On am morning walk, I saw a grown man with a big gulp cup of soda. Triggered some thoughts about societal norms, and social sins. Over the course of my brief lifespan wearing fur and smoking have been increasingly demonized into extinction or ghettoized. Both products can be readily obtained from nature. Fur trade was the primary commerce of colonies in Canada & parts of USA. Smoking has been beaten into our collective unconscious for a few generations as universally bad. However, by comparison prescription pill abuse is largely ignored.
For example, here is a list of some drugs that cause acute pancreatitis, one of which is opiates. After pancreatitis attacks cells in the pancreas can regenerate. However, in the presence of morphine this ceases. Chronic pancreatitis confers a %500 stronger risk factor than smoking for pancreatic cancer. One key distinction between the influence of the pharmaceutical industry and the agricultural industry is the near monopoly protection that patented compounds confers to parent companies. Patent protection provides profits for companies to reinvest in advertising and political protection through to achieve a feed-forward (amplifying)network effect. Once critical mass is reached the power function distribution of an association in the collective consciousness is acheived. SSRIs are paired in the mind of this mass consciousness as the main treatment of mood disorders such as depression, benzodiazepines with anxiety, etc.
By contrast, agricultural forces lacking such patent protection are more disparate. Corn farmers in Iowa, Nebraska, Texas won’t lobby on behalf of tobacco farmers in Kentucky. But doctors and large pharmaceutical companies have the capacity to circle the wagons to protect themselves and the medical profession from over prescription.
One of the key traits of Europeans since the industrial revolution is a reliance upon methodological reductionism of natural products. A good example of this is the cultivation of coca leaves which was part of Incan culture for centuries. The Incan tribe in South America would eat leaves raw.
They even measured distance by it. A “cocata” is the distance one can walk chewing 1 leaf. Three hundred years after the Spanish explored South America, a German Albert Neimann had isolated the molecule cocaine. Cocaine binds to dopamine receptors but also noradrenaline and it has the effect of blocking reuptake which gives it a rewarding high. Unfortunately cocaine also blocks sodium channels which can cause heart attacks at high doses. Here is a red flag of reductionism.
The same process occurred for tobacco leaves in North America, it was traded back to Europe for centuries before Europeans determined that nicotine was the key molecule for its effects.It was German chemists again that isolated nicotine from tobacco plants this time it was Posselt and Reiman . Nicotine is a reductionists dream because it binds with an even more selective affinity than cocaine (which binds to several catecholamine receptors) for specific cholinergic receptors
It is with tobacco that the demonization of the agricultural industry begins, while in parallel chemists attempted to optimize the benefits of nicotine in isolation from the tobacco leaf. Galantamine was the first real “success” story which was isolated by Russians and Bulgarians from other plants and binds to alpha4beta2 nicotinic receptors. This compound also acts as a cholinesterase inhibitor to increase the amount of acetylcholine in the extracellular space in the brain.
However recent trials of nicotine receptor ligands have been promising but keep failing in phase 3, trials for individual nicotinic compounds targeting schizophrenia or depression all failed. The most recent success story has been Chantix an alpha4beta2 partial agonist, as smoking cessation tool. Chantix can only be sold if smoking is social sin.
Intriguingly single ligands binding to nACHRs (nicotinic acetylcholine receptors) all did well on Phase 1 & 2 trials for Schizophrenia or Depression. Epidemiological evidence supports the efficacy of nicotinic receptor activation Schizophrenics smoke 3 to 4 times as much as normal peoples. Depressed patients smoke 2x normals. So perhaps there is some alchemical, holistic reasoning suggesting that smoking tobacco and activating nicotine receptors in addition to 100s of other compounds in the tobacco leaf does ameliorate some of the symptoms of these mood disorders.
Allosteric modulation and a new holistic approach
Neurons communicate through the transmission of specific compounds (neurotransmitters and neuropeptides) which bind to receptors. Receptors have channels which allow ions and when neurotransmitters like glutamate bind to those sites the channels open. When these channels open positively or negatively charged ions produce electrical spiking activity or action potentials. The receptors on pre- and post- synaptic neurons are made of proteins and are subject to allosteric regulation. Allosteric sites do not directly open channels. It was two French biochemists, Jean Pierre Changeaux and Jacques Monod, joined by an American Jeffry Wyman that posited this model based on Jean Pierre Changeaux’s experiments. I am using receptors but this could apply to any protein, such as enzymes like monoamine oxidase (which breaks down catecholamines). Proteins can have tense and relaxed states. One interesting target of allosteric modulation is the alpha7 nicotinic receptor.
This receptor has a higher affinity for nicotine than acetylcholine and is located on astrocytes (housekeeping support cells) and neurons. Nicotine is a direct agonist of these receptors. Allosteric modulators help boost efficacy of endogenous acetylcholine by changing the conformational state of the receptors, shifting it from tight to relaxed. Galantamine, isolated from the Green Snowdrop, is an allosteric modulator of alpha7 receptors. The snowdrop was first described in book ten of Homer’s Odyssey based on knowledge of Greek herbalists.
“As he spoke he pulled the herb out of the ground an showed me what it was like. The root was black, while the flower was as white as milk; the gods call it Moly, and mortal men cannot uproot it, but the gods can do whatever they like.”
Galantamine’s effects on Alzheimers were thought to be based on CNS cholinergic neurons, but new focus is on a7 receptors on immune system. This illustrates how varied the effects of individual compounds are on the nervous system.
In the case of the search of nicotinic compounds for alleviating mental illness, reductionism has reached its limit. The reputation of the term “holistic” must be rehabilitated. Synergistic, combinatorial approaches must be tried in mental illness. Specifically we must re-evaluate whether compounds such as beta carbolines embedded within the tobacco leaf further enhance nicotines effects on mood and cognition through allosteric modulation of either degrading enzymes such as monoamine oxidase or catecholaminergic receptors. If adjunct compounds derived from the tobacco leaf can be added back into nicotine based products (e.g. vapes) in a way that minimizes the harmful effects of smoking, this approach should be actively encouraged. Then the dosage and administration could be improved to optimize a holistic and thoughtful approach to patients with cognitive and mood disorders such as schizophrenia and depression.