Monday, September 14, 2015

A Scientific Explanation of the Psychedelic Experience

"Protesting all the while that their sensations cannot be explained, mystics, psychedelic explorers, meditators, and contemplatives of all stripes describe experiences of inspiration, peace, serenity, and all-rightness with the universe; of moving into another order or dimension of consciousness; of fusing in oneness with God, the universe, others, everything, eternity; of transcending time, space, and ego; of being infused with knowledge, recognition, awareness, insight, certainty, illumination; of having a sense of endowment, of gaining more from the experience than they can intellectually understand."
Disregard Everything I Say:
This puts psychedelics in a class known as serotonin receptor agonists, because they excite our 5-HT receptors. More specifically, they hold a particular affinity with a subset of our 5-HT receptors known as the 5-HT2a receptors.

It is likely that the 5-HT2a receptor is the primary site of action for psychedelics for many reasons and this claim is backed up by a large body of evidence. The first evidence that psychedelics act via the 5-HT2 receptor was published in the paper by Glennon et al., (1983). This paper, using a drug discrimination task, trained rats to discriminate between the phenethylamine psychedelic DOM and a placebo in a two-lever operant choice task. Successfully demonstrating that when rats were administered doses of mescaline, LSD and 5-MeO-DMT, they still chose the DOM stimulus lever. This heavily suggests that the effects of DOM can be generalized to both indole and other phenethylamine hallucinogens, but not other 5-HT receptor agonists which the rats were also exposed to. It was also shown in the same study that this stimulus generalization was consistently blocked by the 5-HT2 receptor antagonist, ketanserin, showing that these three psychedelic compounds must involve those sub-populations of serotonin receptors that are blocked by ketanserin (i.e. 5-HT2 sites).

Glennon et al., (1984) then reported that the affinity of various hallucinogens for 5-HT2 subtypes, but not for other receptors, was tightly correlated with the drugs’ ED50 in human usage and rat drug discrimination experiments. ED50 is a pharmacological term that simply means the dosage at which a drug begins to show effects in 50% of the population using it. This is a correlation that has been shown multiple times (Sanders-Bush et al., 1988) alongside a large number of agonist/antagonist experiments (reviewed by Nichols, 2004) and it is due to this consistent evidence that the scientific consensus has generally agreed on 5-HT2 receptor subtypes as the primary site of action of psychedelics.

Jakab and Goldman-Rakic (1998) examined macaque brains using immunocytochemistry and found dense 5-HT2A receptors throughout all cortical regions, specifically in areas heavily involved in consciousness and sensory processing or more specifically the frontal, prefrontal, temporal and occipital cortices.

Besides these, it has also been shown that 5-HT2a receptors are contained within multiple parts of the thalamus which is an area at the top of the brain stem with functions that include relaying sensory and motor signals to the cerebral cortex, along with the regulation of consciousness, sleep, and alertness. Pompeiano et al., 1994 used yet another method of tissue staining known as in situ hybridization to show that the reticular, lateral geniculate nuclei of the thalamus all contain 5-HT2a receptor mRNA. These two areas are both involved in the relaying of information from sensory organs to their appropriate cortex and have been heavily speculated to play a large role in the psychedelic experience (Lambe & Aghajanian, 2001; Marek et al., 2001).

"They predict that LSD may behave in a similar way to psilocybin, reducing blood flow to the control centers of the brain and thus dampening their activity, which ultimately enhances brain connectivity. In doing so, psilocybin seems to help brain regions that are normally distinct begin to communicate with one another, which could be why we see an increase in creativity with the use of this substance. However, we won’t know if LSD works in a similar manner until the second stage of the study is completed, and that requires the public to dig deep into their pockets."
The frontal lobe, which is in the front of the brain, controls “executive function” activities like thinking, organizing, planning, and problem solving, as well as memory, attention, and movement.

The parietal lobe, which sits behind the frontal lobe, deals with the perception and integration of stimuli from the senses.

The occipital lobe, which is at the back of the brain, is concerned with vision.

The temporal lobe, which runs along the side of the brain under the frontal and parietal lobes, deals with the senses of smell, taste, and sound, and the formation and storage of memories.

Changes in the Brain

Frontotemporal disorders affect the frontal and temporal lobes of the brain. They can begin in the frontal lobe, the temporal lobe, or both. Initially, frontotemporal disorders leave other brain regions untouched, including those that control short-term memory.

The frontal lobes, situated above the eyes and behind the forehead both on the right and left sides of the brain, direct executive functioning. This includes planning and sequencing (thinking through which steps come first, second, third, and so on), prioritizing (doing more important activities first and less important activities last), multitasking (shifting from one activity to another as needed), and monitoring and correcting errors.

When functioning well, the frontal lobes also help manage emotional responses. They enable people to avoid inappropriate social behaviors, such as shouting loudly in a library or at a funeral. They help people make decisions that make sense for a given situation. When the frontal lobes are damaged, people may focus on insignificant details and ignore important aspects of a situation or engage in purposeless activities. The frontal lobes are also involved in language, particularly linking words to form sentences, and in motor functions, such as moving the arms, legs, and mouth.

The temporal lobes, located below and to the side of each frontal lobe on the right and left sides of the brain, contain essential areas for memory but also play a major role in language and emotions. They help people understand words, speak, read, write, and connect words with their meanings. They allow people to recognize objects and to relate appropriate emotions to objects and events. When the temporal lobes are dysfunctional, people may have difficulty recognizing emotions and responding appropriately to them.

Which lobe—and part of the lobe—is affected first determines which symptoms appear first. For example, if the disease starts in the part of the frontal lobe responsible for decision-making, then the first symptom might be trouble managing finances. If it begins in the part of the temporal lobe that connects emotions to objects, then the first symptom might be an inability to recognize potentially dangerous objects—a person might reach for a snake or plunge a hand into boiling water, for example.

The most common frontotemporal disorder, behavioral variant frontotemporal dementia (bvFTD), involves changes in personality, behavior, and judgment. People with this dementia can act strangely around other people, resulting in embarrassing social situations. Often, they don’t know or care that their behavior is unusual and don’t show any consideration for the feelings of others. Over time, language and/or movement problems may occur, and the person needs more care and supervision.

"The National Survey on Drug Use and Health reports that roughly 200,000 people use LSD for the first time in the United States each year, but use has been on a steady decline since 2002."

More information:
» Vollenweider, 2001: "Brain mechanisms of hallucinogens and entactogens"
» Watakabe et al., 2009: "Enriched expression of serotonin 1B and 2A receptor genes in macaque visual cortex and their bidirectional modulatory effects on neuronal responses."
» Hoffman et al., 2001: "Effects of a Psychedelic, Tropical Tea, Ayahuasca, on the Electroencephalographic (EEG) Activity of the Human Brain During a Shamanistic Ritual"

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