing the trauma, and even chronic emotional numbing.

 
  The traumas of war are a common trigger for post-traumatic stress disorder (PTSD).   Manhhal/Flickr  (CC BY 2.0) 

The traumas of war are a common trigger for post-traumatic stress disorder (PTSD). Manhhal/Flickr (CC BY 2.0) 

 

Present drug treatments for PTSD have a number of limitations. The UK’s National Institute for Clinical Excellence states that the evidence for drug-based treatments for PTSD is “very limited” and should not be used as a first-line treatment. Rather, the Institute recommends trauma-focussed counselling or psychotherapy. Drug-based treatments are reserved for patients who either do not respond, or do not have access, to therapy. This means that there are few evidence-based treatments available for patients who do not respond to therapy.

Recent research has investigated the use of MDMA with people experiencing PTSD. One study recruited 20 people with chronic PTSD, who had not been responsive to either psychotherapy or medication. In other words, the typical first-line treatments had not been successful, leaving these people with fewer options and less hope for recovery. Michael Mithoefer and colleagues assigned the 20 patients into two groups; both received psychotherapy, supplemented by either MDMA (treatment) or a placebo pill (control).

The pills were given during two eight-hour psychotherapy sessions, in addition to their usual treatment. The researchers measured the severity of PTSD symptoms four days after each MDMA-assisted psychotherapy session, as well as two months after therapy ended. Each time, the patients who had been administered MDMA were doing better than the placebo group. At the end of the study, 83% of the treatment group had experienced a clinical response, defined as a reduction in symptoms of 30% or greater. In contrast, only one quarter (25%) of participants in the placebo group had a clinical response. 

The researchers also took several measures to investigate potential harm to participants, including blood pressure, temperature and neurocognitive functioning. No adverse events were recorded, leading the researchers to suggest that MDMA-assisted psychotherapy may be safe for use in people experiencing PTSD.

  Three forms of the psychedelic drug MDMA, also known as ecstasy.   Drug Enforcement Administration/Wikimedia Commons  (public domain);  T to the A/Wikimedia Commons  (CC BY-SA 3.0);  Thawt Hawthje/Wikimedia Commons  (CC BY 2.0) 

Three forms of the psychedelic drug MDMA, also known as ecstasy. Drug Enforcement Administration/Wikimedia Commons (public domain); T to the A/Wikimedia Commons (CC BY-SA 3.0); Thawt Hawthje/Wikimedia Commons (CC BY 2.0) 

One major concern in mental health treatment is that patients may relapse after treatment is finished. For example, a striking 80% of people who have been through two episodes of depression go on to experience another depressive episode. Likewise, half of people with PTSD experience a 25% exacerbation in symptoms once they cease taking antidepressants; and one study of a community sample found that approximately half of PTSD patients remained ill after 5 years, even though treatments were available.

Yet when the PTSD patients treated with MDMA were followed up over three years later, 74% of them still demonstrated a meaningful reduction in their PTSD symptoms. This suggests that improvements caused by MDMA-assisted therapy are sustained over long periods of time.

Another area that may be ripe for the use of psychedelics is end of life care, specifically with regards to the psychological and emotional difficulties that accompany terminal illness. This is an interesting area, as potential long-term risks or side effects may not be as salient in this population; rather, increasing quality of life may be more important. Researchers have to date experimented with two psychedelic drugs: LSD and psilocybin. A small, randomised controlled trial was conducted in Switzerland in 2014, looking at the effects of LSD-assisted therapy for anxiety in the context of terminal illness.

Twelve patients were recruited for the study, each of whom was given drug-free psychotherapy sessions, as well as two LSD-assisted psychotherapy sessions two to three weeks apart. The active control group was administered a very low dose of LSD, which was believed not to have a significant therapeutic effect, while the active-intervention group received a much higher dose. Two months after treatment, the patients in the therapeutic-intervention group demonstrated a reduction in anxiety symptoms. A further one-year follow up with nine of the remaining participants showed that the reduction in anxiety remained. No adverse effects were reported that lasted beyond a day after receiving LSD.

A similar study investigated psylocibin in 2011. Terminally ill people who received psilocybin, compared to an active placebo, showed lower anxiety and increased mood. Once again, no adverse effects were reported.  

Ketamine, which is approved for use in anaesthesia, is now being investigated as a new treatment for depression, particularly as an option for treatment-resistant patients. Duncan George, a researcher involved in the ketamine trials, has described the results he’s seen as “extraordinary”, commenting on the rapid improvements shown by patients. Some of this research is occurring in Australia, with the Black Dog Institute conducting trials in Sydney, Melbourne, Ballarat, Adelaide and Perth. Formerly, the Institute has also investigated dosage of ketamine, finding that patients didn’t tolerate higher doses well.

 
  Ketamine has already shown promise for treating patients with depression.   Psychonaught/Wikimedia Commons  (public domain)

Ketamine has already shown promise for treating patients with depression. Psychonaught/Wikimedia Commons (public domain)

 

One 2014 meta-analysis looked at seven randomised controlled trials (with 73 subjects in total) and found that single administrations of ketamine have a significant and rapid effect on depression, lasting at least seven days. However, a separate meta-analysis found that antidepressant effects of ketamine were not sustained 14 days after treatment. The primary concern about the ketamine treatment, therefore, is the length of the effect, which is why the Black Dog Institute is looking at whether sustaining ketamine treatment can extend the antidepressant effects. 

Like ketamine, both psylocibin and LSD have also been suggested as alternative treatments for depression. A recent neuroimaging study of psilocybin found that the compound resulted in areas of the brain connecting in ways that don’t occur in normal brain activity. The researchers speculate that the novel connection may account for the synaesthesia that participants describe while on the drug, as parts of the brain that may process hearing may connect with brain regions involved in sight.

Patients experiencing depression frequently are stuck in rigid, unhelpful ways of thinking, which can maintain their disorder and distress. Paul Expert, lead researcher of the aforementioned psilocybin study, suggests that the drug may promote new, flexible ways of thinking ‒ this change in thinking, in turn, may improve symptoms of major depressive disorder. Indeed, psilocybin has been found to improve depression in patients diagnosed with life threatening cancer, suggesting that these effects may be possible in other populations. Clinical trials are also underway investigating whether psylocibin can assist in the treatment of obsessive compulsive disorder, another disorder associated with rigid, obsessional thinking.

With clinical research occurring worldwide, the stigma surrounding these drugs raises an important question: are they safe? Erich Studerus, a Swiss researcher at the University of Basel, and his colleagues conducted a pooled analysis of the acute and long-term effects of psilocybin in healthy volunteers. Data from 110 participants and eight separate double-blind randomised controlled trials were combined.

It was found that some of the subjects did have unpleasant experience while on psylocibin, but these participants were in the minority, and negative experiences only occurred when subjects were given high doses. Moreover, all distressed participants in the studies could be calmed down through talking ‒ not one required an emergency medication to stop the psychedelic effects. Despite this, the authors excluded participants with personal family history of a psychiatric condition, limiting the generalisability of the safety reassurances. 

 
  Subjects at Johns Hopkins University experience the effects of psilocybin in controlled conditions, monitored closely by experienced guides, in 2008.   Matthew W. Johnson/Wikimedia Commons  (CC BY-SA 3.0)

Subjects at Johns Hopkins University experience the effects of psilocybin in controlled conditions, monitored closely by experienced guides, in 2008. Matthew W. Johnson/Wikimedia Commons (CC BY-SA 3.0)

 

One paper, published by David Nutt and colleagues, estimated the cumulative risk of 20 “drugs of abuse”. It was found that psilocybin carried the least risk out of all the studied drugs; moreover, psilocybin had a 12-fold decreased risk compared to alcohol. Similarly, LSD was the third least-harmful drug, meaning that both psychedelics were deemed less dangerous than commonly prescribed drugs like benzodiazepines and methadone. Indeed, both psilocybin and LSD have rapidly occurring tolerance, meaning that frequent, repeated use is not possible. This severely limits their potential as addictive substances. There has also never been a single reported death directly caused by ingesting psilocybin. 

An overarching theme of these clinical trials is that beneficial effects have been observed under the supervision of a trained physician or mental health professional. This professional involvement facilitates a safe environment, where people can be safe physically, as well as having a greater chance of remaining safe psychologically. For example, emergency “blocking” drugs may be available to cancel hallucinogenic effects, creating a safety net. The unsupervised use of these drugs, particularly by someone who is already struggling emotionally, has the potential to be dangerous. Therefore, it’s highly unlikely that these psychedelic compounds will ever be handed out over the counter at your local pharmacy.

Recent results for these compounds are encouraging, but there are presently only a small number of studies, including many with limited sample sizes. As a result, further large-scale research studies are needed before we can draw firm conclusions about their efficacy.

The scientific method, by its very nature, is prudent. Stigma has crippled the entire field of psychedelic research, yet the fact remains that these substances have the potential to reduce mental suffering. The World Health Organisation predicts that depression will be the second leading contributor to the global burden of disease by 2020, highlighting the importance of developing new, effective psychiatric treatments. These re-emerging drugs offer hope to patients, clinicians, and people like you and me the hope that science can make the world a little brighter. And as the writer Samuel Johnson said, “Hope is itself a species of happiness”.

Edited by Andrew Katsis and Ellie Michaelides, and supported by Sabine Wolff.