In his article for the Journal of Psychopharmacology, David Nutt compared psychopharmacology to the Greek mythology of Sisyphus. He said specificity was the Holy Grail of pharmacology, and it has “pursued the ambition of more specific and selective drugs for the treatment of mental illnesses.” While there have been spectacular accomplishments with medicines developed for systemic diseases (medical conditions that affect multiple organs and tissues or the entire body as a whole), there have been few successes within the province of brain medicines. “Few target-specific medicines have made it to the market, and many have failed.”
In Greek mythology, Sisyphus was the king of Corinth, who thought he was cleverer than the god Zeus. He was condemned by Zeus to eternally roll a massive boulder up a hill, only for it to roll back down every night, forcing him to repeat his climb daily with the same outcome. This myth has been used by many writers as a metaphor for the human condition. In The Myth of Sisyphus, Albert Camus used it to describe a philosophy of the absurd; meaning the fundamental human need to attribute meaning to life and the “unreasonable silence” of the universe.
In “What Sisyphus Can Teach Us About Psychiatric Drug Development,” Hannah Barnett interpreted what Nutt was saying for a broader audience of non-psychopharmacologists. She said he thought psychopharmacology had fallen into its own Sisyphean cycle of absurdity by relentlessly pursuing specific psychiatric drugs (i.e., SSRIs and SNRIs for depression). He seemed to be saying it may be time to question whether “specificity” with medications should remain the ultimate goal of psychiatry.
These drugs target one precise receptor, enzyme, or neurotransmitter system, pursued out of the belief that greater specificity would lead to safer, cleaner, and more effective treatments. Yet despite enormous scientific advances, progress in the development of fundamentally new psychiatric medicines has been slow.
In his article, Nutt concentrated on three reasons why narrowly target psychiatric drugs have consistently failed to deliver clinical breakthroughs. In a nutshell (no pun intended), he said the brain works through many connected systems simultaneously. Mental health conditions are not caused by a single biological abnormality and involve broad brain networks. Barnett described Nutt’s three reasons as follows:
- Most mental health conditions are not caused by one single biological abnormality. Unlike many physical illnesses, conditions such as depression, schizophrenia, and anxiety do not appear to come from one gene, chemical, or brain mechanism.
- The brain works through many connected systems at once. The brain is not a simple machine with “on/off switches”, but instead is controlled by overlapping systems working together simultaneously. This means that changing one brain chemical may have a limited effect, because other systems continue compensating or functioning alongside it.
- Mental health conditions involve broad brain networks, not just one target. Many psychiatric disorders appear to involve patterns of activity across large brain circuits rather than one specific receptor or pathway. This makes it difficult to develop highly precise drugs. Even if researchers successfully target one small part of the system, it may not substantially change the wider brain patterns linked to the condition.
Significantly, Nutt said many of psychiatry’s most effective medications did not originate from elegant neuroscience theories but were the result of serendipity and empirical observation. Many of these drugs were pharmacologically “messy,” meaning they affected several brain systems at once. For example, SSRIs (selective serotonin reuptake inhibitors) target the neurotransmitter serotonin, which not only seems to play a role in depression and anxiety, but also influences learning, memory, body temperature, sleep, sexual behavior, and hunger.
Serotonin in your brain regulates your mood. It’s often called your body’s natural “feel good” chemical. When serotonin is at normal levels, you feel more focused, emotionally stable, happier and calmer. Low levels of serotonin are associated with depression. Many medications used to treat anxiety, depression and other mood disorders often target ways to increase the level of serotonin in your brain.
This lack of precision has historically been seen as a weakness in drug treatment, but Nutt seems to think it explains why many of these narrowly targeted psychiatric drugs didn’t work; why they didn’t deliver on the clinical breakthroughs their marketing publicized. “According to Nutt, many of psychiatry’s most effective treatments were not born from elegant neuroscience theories, but from serendipity and empirical observation.” Rather than targeting a narrow symptom pathway, they influenced broader patterns of brain activity and communication. Nutt proposed some possible solutions, which Barnett described as better serendipity, multi-target drugs, and network-changing treatments.
Better Medications Through Serendipity, Multiplicity, and Plasticity
Nutt thought there was value in placing greater emphasis again on observation and unexpected discoveries, or serendipity. He did not mean random effects without direction. But paying attention to patterns that emerged in “real-world patient experiences, population health data, and reports from clinicians and people using drugs themselves.” If large numbers of people consistently report improvements (in mood, addiction, quality of life) with particular substances, further scientific investigation is warranted—regardless of whether why they work is understood.
Instead of developing drugs that act on one receptor of brain chemical, future psychiatric medicines should be designed to affect several systems at once. These treatments (medications) need to be developed with the understanding that mental health conditions “involve complex and interconnected brain processes.” This new approach would mirror the reality that mental health conditions are fashioned by many interacting brain systems, and not one isolated biological problem.
The third strategy proposed by Nutt was altering functional brain networks rather than targeting a specific neurotransmitter. Nutt said this idea emerged from observations of serotonergic psychedelics such as psilocybin, LSD, DMT (ayahuasca), and ketamine. “Rather than simply dampening symptoms, these compounds may temporarily interrupt rigid patterns of thought, emotion, and behaviour while also increasing the brain’s ability to adapt and form new connections.” This “window of plasticity” may help explain why psychotherapy, environmental context and integration are so important to therapeutic outcomes. Nutt said:
This state persists for many weeks and is believed to allow the laying down of new learnings and more adaptive behaviours that facilitate and strengthen the recovery processes so that a single psychedelic experience can lead to enduring, even lifelong, benefits. It has been suggested that neuroplasticity may be enhanced without a psychedelic experience – either by using sub-psychedelic doses of psychedelics or by developing new agents. There is some evidence that this approach can have therapeutic utility … to facilitate psychotherapy.
A Paradigm Shift with Psychedelics?
Barnett said for Nutt, psychedelics are more than another drug class. “They are presented as part of a fundamentally different treatment paradigm.” She said psychopharmacology has operated under the assumption that more specific drugs would lead to better treatments (medications). “But if mental health conditions arise from disruptions across wider brain systems rather than one isolated biological problem, future progress may depend less on narrowly targeted drugs and more on approaches that work across multiple systems at once.”
Nutt appears to be frustrated with how the existing methodological hurdles presented with psychedelic drugs as “treatment” for mental health conditions have slowed down or stalled their approval process. That is, placebo-controlled clinical trials and regulating the psychotherapy concurrent with the psychedelics. He said, “The current excessively puritanical approach of denying the value of studies of new psychiatric drugs that are either not fully placebo-controlled or fully blinded needs rectifying.” He observed it wasn’t applied to many other serious indications, like new oncology treatments.
Neuroplasticity-promoting agents may only work if given with psychotherapy, so clear guidance on how to do this to meet the approval of drug regulators who don’t regulate psychotherapy must be resolved quickly, ideally in conjunction with the professional bodies overseeing psychotherapists.
Placebo-controlled clinical trials have been considered the gold standard for the clinical investigations of new drugs. Research has shown that placebo effects can be robust in both laboratory and clinical settings. There is even evidence that suggests placebo effects can exist in clinical practice, even if no placebo is given. “The interest in placebo effects only began with the widespread adoption of the randomized controlled trial (RCT) after world war II.”
The randomized clinical trial was a major methodological breakthrough in medicine and the best evidence for new treatment came from randomized placebo-controlled (RCT) double-blind studies. It was noticed that patients improved, sometimes dramatically, in placebo control arms. Henry Beecher popularized this observation in his famous proto-meta-analysis which claimed that about 35% of the patients responded positively to placebo treatment.
Placebo-controlled psychedelic studies have been shown to break the double-blind of studies regularly, introducing potential bias when researchers interpret the study’s results. This occurs because of the psychoactive effects of substances like LSD and psilocybin make it obvious to both participants and researchers who received and who did not receive the active drug. The use of active placebos instead of inert ones may lessen the unblinding that occurs with psychedelic trials. But more research needs to be done here, and I think David Nutt needs to be patient with the process.
Safety and efficacy with psychedelic-assisted therapy relates to developing effective protocols for regulating the psychotherapy concurrent with the psychedelics. The overdose death of Matthew Perry from the acute effects of unsupervised ketamine use illustrated the need for concurrent psychotherapy with these substances. This adds to the cost and limits the number of people who can afford psychedelic-assisted treatments. Before psychedelic-assisted therapy can be more widely introduced this hurdle needs to be addressed. If our brains work through many connected systems at once, and mental health conditions involve broad brain networks, research needs to be particularly aware of the safety and efficacy concerns with psychiatric drug development.
Returning to the application of the Sisyphus myth to drug development, perhaps the absurdity is expecting the standard scientific methodology to change faster than it is. Or maybe the absurdity is to pin our hopes for mental health improvement on finding the “right” brain medications. British psychiatrist Joanna Moncrieff has suggested we need to have a paradigm shift with our understanding how drug treatments work. She has proposed two models of drug action, the ‘disease-centered’ model, and the ‘drug-centered’ model.
The disease-centered model suggests psychiatric drugs work by reversing the abnormality or disease that manifests the symptoms of a particular psychiatric disorder. The drug-centered model suggests psychiatric drugs induce an abnormal or altered brain state. As psychoactive substances, they “modify the way the brain functions and by doing so produce alterations in thinking, feeling and behaviour.” The psychoactive effects produced by some drugs can be useful therapeutically in some situations. But they don’t do this by normalizing brain function.
For more information on Moncrieff’s thought, see the above link to “models of drug action,” The Myth of the Chemical Cure or “A Drug is a Drug is a Drug.” There is also a YouTube video of Moncrieff here. For further thought on psychedelics for mental health, see “Pursuing Psychedelic Therapy,” “Psychedelic Hype Ahead of Science,” and several other articles on Faith Seeking Understanding.
