Psychedelic drugs to treat depression

What are psychedelic drugs? 

Psychedelic drugs are substances which can have a range of psychological effects on their users, such as changing sensory perceptions, thought processes, and energy levels or mood. Some occur naturally (in some plants and fungi) while others are synthesised in laboratories. The common feature of all these drugs is that they act on specialised proteins (called receptors) in the central nervous system (the brain and spinal cord). Ketamine acts at glutamate receptors, while the drugs listed below target serotonin receptors: 

• dimethyltryptamine (DMT) 
• lysergic acid diethylamide (LSD) 
• 3,4-methylenedioxymethamfetamine (MDMA, also known as ecstasy) 
• mescaline 
• psilocybin 

Legal controls on psychedelic drugs  

The production, supply and possession and distribution of drugs is controlled under the Misuse of Drugs Act (1971). The Misuse of Drugs Regulations 2001 allows for lawful possession of drugs for medicinal or therapeutic uses. Schedule 1 includes all the drugs listed above (except ketamine); they are classified on the basis that they have no therapeutic value. These drugs may be researched but require a special licence from the Home Office. Schedule 2 drugs (ketamine) can be prescribed, lawfully possessed and supplied by doctors and pharmacists and researched without a controlled drugs licence. 

In order to conduct research into most psychedelics, academics must apply to the Home Office for a special licence allowing them to obtain and administer them for research purposes. There is debate as to whether psychedelic substances – such as psilocybin – should have their Schedule 1 status (the most stringent category) under the Act reduced. It is argued that this would remove barriers to researchers being able to use them in carefully controlled studies.  

How do psychedelic drugs act on the body? 

Most psychedelic drugs exert their effect by binding to special proteins in the brain called serotonin receptors. For example, psilocybin (found in ‘magic mushrooms’)  can alter sensation, and cause visual hallucinations at higher doses, as can LSD, through activating this receptor. Mescaline and dimethyltryptamine (DMT) also operate predominantly via the serotonin system. Substances exerting their effect in this way are sometimes referred to as ‘classical psychedelics’. 

 However, some researchers use the term ‘psychedelics’ to refer to other drugs, which may exert hallucinogenic effects via other mechanisms and are not considered ‘classical psychedelics’. For instance, drugs like ketamine are used routinely as anaesthetic agents but can induce hallucinations and dissociative effects at higher doses – leading to a sense of detachment from the world. Meanwhile, ecstasy (3,4-methylenedioxymethamfetamine; MDMA) primarily affects an individual’s mood and emotional processing of social stimuli, and some individuals suggest it should be considered alongside ketamine as a ‘non-classical psychedelic’.  

This briefing combines these definitions and refers to them under the umbrella term ‘psychedelics’. However, it is important to note different researchers or commentators use these interchangeably and there is an active community of research into the specific mechanisms of action of these chemicals and their resulting physiological effects, with overlap between them. 

Depressive disorders and their assessment 

Depression is a type of affective disorder (also known as mood disorder). Depression is the most common affective disorder and is estimated to affect 14.6% of adults in high-income countries. It  affected 1 in 6 adults aged 16 and over in Great Britain in 2021. The main symptoms of depression generally include:  

• low mood 
• disturbed sleep (more or less than usual) 
• changes in appetite and/or weight 
• fatigue or loss of energy  
• agitation or slowing down of movements and/or thoughts  

• poor concentration or indecisiveness 
• feelings of worthlessness, or excessive and/or inappropriate guilt  
• recurrent thoughts of death, recurrent suicidal ideas, or a suicide attempt or plan.  

These symptoms are reflected in the diagnostic criteria used internationally by psychiatrists and other mental health professionals – the ICD-11 (International Classification of Diseases-11) and the DSM-5 (Diagnostics and Statistics Manual-5). 

Once an individual has been diagnosed with depression, its severity can be assessed. Researchers have created validated questionnaires for assessing the symptoms of depression. A patient’s score can help the clinician determine an appropriate treatment and to monitor their response to it. They are also used in clinical trials to assess the impact of psychedelic drugs on depression. Different research groups use different depression questionnaires with their participants, which is important to be aware of when evaluating the results from different clinical trials. For example, an average reduction by three on one questionnaire may be more clinically significant than the same reduction on another.  

Approaches to the treatment of depressive disorders  

Treatments for depressive disorders are typically classified as either pharmacological (using drugs such as antidepressants) or psychological (such as talking therapies). However, pharmacological and psychological interventions are often employed as adjuncts to one another to improve outcomes, rather than being considered as distinct. For example, it is common for a GP or psychiatrist to offer a patient a pharmacological treatment if  they are waiting to be seen for psychological interventions. For some patients, psychological interventions have profound impact on their symptoms, whereas medications have little effect, and vice versa. Certain people with some forms of depression do not respond to any standard treatment. There is particular interest as to whether psychedelic drugs can have a therapeutic role for these people as current clinical trials suggest that these can be effective where other treatments have failed.  

Pharmacological approach 

The main first-line pharmacological treatment for depressive disorders is selective-serotonin reuptake inhibitors (SSRIs). Broadly, these medications work by increasing serotonin levels in the brain. Common SSRIs include medications such as sertraline, fluoxetine, or escitalopram, all of which have been demonstrated to be safe and effective for the treatment of depression. However SSRIs, whilst efficacious, can take several weeks to work and in some patients still do not improve their symptoms.  

There are other pharmacological agents recommended by NICE for use in depressive disorders in the UK, but generally SSRIs are preferred as the first choice as they are generally better tolerated and safer in overdose than other antidepressants. For this reason, the research into effectiveness of psychedelics often compares the outcomes with SSRIs as the current treatment of choice. The other medications that can be used for depressive disorders include: 

• Serotonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine or duloxetine. 
• Tricyclic antidepressants (TCAs) such as imipramine or clomipramine. TCAs work by blocking re-uptake of serotonin and noradrenaline, but to different extents than SNRIs or SSRIs and have more toxic adverse effects 
• Monoamine oxidase inhibitors (MAOIs) such as tranylcypromine or phenelzine. However, MAOIs are prescribed less frequently because of their dangerous dietary and drug interactions.  

Psychological approach 

Psychological intervention can be as effective as medication for treating some forms of depression. The most common form of psychological intervention is in the form of cognitive behavioural therapy (CBT). This is a type of talking therapy which focuses on negative thoughts, beliefs, attitudes, feelings, and maladaptive behaviour, and teaches coping skills to deal with challenging situations in life better. CBT is available in group and individual format and has been proven to be clinically effective both alone and in combination with SSRIs for the treatment of depression.  

There are other forms of psychological intervention also recommended by NICE for the treatment of depressive disorders: 

• Individual behavioral activation – focusses on identifying the link between an individual’s activities and their mood.  
• Group mindfulness and meditation.  

• Interpersonal psychotherapy – focuses on identifying how interpersonal relationships or individual circumstances can lead to feelings of depression and exploring these emotions to change responses.  
• Counselling – the focus is on allowing emotional processing to help people find a meaning in their experiences, and possibly facilitate people finding their own solutions or coping mechanisms. 
• Short-term psychodynamic psychotherapy – focuses on recognising difficult feelings in important relationships and challenging situations to identify how patterns can be repeated and perpetuated.  

Not all psychological options for the treatment of depression have been compared directly to SSRIs.  

Other interventions 

For people with the mildest symptoms of depression, guided self-help is often offered before any other intervention. This can include printed or digital materials that may include some principles of CBT or behavioural activation. Social prescribing can also feature in the management of depression – for example NICE recommends referral for group exercise in some cases. Electroconvulsive therapy (ECT) is also recommended by NICE for treating severe episodes of depression that are resistant to other treatments (treatment-resistant depression)   

How effective are psychedelics at treating depressive disorders? 

Psychedelic assisted psychotherapy (PAP) involves the professionally supervised use of psychedelic substances as part of a psychotherapy programme. Participants in studies will sometimes receive therapy sessions with professionals without administration of any psychedelic medication – either as preparation sessions, or to debrief after the administration of the medication. The exact type of psychotherapy used can be tailored towards both the psychedelic medicine used and the condition being treated. It is thought that the altered perception and increased openness provided by the ‘trip’ experience increases the effectiveness of the therapy. A recent review found that some of the perceived negative perceptions of the psychological risks with using PAP are not supported by scientific evidence.  

Most recent research into psychedelics for the treatment of depressive disorders has focussed on psilocybin. Psilocybin was demonstrated to have possible benefits as an adjunct to psychotherapy in the 20th century, but research largely halted in part due to legislative restrictions on access to psychoactive substances.   

Psilocybin 

Psilocybin has received increased attention for the treatment of depression in the last decade and is the psychedelic drug for which there is most evidence for its effectiveness. In 2016, a small study in 20 people with treatment-resistant depression reported that a single psilocybin ‘trip’ treatment significantly decreased depression symptoms for up to six months after two doses of psilocybin. This was an open-label trial, meaning both the researchers and participants knew what was being administered to each participant and there was no placebo. However, these findings were then replicated in two double-blind studies in patients with life-threatening cancer, again demonstrating significant decreases in depressive symptoms, this time in comparison to a placebo, an effect that was sustained for at least six months.  

Researchers have since conducted several further studies to determine whether psilocybin is safe and to characterise adverse effects, for which conditions they may be effective, and at what dose. They use a robust research method to test this. A randomised controlled trial (RCT) compares the drug against a placebo control group or against a drug which is the best existing treatment; the researchers and participants do not know who receives which intervention. Other studies offer the drug to all participants, with one group treated immediately and the other group offered the treatment later (several weeks). These studies have shown that psilocybin has a positive effect on symptoms of depression and with some evidence that the benefits endure for many months after one or two doses: 

• In 2021, a Phase II RCT of psilocybin involving 59 patients with major depressive disorder (30 received psilocybin and 29 received escitalopram, a commonly prescribed SSRI) which found that psilocybin is non-inferior to escitalopram at reducing depression symptoms and better at producing remission. All patients received psychological support alongside their allocated pharmacological treatment.  
• Similar findings were reported in 2021 by another group assessing psilocybin-assisted therapy in 24 participants with major depressive disorder at one-month follow-up. 
• A 2022 study reported that a randomised waiting-list controlled trial of psilocybin-assisted psychotherapy in 27 patients with major depressive disorder improved their symptoms, and the benefits lasted when 24 participants were followed up at twelve-months.  
• In another Phase II trial in 2021, participants with treatment-resistant depression received different doses of psilocybin (1mg, 10mg or 25mg). Those who received a 25mg (‘trip’) dose had reduced symptoms after 3 months; some participants reported adverse effects including headache and nausea. These adverse effects have also been reported in individuals undergoing SSRI treatment. 

• In 2022, results from a study conducted in 89 participants receiving either 10mg or 25mg of psilocybin showed these doses were generally well-tolerated and that there were no clinically relevant differences in detrimental short or long-term effects between those receiving psilocybin and the control group.  

Participants in such trials are allocated to mental health professionals who monitor them and care for their physical and psychological needs during and immediately after administration of the drug. Researchers have published guidelines to ensure the safety of participants undergoing research involving psychedelic drugs and these strategies were employed in the above studies.  

Ketamine 

Ketamine, and related compounds, have also been studied for the treatment of depression. Esketamine, a form of ketamine, was approved for the treatment of depression by the US Food and Drugs Administration in 2019. Whilst studies have indicated that esketamine may be effective in reducing depression symptoms, there is little long-term data about the possible risks and side effects. Recently, NICE commenced an evaluation of the use of esketamine for treating major depression in adults at imminent risk of suicide but did not receive the evidence required to create a recommendation. In their decision to not recommend esketamine as a treatment for treatment-resistant depression, NICE stated: 

‘the clinical evidence at this positioning is uncertain because it only considers a small number of people from the full clinical trial population. But it suggests that for people who have had at least three antidepressants with or without another treatment, esketamine with an SSRI or SNRI is likely more effective than placebo with an SSRI or SNRI. Because the trials were short the long-term benefits of esketamine are uncertain.’ 

Research investments to explore the value of psychedelic drugs to treat mental health conditions 

In 2019, Imperial College launched the first formal centre for psychedelic research in the world, with £3 million funding from five founding philanthropic donors.  

In 2022, a partnership between the Institute for Psychiatry, Psychology and Neuroscience and South London NHS Foundation Trust, alongside the healthcare company COMPASS Pathways, was launched to investigate the use of psychedelics for treatment-resistant depression.  

Some stakeholders have argued that more public funding should be made available to research psychedelics due to their potential to improve symptoms of depression and other mental illnesses. 

Meanwhile, other individuals contend that the UK’s current rules and attitudes are acting as a barrier to research with psychedelics. Professor David Nutt, who is Head of Imperial College’s Centre for Psychedelic Research, has previously written that the perceived dangers about possession and use of psychedelic drugs has led to the ‘unfortunate outcome’  that research into the possible benefits of these drugs clinically is now ‘almost impossible’. 

A qualitative study conducted amongst researchers using Schedule 1 drugs in the UK found that there was a perception of a lack of scientific understanding  amongst decision-makers involved in the scheduling of psychedelic drugs. A similar discussion has taken place in the US, with proponents of the use of psychedelics for mental health conditions arguing federal funds should be made more available for research in this area.  

Further Reading 

• Psilocybin-assisted therapy for depression – National Institute for Health Research 
• The Royal College of Psychiatrists published a newsletter on the use of psychedelics in psychiatry in 2018. 
• Debate on access to psilocybin treatments – Debate Pack 17 May 2023 Number 2023/0108, House of Commons Library  

Acknowledgements 

POST is grateful to Dr Stephen Naulls, National Medical Director’s Clinical Fellow at UK Parliament, for researching this briefing. POST would like to thank Professor David Nutt (Director of the Centre for Psychedelic Research, Division of Psychiatry, Imperial College London) and Professor Joanna Neill (Professor of Psychopharmacology, University of Manchester) who acted as external peer reviewers in preparation of this article. 

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