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Psychedelics: A new kind of trip

When we think about consciousness, we often consider it as being aware of one’s internal and external existence. But while there’s been decades of analyses and debate among philosophers and scientists regarding the definition of consciousness, it still remains a controversial subject today. Nevertheless, altering this state can lead to bizarre visual effects. Objects bend, colours begin to merge, intricate geometric patterns appear over everything you see. Basically, a Tim Burton film. While for most this could feel like you are having a sudden stroke, these effects are familiar to those who take psychedelic drugs.

Most frequently associated with the counterculture of the 1960s, psychedelics have a long history of stigma that still exists today. Despite the fact that psychedelic drugs are largely illegal worldwide, recreational use is still common. As such, legal barriers have made scientific research of psychedelics extremely difficult. Nonetheless, promising evidence continues to emerge showing that psychedelics are physiologically safe and can in fact be used to treat mental health disorders.

In this blog, we delve into the history of psychedelics, how genomics has provided greater insights into the mechanisms of these drugs, and how they can be harnessed to treat a range of debilitating disorders. 

Mind manifesting

The term ‘psychedelic’ is derived from the Greek words ψυχή (psyche, ‘soul, mind’) and δηλοῦν (deloun, ‘to manifest’), hence the term ‘mind manifesting’. It was first coined by British psychiatrist Humphry Osmond in 1957. While this term has been popular among the lay public for decades, its use has generally been frowned upon by the scientific community as it implies that these substances have useful properties. In fact, in the late 60s, it was politically correct in scientific circles to refer to these substances only as ‘psychotomimetics’, which suggested that these drugs fostered a mental state resembling psychosis.

It was later realised that these compounds did not provide realistic models of psychosis or mental illness. This led to the term ‘hallucinogens’ being more commonly used. Yet, this term again has negative connotations, implying that these drugs principally produce hallucinations. In reality, at ordinary doses most users do not experience hallucinations. Nonetheless, this terminology is still widely used today and remains the preferred name for these substances within scientific writing.

In pursuit of serotonin

Substances that act primarily as an agonist (or partial agonist) on brain serotonin 5-hydroxytryptamine (5-HT) 2A receptors (Figure 1) are referred to as classical serotonergic hallucinogens (psychedelics). 5-HT2A receptors, or serotonin receptors, are a group of G protein-coupled receptors and ligand-gated ion channels that are found in the central and peripheral nervous systems. They can mediate both excitatory and inhibitory neurotransmission. Moreover, these receptors are involved in modulating the release of many neurotransmitters, including dopamine, epinephrine and acetylcholine. Ultimately, serotonin 5-HT2A receptors influence various biological and neurological processes such as aggression, anxiety, appetite, mood and memory. In the context of psychedelics, these chemicals bind to serotonin 5-HT2A receptors, which modulate the activity of key circuits in the brain, particularly those involved with sensory perception and cognition.

Figure 1 | This figure highlights the chemical architecture of amino acids that make up the 5-HT2A serotonin receptor complex bound to a psychedelic compound (pink, magnified on the right). Source: Bryan Roth Lab (UNC School of Medicine)

Pick and don’t mix

Most psychedelic drugs fall into one of the three families: tryptamines, phenethylamines, or lysergamides. The main classical hallucinogens include:

  • LSD (d-lysergic acid diethylamide): First synthesised in 1938 by Swiss Chemist, Albert Hofmann, LSD (also known colloquially as ‘acid’) is considered one of the most potent mood- and perception-altering hallucinogenic drugs. It is derived from compounds found in a parasitic fungus (ergot) that primarily grows on rye. Typical effects include intensified thoughts, emotions and sensory perception.
  • Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine): Psilocybin was first isolated by Hofmann in 1957 from the Psilocybe mexicana mushroom. Since then, it has been identified as a component of over 75 distinct mushroom species. In the past, psilocybin was ingested by indigenous cultures (e.g., Northern Eurasian and Mesoamerican) during religious ceremonies. The effects of psilocybin are typically similar to those of LSD, including an altered perception of time and space, and intense changes in mood and feeling.
  • Mescaline (3,4,5-trimethoxyphenethylamine): Mescaline was first isolated and identified by German chemist, Arthur Heffter, in 1897, and then first synthesised by Ernst Späth in 1918. It is found naturally in the San Pedro cactus (Trichocereus (Echinopsis) pachanoi), the Peruvian torch (Trichocereus peruvianus (Echinopsis peruviana)), the peyote cactus (Lophophora williamsii) and other species of cactus. Although mescaline induces a psychedelic state similar to LSD and psilocybin, it results in some other unique characteristics. It alters thinking processes, sense of time and self-awareness and results in geometrisation of 3D objects.
  • DMT (Dimethyltryptamine): Although DMT was first synthesised in the 1930s, its psychotropic properties were not discovered until some 20 years later by Hungarian chemist and psychiatrist, Stephen Szara. DMT is produced in many species of plants and is usually one of the main active constituents of the drink ayahuasca (a South American psychoactive brew). It is known for giving users a very intense ‘trip’, with distortions of colours, sounds and objects.

The psychedelic experience

The ‘psychedelic experience’ is not just one experience. Different psychedelics induce different experiences. Not only this, but the individual, their mood, their environment and ultimately the dose they take can influence their overall experience.

In fact, despite attempts, a universally accepted taxonomy of common structures produced by classic psychedelics does not exist. But, in general, psychedelic substance use is significantly associated with a positive mood. It can also result in a temporary loss of ‘self’ from the rest of the world. At lower doses, features include sensory changes, such as colour variations and repetitive geometric shapes. Whereas at higher doses, individuals often experience intense alterations, such as additional spatial or temporal dimensions. The experiences of users have led to the development of some stimulating psychedelia and inspired a lot of music in the late 1960s. Moreover, documenting these feelings won Michael Pollan’s book, How to Change Your Mind, the New York Times best-seller in 2018. 

But scientifically, what is the psychedelic experience?

Over the years, several useful rodent models have been developed to help unravel the neurochemical effects of 5-HT2A receptor activation. In addition, the advent of powerful brain imaging technologies has enabled rapid advances in our understanding of brain function and connectivity. While these studies have offered some preliminary answers, our understanding of the overall action of psychedelics in the brain is far from being fully understood. Nevertheless, a few studies have begun to characterise these effects.

One of the key findings has been the interaction of psychedelics with the default mode network (DMN), a part of the brain associated with mental chatter, self-absorption, memories and emotions. A 2014 study looked at brain images of individuals on psychedelics and found that the DMN shuts down almost entirely. Interestingly, in this same study, the researchers found that psilocybin caused a stronger communication between parts of the brain that are normally disconnected from each other (Figure 2). It demonstrated that psilocybin disrupts the normal organisation of the brain with the creation of topologically long-range functional connections that are not present in a normal state. This phenomenon is likely one of the most relevant pharmacological mechanisms underpinning the psychedelic experience, particularly the loss of subjective self-identity (ego death).

Figure 2 | A visualisation of the persistence of homological scaffolds. The image on the left (a) is of a human brain on a placebo, and the image on the right (b) is of a brain on psilocybin. These images highlight the striking differences in connectivity structure in the two cases. Source: Petri et al, 2014.

Meanwhile, some researchers have been exploring the importance of context when it comes to the experience of individuals taking psychedelics. Robin Carhart-Harris and David Nutt in 2017 proposed the extra-pharmacological (EP) model of drug action (Figure 3). This model provides a comprehensive account of the action of psychoactive drugs. Its components include:

  • Trait factors: These factors can be biological (e.g., receptor polymorphisms), psychological in nature (e.g., personality) or suggestibility.
  • Pre-state: This relates to anticipatory anxiety, expectations and assumptions and an individual’s readiness to ‘let go’ to the drug effects.
  • State: This refers to the acute subjective and biological quality of the drug experience. This can be measured via brain imaging.
  • Dose: This relates to the drug dosage, which can be a critical determinant of the state.
  • Environment: This is about the various environmental influences and is traditionally referred to as the ‘setting’.
  • Long-term outcomes: This can include symptoms of a specific psychiatric condition and also pathology-independent factors, such as personality and outlook.

A recent opinion piece drew upon this model and noted that insufficient appreciation of these extra-pharmacological factors could lead to risky and potentially harmful applications of psychedelics. The authors hope that this model could help optimise treatment models in the future. 

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Figure 3 | Extra-pharmacological (EP) model of drug action. This model considers salient contextual factors. Source: Carhart-Harris and Nutt, 2017

The shadow of the counterculture revolution

While the science behind psychedelics is becoming clearer, psychedelic plants have been used in rituals and ceremonies for thousands of years. As a result, these substances have been hugely influential in shaping certain cultures and religions, particularly in the Americas, dating back to 4,000 BC. These groups learned how to utilise these plants and mushrooms for medical purposes or for entering a state of altered consciousness.

Psychedelic drugs entered into popular culture in the 1960s. The use of psychedelics, such as LSD, by so-called hippies demonstrating against the Vietnam War created great dismay among authorities and legislative bodies. Mainstream culture perceived anti-war attitudes and rejection of conventional social norms as a consequence of drug use. This led to strict laws being approved quickly. The passage of the Controlled Substances Act of 1970 by President Richard Nixon placed LSD and other psychedelics into the most restrictive category of drugs, Schedule 1. This in turn made them virtually impossible to study clinically and essentially ended any significant research in this area for over three decades.

The ‘60s counterculture was transformative in many regards. It catalysed several movements, including the environmental movement, the civil rights movement, the anti-war movement and contemporary feminism. However, these movements also produced a backlash against psychedelics that lasted decades. The speed at which these drugs were adopted, ultimately, was their downfall. There were no structures in place or norms surrounding them. This, coupled with general ignorance about drugs themselves, was too much for society to handle at the time.

But a lot has changed since then. Both the political and cultural landscape is completely different. Concepts and ideals that were once alien to us, are now integrated into society. Subsequently, people have generally become more receptive to psychedelics. 

The psychedelics renaissance

Although the psychedelics industry became largely inactive around the ‘60s, in recent years there has been an explosion of unprecedented research surrounding the therapeutic potential of psychedelics. This has triggered many countries to reassess their decision to criminalise psychedelics. Researchers are now looking to harness these drugs to help people with mental disorders, such as post-traumatic stress disorder (PTSD), alcoholism and depression. Nonetheless, in order to use these drugs in a therapeutic setting, researchers must still understand the transcriptional programmes (differentially expressed genes) initiated by psychedelics to gain insight into their potential long-term clinical benefits and risks.

Much work, like in Figure 2, has focussed on imaging studies, which have shown that psychedelics impact brain network connectivity. These alterations are likely mediated by effector pathways downstream of serotonin 5-HT2A receptor activation. One area of research that is being explored is how these downstream effector pathways influence gene expression changes, and in turn impact synaptic plasticity and long-term changes in brain neurochemistry. Synaptic events, such as late long-term potentiation, require the transcription and translation of a number of genes important for forming memories and mediating learning. Examination of the patterns of mRNA can provide information about the signalling pathways these drugs modify. For example, the first microarray screen of LSD-induce gene expression identified that the ania3 transcript was differentially expressed.  

As molecular technologies have evolved, researchers have been capable of performing more in-depth analyses on psychedelics, including RNA sequencing. For example, a research study in rats showed that genes altered by LSD were significantly concentrated in pathways related to neurotransmission, synaptic plasticity and metabolism. In fact, researchers identified no genes that were indicative of damage or stress.

Researchers have also been looking to explore the role of epigenetic changes on the long-lasting effects of psychedelics. For example, it has been found that ketamine’s antidepressant effects can wear off after about two weeks. Whereas psilocybin has been demonstrated to last upwards of four years. To further gain clues about what populations of cells are being affected by psychedelics, researchers are also hoping to apply single cell RNA sequencing methods to identify their mechanisms of action at high resolution.

Without the trip

Aside from recreational use, there is a growing body of evidence supporting psychedelics’ therapeutic applications. Preliminary evidence has shown that these drugs may be useful in treating several different conditions. For example, a study published in 2021, showed that two administrations of psilocybin produced antidepressant effects in patients with major depressive disorder. In another study, researchers found that LSD reduced anxiety in patients with life-threatening diseases. Ayahuasca has also been shown to improve several factors related to problematic substance use disorders, and was also able to reduce alcohol, tobacco and cocaine use.

Interestingly, more recent research using animal models has revealed that psychedelics can also have anti-inflammatory effects. Researchers have found that the drugs can induce potent suppression of many symptoms and pro-inflammatory biomarkers in models of asthma and cardiovascular disease. This indicates that psychedelics may not only directly affect neural processes and circuitry, but they may also have anti-inflammatory properties that could be key in treating a wider range of conditions.

Researchers also hope that advanced technologies will enable us to identify key genes and mechanisms that are inducing psychedelics’ anti-depressant effects. Then, by combining this knowledge with receptor pharmacology drug design, it may be possible to develop a new class of psychedelics that will preferentially activate the necessary effector pathways.

As these drugs’ hallucinogenic properties make them difficult to administer and monitor, researchers are looking to producing drugs that keep the beneficial properties without the hallucinogenic side effects. For example, Bryan Roth’s Lab at the UNC School of Medicine was recently awarded $26.9 million from the United States Defense Advanced Research Projects Agency (DARPA) to develop more precisely targeted pharmaceuticals with fewer undesirable side effects for the US military. Elsewhere, Dong et al (2021) recently developed a sensor technology that can predict a molecule’s hallucinogenic properties in mice. This technology represents an innovative approach to screen for non-hallucinogenic psychedelics.

The next psychedelic journey

At the end of the day, psychedelics are Schedule 1 drugs. Even writing this, despite the abundance of ground-breaking evidence, I would still be apprehensive about their mainstream use. This is not because I don’t trust the evidence, but more because my opinions have been shaped by the narratives portrayed by the media and public opinion. Society has created negative connotations surrounding the use of psychedelics, which in turn, will be difficult to shift.  

We are now entering into unknown territory, which is exciting in many ways. Psychedelics are now in a phase of mainstreaming, where those who might not have ever considered taking these drugs are curious. Researchers are beginning to obtain a clearer picture of what factors may influence an individual’s psychedelic experience. For example, individuals with a history of psychosis have been suggested to have an increased likelihood of experiencing a ‘bad trip’. In turn, scientists exploring the effects of psychedelics must adopt rigorous screening protocols to ensure only low risk individuals receive these therapies. Eventually, we will have to come up with new treatment strategies and regulatory policies to effectively and safely control the use of these drugs. Most importantly, the desire to use psychedelics, albeit illegally, is currently outpacing regulators’ willingness to decriminalise. It therefore imperative to accelerate research in this area to identify patients who may be at risk of adverse reactions.

The Multidisciplinary Association for Psychedelic Studies (MAPS), for example, is a non-profit organisation that aims to raise awareness and understanding of psychedelic substances. It helps scientists design, fund and obtain regulatory approval for studies exploring the safety and effectiveness of a range of controlled substances. In addition, MAPS works closely with regulatory authorities worldwide, such as the FDA and EMA. Some of MAPS’ ongoing research efforts include exploring the effects of LSD and psilocybin for the treatment of anxiety, cluster headaches and depression associated with end-of-life situations.

Millions of individuals worldwide continue to suffer the burden of illnesses such as post-traumatic stress disorder and depression, for which current treatments simply fall short. It is therefore reasonable to argue that it is researchers’ moral responsibility to explore every available treatment option. Even if that treatment is not currently legalised. Nonetheless, emerging data is continuing to indicate the high safety and feasibility of psychedelic drugs when conducted under the appropriate environment. It is hoped that the continued validation of the positive therapeutic effects of psychedelics and the identification of the underlying mechanisms of these drugs will open up a whole new dimension of medical research. This in turn, will shake up the field of psychiatry and enhance the discovery of better treatments for a host of extremely debilitating and stigmatised human disorders.


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