The Meyer-Overton Theory of Anesthesia

Charles Ernest Overton

[Part 2 of 5]

In 1896, Hans Horst Meyer, a German pharmacologist and Director of the Pharmacological Institute at the University of Marburg, became interested in Ernst von Bibra’s theory of anesthesia. Meyer hypothesized that anesthetics were hydrophobic (repelled by water) and in turn attracted to other hydrophobic molecules. Lipids, the fatty molecules in brain cells, are also hydrophobic as evidenced by the separation of lipid-based substances (such as vegetable oil, grease, and butter) in water. Meyer believed that this mutual hydrophobia led anesthetics to bond to and dissolve the lipid molecules in brain cells.  His hypothesis  further argued that increasingly-hydrophobic anesthetic molecules were capable of forming stronger bonds with lipids, thereby bonding more readily and increasing the potency of the anesthetic effect.

In order to test his hypothesis and expand upon von Bibra’s work, Meyer began a small-scale research program on anesthetics, using his position at the University of Marburg to acquire the necessary assistants and apparatus for his experiments. His intention was to demonstrate some degree of correlation between a substance’s ability to bond with fatty substances and its anesthetic power.

As a means of assessing interactions between anesthetics and lipids, Meyer measured the solubility of known anesthetics (including, but not limited to, ketones, alcohols and ethers) in olive oil, which was meant to represent the fatty molecules in brain cells. He then tested the same anesthetics on tadpoles, measuring the quantity of anesthetic agent required to induce what he defined as abnormal behavior. Though his use of tadpoles as experimental subjects led to imprecise and often subjective observations, he was able to positively correlate lipid solubility with anesthetic potency. By equating lipid solubility with anesthetic affect, Meyer was able to offer experimental support for von Bibra’s hypothesis. In 1899, Meyer published his theory on the anesthesia-lipid relationship in his paper “Zur Theorie der Alkoholnarkose,” Arch. Exp. Pathol. Pharmacol. 42: 109–118.

In 1901, Charles Ernest Overton published his own theory of anesthesia independently of Meyer’s. He too had found a positive correlation between lipid solubility and potency. Moreover, he had discovered that the power of an anesthetic was unrelated to the method by which it had been delivered. In other words, Overton was able to show that lipids in the brain were affected by anesthetic agents regardless of whether they had been administered in a liquid or gaseous form.

Because Meyer and Overton, both established researchers, came to the same conclusions using different experimental methods, their work gained traction in the scientific world and quickly became known as the Meyer-Overton theory of anesthesia. In its simplest form, the theory claims that once an anesthetic agent reaches a critical level in a lipid layer, the anesthesia molecules bond to target sites (sometimes known as receptors) on the lipid molecules, in the process dissolving the fatty part of the brain cells affected by the anesthetic agent. In response to the dissolution of the lipid layer, the brain reaches an anesthetized state and the patient is rendered unconscious.

To much of the early twentieth-century scientific community, the theory seemed to adequately describe the well-established relationship between anesthetics and lipid solubility that seemed to underlie the anesthetic effect. The theory had been substantiated by multiple experimental tests and, in the end, was the best existing explanation of the phenomenon. Meyer and Overton seemed to have decoded the mystery behind a major medical practice.

As is common with major discoveries, however, the Meyer-Overton discovery eventually succumbed to scientific scrutiny. Nearly six decades after Meyer’s and Overton’s original publications, researchers were finally able to identify a key flaw in the lipid theory:  namely that anesthetics interacted with lipid-free proteins in the same way that they interacted with lipids. This suggested that anesthetics did not require lipid target sites for binding, but could instead bind to other sites with the same resulting anesthetic effect. This discovery greatly reduced the perceived importance of lipids in the anesthesia-brain interaction.

Moreover, researchers found that as anesthetics in a given series of tests became increasingly hydrophobic (through the lengthening of the carbon chain), their potency did not increase indefinitely. Instead, molecules appeared to reach what is known as a “cutoff point” where otherwise-effective anesthetics lose their ability to anesthetize the brain. According to the Meyer-Overton theory, the loss of anesthetic effect would imply an inability to bond with lipids. Scientists, however, found that long-chain anesthetics continued to bond with lipids despite the loss of anesthetic ability, further strengthening the argument that anesthetic-lipid bonds are not responsible for the sensory-altering effects of anesthesia.

With these breakthroughs, the Meyer-Overton theory was crushed. If anesthetics could be effective without bonding with lipids, and could be ineffective when bonded to lipids, the original Meyer-Overton theory could no longer be considered valid.

Click here to view our previous posts on the theory of anesthesia. For more information on Pauling’s life and work, visit the Linus Pauling Online Portal or the OSU Special Collections homepage.