A short history of psychedelics as an antidepressant

Author: Lydia Nichols is an undergraduate student at Macquarie University. As part of her studies, she collaborated with Blossom on writing the following deep dive on psychedelics as antidepressants. After her studies at Macquarie, she’s looking to continue working in science communication.

A brief background to psychedelics

Psychedelic substances, like psilocybin, have had an interesting history as public opinion approaches and understanding of the substances have changed over time. A psychedelic substance elicits hallucinations and can alter the perception and mood of the individuals who ingested the substance (Nichols, 2016). This unique ability to alter mood and cognitive processes has led to researchers investigating the effect of these substances in several clinical conditions, including various depressions. 

The usage of psychedelics, in both a recreational and clinical setting, is controversial due to these substances being banned in most countries. Psychedelics have been an important part of many cultures for thousands of years, but in more recent times, the unregulated mass usage throughout the 1960s has caused widespread criticism, banning and fear across the world. Psychedelics have had a complicated past, with the majority of the negative public opinion stemming from the 1960s. In the 1950s, Albert Hofmann famously studied LSD and its properties, which sparked widespread research into this substance. This research led to psychedelic substances being termed “psychotomimetics”, as LSD induces psychosis-like symptoms. This term negatively suggests that these substances produce clinical psychosis, delusions, and delirium, but clinicians have since classified this “psychosis” as different to psychosis in patients with bipolar or schizophrenia and instead termed these substances “hallucinogens”.

Due to the widespread banning of psychedelic substances, it is difficult for researchers to create and run an experiment on their effects; however, many studies have been published, and future trials are planned on using psychedelic substances as antidepressants. The vast majority of currently published research is on the usage of ketamine however, there have been a handful of studies using psilocybin, nitrous oxide, DMT, LSD and MDMA and ayahuasca. Research from the 1960s onwards was sporadic, with many published studies, but their quality was relatively low. Once we reached the 2000s, the number of published trials began to grow. Studies on the usage of ketamine as an anti-depressant begin after its initial usage as an anaesthetic and later as a treatment by first responders for agitated patients, particularly those who had just attempted suicide.

What are some conditions psychedelics are used to treat?

Depression is a clinically difficult condition to study and treat because there is such a variety in both the recognised types of depression and the treatments available and needed for the patient. One specific class of depression that has been studied in many papers is treatment-resistant depression (TRD). TRD is clinically very interesting as it is a type of depression where a patient has not received adequate benefits from treatment with at least one oral antidepressant and psychotherapy (Fava, 2003). According to a meta-analysis by Fava and Davidson (1996), roughly 19-34% of depression patients are partially or entirely nonresponsive to treatment which is a puzzle many researchers aim to solve.

How does it work?

Current research has shown that the most commonly used class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), can take weeks or months to become effective and may not be effective for all patients and are only effective 30-40% of the time (Artin et al., 2021). In contrast to this, the majority of evidence from studies on ketamine has shown that this substance can improve a patient’s symptoms rapidly and effectively after treatment for a more sustained period of time than SSRIs.

Each psychedelic substance affects the brain slightly differently to alleviate depression symptoms but all currently studied substances reduce depressive symptoms faster and produce longer-lasting effects than currently depression treatments. Ketamine has been shown to act primarily on glutamate and opioid receptors and help regenerate connections, called synapses, between neurons. In many patients with depression, it has been hypothesised that the number of synapses decreases due to the stress of the condition on the participant. Ketamine has been shown to regrow these synapses and cause changes in the brain. These changes have been hypothesised to help the patient out of the depression mindset and have stemmed from TRD patients responding positively to ketamine treatment. Ayahuasca, another type of psychedelic substance, has been used to treat patients with TRD and was able to restore the associated corticosteroid insufficiency, an adrenaline deficiency, of depressed patients and increase the cortisol response to that of the healthy controls.

There is overwhelming evidence that the usage of ketamine as an antidepressant is highly effective in treating both major depressive disorder (MDD) and TRD, with many papers presenting patients with improved quality of life, depression scores and overall wellbeing for varied periods of time. Another type of psychedelic, nitrous oxide can lead to full remission of a patient’s condition after as little as one treatment for an hour at 50% concentration (Nagele et al., 2015). Later studies have shown that as little as 20% nitrous oxide concentration can provide similar, highly effective results whilst also providing lower levels of side effects (Nagele et al., 2021).

What is the current research?

Research into the antidepressant effects of ketamine began around 2000, and many studies have since looked at the effectiveness of this substance for patients with TRD and MDD. Improvements in depression scores were seen as soon as 40 minutes after the session, and some studies found results can last for several weeks after the initial treatment. Most studies have found that individuals return to a baseline level, or experience diminished effects, after around seven days. Not all studies, or conditions, saw this rapid result. Those that didn’t still found that a patient could still benefit from the full course of treatment despite not getting early results. For ketamine, there have been two main types of treatment administration, intravenous (the most common dosage was a standard low-medium dosage of 35mg/70kg) and a nasal spray of esketamine, a form of ketamine (the most common dosage amount was 80mg). The intravenous treatment program varied between studies, but the most common, and most effective, treatment plan was six sessions over a two-week period. For esketamine, most studies used a nasal spray twice a week for four weeks, alongside a daily oral anti-depressant. Both treatment plans have been shown to be highly effective.

Contrary to the multiple doses of ketamine required, only one treatment of other psychedelic substances has shown to provide similarly, or in some cases, more effective, results. Published research on psilocybin has been used primarily for patients with end-of-life depression where patients with a terminal illness (such as cancer) are experiencing depressive symptoms due to their condition. A study by Griffiths and colleagues in 2016 showed that the effects of a single dosage of psilocybin could produce significant and enduring results in increasing the quality of life for terminally ill cancer patients, even six months after treatment.

Where is this research going?

The usage of psychedelics in a clinical setting has had interesting but slow progress throughout the last century, primarily due to the heavy impact of public opinion. Most research on using various psychedelic substances as an anti-depression intervention has shown overwhelming evidence for its effectiveness. Over the last few decades, there has been a steady increase in the number of studies investigating the usage of psychedelics as an intervention option for patients with various depression types. This progress has likely been halted, as much of the world has been, due to the impacts of COVID-19 and increases in difficulties in recruiting participants and running experiments safely. Over 6000 participants have been or will be involved in ketamine double-blinded and randomised trials for depression from 2008 until 2027. In comparison, less than 1800 participants have been or will be involved in psilocybin trials in the same timeframe, with an even lower number of participants for other psychedelic substances.

Previous research has been primarily focused on the usage of ketamine, with only a handful of studies investigating the effects of psilocybin and nitrous oxide. Fortunately, the future for psychedelics holds many studies looking at psilocybin, LSD, nitrous oxide, and other psychedelic substances. Another exciting feature of future planned trials is that they look at a broader range of conditions like post-partum depression, PTSD, and comorbid conditions like alcoholic abuse. This expansion of knowledge is essential and has stemmed from the positive results seen in the ketamine trials, and researchers are using this as justification for investigations into new areas.

A trial on the usage of LSD for patients with MDD, supported by the Basel University Hospital in Switzerland, is currently in Phase II examining several behavioural changes such as depressive symptoms, anxiety, sleep patterns and personality. This study looks at an active dose of LSD and an active placebo of a much lower LSD dosage in combination with psychotherapy and aims to be completed in December 2022.

Small Pharma is conducting a two-part study in the United Kingdom using DMT on healthy controls and patients with MDD. This study uses healthy controls to investigate the safety and tolerability of using DMT as an intervention and compares these results to see the efficacy of DMT in reducing depressive symptoms in MDD patients and is aiming to be completed by February 2023.  

A Phase II study by the Central Institute of Mental Health in Germany aims to look at the dosage-related effects of psilocybin on TRD by using a presumed “sub-effective dose” to compare it to an “effective” dose. This study aims to investigate the safety and effectiveness of psilocybin as a treatment for depression and aims to have results by March 2024.

Several studies also look into the effectiveness of sub-hallucinogenic doses of psilocybin. One study was conducted at Macquarie University in Australia examining mild to moderate depression and aims to conclude in December 2022. The University of Toronto is investigating the effects of a sub-hallucinogenic dose on Persistent Depressive Disorders which the hope of concluding in April 2023.

What’s next?

Now that we have foundational evidence that supports the idea that psychedelics are effective antidepressant interventions, the next step forward is for these interventions to be implemented clinically. There are a few different things that need to happen for this to occur as there are still several roadblocks. In the US, there is a provision within the public policy that can limit the allocation of funds towards research that may promote the legalisation of a substance included in “Schedule I”, which is the current classification of many psychedelic substances (National Institute of Health, 2021). This provision inhibits the ability of researchers to access and study these substances, as currently all research is funded by private companies. Unfortunately, all bills to remove this provision have failed. More studies will need to progress to Phase III to remove provisions like these, and government regulatory bodies will need to complete unbiased reviews of these trials.

Another issue that threatens the future of psychedelic research is that many of these larger stakeholder companies are looking to patent psychedelic compounds and methods of producing and administering them. Whilst patenting compounds itself is not inherently bad, it can mean that whilst this field is still largely emerging, there may be a small number of companies acting as gatekeepers for the accessibility and usage of psychedelic substances, which may halt both research and access to these promising intervention treatments. Marks & Cohen (2021) suggest that it may be necessary to restrict patents on psychedelic substances to promote and nurture their role in improving intervention options for thousands of people.

In Europe, the brand Spravato has been approved as a treatment for MDD in a psychiatric emergency. Spravato is an esketamine nasal spray and is the first NMDA antagonist approved for this clinical application. The approval for this product was reviewed by the European Commission on the results of two separate Phase III ASPIRE studies across the world and poses a promising look forwards for other treatments for similar conditions.

The favourable results that have been seen from hundreds of different studies have led to increased interest in the field and many advancements for both research and clinical applications. There is still a long way forwards from both the clinical and legal perspectives for the future of psychedelics in depression interventions. Still, milestones like the approval of Spravato have paved the way for future advancements.

“Psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is for biology and medicine or the telescope is for astronomy.”– Stanislav Grof