Notes on Engineering Health, November 2023: Notes on How We Drug The Brain

Above:
Detail of Glial cells of the cerebral cortex of a child, Santiago Ramón y Cajal, 1904



The late neurologist Oliver Sacks had his fair share of experience with experiments on chemical compounds altering brain functions. He wrote beautifully in books and articles about how he experimented on himself both to relieve pain and to explore unvisited corners of his self. He was a keen observer of how mental diseases work and what is available to treat them.

How did we get to produce such neuro-active compounds? Are the nervous system and the brain like any other organs? Where is neuropharmacology going?


Definitions
Neuropharmacology is the study of how drugs alter cellular function in the nervous system and the neurological mechanisms by which they influence behavior. It is commonly divided into two branches:

– Behavioral neuropharmacology (or neuropsychopharmacology) focuses on how drugs affect human behavior and how drug dependency and addiction affect the human brain.

– Molecular neuropharmacology focuses on the study of neurons and their chemical interactions. It aims to discover medications that improve brain and neuronal function.

Both domains deal with the interplay of chemical agents controlling neurological functions—neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, secondary messengers, cotransporters, ion channels, and receptor proteins—in the central and peripheral nervous systems. The therapeutic aim of understanding these areas is to create medications to treat a variety of neurological conditions including pain, neurodegenerative diseases, psychological disorders, addiction, and many more.

Short History
Although people have used opium and alcohol for millennia to ease suffering and alter consciousness, the history of formal neuropharmacology really began in the late 19th century with the understanding of how nerve cells communicate. Scientists like Ramón y Cajal made groundbreaking discoveries about the structure and function of neurons, pioneering the field of neuroscience. He and others led the way in understanding how the nervous system is structured and how nerves communicate with one another. Cajal’s early desire to be an artist served his scientific endeavors well, as the exquisite drawings he left behind helped the field to understand neuroanatomy more deeply, and are still in use today for educational and training purposes.

Cajal’s and others work helped create the premise that all states of mind, as well as mental and cognitive diseases, had their basis in neurochemical interactions in the central nervous system. Drugs affecting the nervous system had been generated before these advancements but with no mechanistic understanding. For example, in the 1930s, phenothiazine was tested to combat malaria. Though completely ineffective for its primary purpose, it was found to work as a sedative along with what appeared to be beneficial effects for patients with Parkinson's disease.

This serendipitous approach remained the only way to “drug” the nervous system until the middle of the 20th century when both the ability to keep neurons alive ex vivo and progress in chemistry allowed scientists to isolate and identify specific neurotransmitters leading to the production of epinephrine (adrenaline), the first neurotransmitter to be isolated and synthesized.

Two advances in neuroscience then accelerated the field dramatically in the 1950s: the ability to measure and correlate levels of neurotransmitters in the body with behavior, and the invention of the voltage clamp allowing the study of ion channels and nerve action potential. These two significant advances in neuropharmacology allowed scientists to study how information is transferred from one neuron to another, how a neuron processes this information within itself, and, more importantly, served as a model to screen chemical compounds susceptible to modifying neuron functions.

From then on, the expansion of the pharmacological toolbox, the advances in in vitro central nervous system modeling, and the leaps in genomic understanding led to different types of drugs produced (e.g., agonists, competitive antagonists, and non-competitive antagonists), different types of neurons targeted (e.g., by neurotransmitters they use including GABA, dopamine, serotonin), and different drug functions (e.g., anxiolytics, antidepressants, antipsychotics, mood stabilizers). However, it is important to note that the failure rate for new drugs targeting central nervous system diseases is very high relative to most other areas of drug discovery, a fact reflected in the many pharmaceutical company CNS programs that have been disbanded over time.
‍
Why is it so Tricky to Drug the Brain?
One reason is neuropharmacology is so hard is that the brain and the central nervous system are protected by a blood-brain barrier. The difficulty of crossing the semipermeable border of endothelial cells has been a significant obstacle in developing new chemical matter, as most solutes and chemicals never reach the brain itself. As a consequence, the lack of effectiveness of neuro-focused drugs has plagued the field more than their toxicity profiles. The immense complexity of the nervous system, the poor translatability of in vitro and animal models, and the lack of adequate biomarkers also explain the relatively slow progress of the field.
‍
An Evolving Nomenclature
The development of new drugs and the continued progress in understanding neurological functions has created some confusion about which drugs are best used for which conditions. As such, the nomenclature of drug names has been evolving. All drugs, including psychotropic drugs, have been classified according to the Anatomical Therapeutic Chemical (ATC) nomenclature. Designed by the World Health Organization (WHO) in the 1960s, the ATC system traditionally classifies psychotropic drugs by indication, such as antidepressants for depression. However, this classification system had many flaws, most prominently the fact that psychotropic drugs can nowadays be prescribed for more than one purpose, such as anxiolytics being prescribed for anxiety and depression. Therefore, a new nomenclature system was devised dubbed the Neuroscience-based Nomenclature (NbN). The idea behind the NbN system is that psychotropic drugs are named after the neurotransmitter system that the drug modifies and the mode of action rather than their indication. This naming system has provided a more consistent and precise description of what the drug does based on the current understanding of the drug's biological mechanism of action rather than muddied descriptions based on indication.

Even more innovative attempts have recently been made to categorize antipsychotic drugs. Instead of categorizing them based on chemical structure (phenothiazines, butyrophenones), and on epoch of introduction (first generation versus second generation), scientists have used affinity to a receptor and date of production to create “subway maps” of drugs. Based on current scientific knowledge, this design allows visualization of both the historical classifications by structure and times of introduction and of the binding affinities for key receptors. This effort, while still nascent, is crucial as it should help prescribers and patients understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms.

A Comeback of the Black Box With Psychedelic Science
A renewed interest in ancient medicinal treatments, as well as the popularity of meditation and other non-pharmacological interventions are testaments to the limit of the current format of drug development. The difficulties in creating new drugs targeting the brain have in fact prompted scientists to look to the past and explore the black box “strategy” that “worked” in the early days of drug development.

During the 1950s and into the 1960s, more than 1,000 scientific articles appeared as researchers around the world interrogated the potential of psychedelics for healing addictions and trauma. This line of research was paused for obvious safety concerns, and over time rational methods became the preferred route for development. However, the safety profile of these drugs is being reassessed, and major scientific journals and many serious research institutions are investing time and effort into understanding better how to use these once-controversial compounds. This work includes evidence that psilocybin (a.k.a., mushrooms) significantly reduces anxiety in patients with life-threatening illnesses like cancer, and that MDMA (3,4-methylenedioxy-methamphetamine; a.k.a., ecstasy) improves outcomes for people suffering from PTSD.

Drug development is an arduous endeavor, and perturbing neuronal connections to improve the human condition has proven to be a particularly challenging, if fascinating, area in particular. Modifying our perceptions to reduce pain or anxiety touches on basic questions of consciousness and identity, and the risk-benefit tradeoff that is the hallmark of any drug reaches paroxysmal importance when the brain is involved. The combination of well-understood drug development methods, the use of ancient knowledge, changes in lifestyle, and a touch of AI may all be required to dream the next chapter of neuropsychopharmacology, and would have all pleased an adventurer such as Oliver Sacks.

– Jonathan Friedlander, PhD & Geoffrey W. Smith



Engineering Biology
Jacob Oppenheim, PhD, and Entrepreneur-In-Residence at Digitalis Ventures, writes Engineering Biology at Digitalis Press:

In case you missed it, Jacob wrote about where and why big data has failed to meet expectations and how the web became a panopticon of tracking tools. In a follow-up piece, he proposed a new way of thinking about how to pair the need for privacy with the serious benefits of population-level datasets.



First Five
First Five is our curated list of articles, studies, and publications for the month.

1/ Scratch That Itch
Some may remember the troubling article published by the New Yorker in 2008 about a frightening and persistent itch. Scientists recently showed for the first time that bacteria can cause itch by activating nerve cells in the skin. This discovery might help develop new strategies to treat skin conditions affected by this tickling guest.

2/ The Taste of Enough
We knew the feeling of satiety came from how full the stomach is and some neural signal coming from the gut. A team from UCSF just published in Nature that neurons controlling ingestion are present in our taste buds. This discovery may help to design better foods, but also to uncover some of the mechanisms of recent sensational weight loss drugs.

‍3/ Zoom Fatigue
We knew it, scientists proved it. Using EEG and ECG data, researchers demonstrated that video conferencing lead to greater fatigue than face-to-face alternatives. Adding to self-reports through questionnaires, this neurophysiological perspective confirms one may feel better after an in-person meeting than after talking to the screen.

4/ The Brain Wave
As mentioned in the opening section, the integration of information from different neurotransmitters is partly how neurons transmit signals. A team of scientists described a new kind of neurochemical wave in the brain important for motivating actions and habitual behaviors. Using state-of-the-art genetic tools and advanced imaging techniques, they propose a mathematical mechanism by which simultaneous waves of acetylcholine and dopamine arise, which may represent how an adequate balance of neurotransmission is realized.

5/ The Immune Response of Exercise
Exercise is good! But why? New research published in Science Immunology shed new light on the immune response linked to exercise. In mice, scientists showed that the anti-inflammatory properties of exercise may arise from immune cells mobilized to counter exercise-induced inflammation. Regulatory T cells (Tregs) prevent muscle damage by lowering levels of interferon, a key driver of chronic inflammation, inflammatory diseases, and aging.

‍