Modes of administration – evolutionary adaptive gaps
Humans are (so far) the most evolved species within the ecosystem of planet Earth, and the end result of a long evolutionary process going back to the primordial soup, out of which, as the dominant theory goes, all forms of life differentiated and evolved. It is increasingly apparent that the competition-driven Darwinian model is incomplete and that evolution is driven just as much by cooperative interaction as by competition, the yin and yang of evolution. Cooperation as a major force of evolution may have escaped evolutionists because of its ubiquity: for billions of years, life on our planet consisted of unicellular organisms that eventually congregated to form unicellular systems and then multicellular organisms. Interactive cooperation allowed the division of labor and the creation of specialized cells that eventually congregated in organs, allowing further specialization and differentiation, thus speeding up the evolutionary process. Just imagine survival of the fittest ruling the cells of your brain or your liver! Likewise, the major driving force of social systems, whether in the animal or human kingdom, is not competition, but interactive cooperation.
All life forms co-evolved interdependently in competitive symbiosis in which the vegetal kingdom plays a critical and distinctive role in the evolution of the animal kingdom. The vegetal kingdom provides directly or indirectly to the animal kingdom not only its food, but also its medicine, as well as substances that affect its mind, and may have been key to some critical evolutionary steps. This is indeed one of the great wonders and mysteries of life, and a powerful testimony to the prevalence of cooperation in the evolutionary process. The affinity between plants like poppy and cannabis and some of the most fundamental systems of brain activity, the dopaminergic and the cannabinoid system, both found in even the most primitive animal species, is nothing short of remarkable. Likewise, alcohol, as we will see in the chapter dedicated to that substance, is not only present in interstellar space, it was most likely one of the ingredients of the primordial soup theorized to be at the origin of life.
Humans co-evolved with psychoactive substances of natural origin in symbiosis with the vegetal kingdom. However, concentrates and extracts, such as distilled alcohol, heroin, cocaine, or amphetamines, or purely synthetic drugs, as well as direct routes of administration such as injection or inhalation, are novel features of our environment. As such, they create an evolutionary adaptive gap and are inherently pathogenic, although their use may be safe and warranted in some circumstances.
Psychoactive substances can cross the blood-brain barriers and can be absorbed via various pathways. The digestive system, via the oral route, is the overly prevalent channel of administration of food and other substances in the animal kingdom, and is set up to withstand a wide variety of ingests. Furthermore, substances absorbed through the digestive system take a relatively long time to reach the brain as they are partly metabolized within the digestive system and the liver before they can reach the brain, which they do gradually. Therefore, ingestion is always the least dangerous and least addictive form of administration for a given substance. The digestive administration process can be modulated to a certain extent. Thus, substances taken on an empty stomach reach the brain much faster than when they are taken with a meal.
The lungs, on the other hand, were designed to absorb air, and not much else. Even the smell of roses and other olfactory environmental signals are meant for the olfactory system located within the nose cavity, and not for the lungs. The lungs having a fractal structure, their total surface area is about the size of a tennis court, allowing fast and efficient oxygenation of the blood. Absorption through the lungs is extremely fast and powerful. Substances than can be absorbed through the lung tissue promptly reach the brain. Smoked heroin, cocaine or methamphetamine reach the brain within seconds of inhalation and peak within minutes. However, as we will see in a further chapter, cannabinoids and THC are different as they are strongly lipophilic. Their access to the brain is delayed upon inhalation, and the maximum “high” of cannabis is reached within 15 to 30 minutes.
As for veins, they were never designed to be punctured. Thus, it shouldn’t come as a surprise that intravenous injection is the fastest, most powerful and most damaging form of administration. Nasal absorption is notably slower than inhalation but still quite powerful and fast acting. Still, the nasal tissue is not meant to absorb anything more than infinitesimal doses of subtle and not so subtle aromatic substances ranging from utterly repulsive to sublime, from skunks to roses. Sublingual absorption is another fast track to the brain that is about on a par with nasal absorption. Chewing, such as chewing coca leaves or tobacco, involves a substantial amount of absorption through sublingual and other buccal mucosae.
Recreational drug users are motivated by the hedonistic reward provided by the substance. For most psychoactives except psychedelics, the intensity of the hedonistic reward depends in large part on the acuity of the peak intensity and the speed to reach this peak. A gradual rise of psychoactive concentration in the brain allows it to somewhat adapt to the substance and to modulate its effects to a certain extent, smoothing out its most damaging effects. A steep peak, on the other hand, doesn’t allow any adaptation; the more intense the peak, the more acute its effect. The most acute peaks create a surge of pleasurable sensation, the “rush” described by many injecting addicts, that they crave intensely. The steeper the peak, the more intense the rush, the more acute and disruptive will be the effects on the brain, causing a homeostatic imbalance which results in chronic dysregulation of the brain reward mechanisms and the brain’s neurotransmission in general.
Routes of administration that result in the rapid entry of a substance into the brain and/or faster rates of delivery have a greater effect on the neurotransmission systems in the brain, especially the reward systems, producing sensitization. Hard liquors are more damaging than beer or wine, especially on an empty stomach. Smoked opium reaches the brain faster and is more addictive than ingested opium. Injection and inhalation of active ingredients such as amphetamine, heroin or cocaine have the quickest entry and fastest rates of delivery. Therefore, they represent the most drastic evolutionary gap and have the most damaging effects.
Set and setting, expectation and intentionality affect the neuronal epigenetic environment. As such, they may influence the effects of particular substances. Thus, ritualistic use of tobacco where the plant is used with veneration and respect is vastly different from chain smoking of industrial cigarettes. Likewise, chronic pain sufferers under long-term opiate medication can usually discontinue without much problem once their medication is not needed anymore. The absence of secondary reinforcers in the case of pain medication probably plays a critical role in preventing addiction. Nowhere is the set and setting more important than in the use of psychedelics.
 Randolph M. Nesse* and Kent C. Berridge, “Psychoactive Drug Use in Evolutionary Perspective,” Science 278, 63, 1997.
 Cannabis is somewhat an exception as ingested cannabis has stronger psychoactive effects than smoked cannabis (see Chapter 10).