History Of Lysergic Acid Diethylamide (LSD) Usage In Society: [Essay Example], 1575 words GradesFixer
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History of Lysergic Acid Diethylamide (lsd) Usage in Society

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Lysergic Acid Diethylamide, also known as LSD-25, has been long regarded as one of the world’s most potent hallucinogens. The study in review from 2017 was the first able to obtain an X-ray Crystallography image of LSD bound to the Serotonin 5-HT2B Receptor. The X-ray crystallography image gives us a in depth look at the conformational changes within the 5-HT2B receptor. It has been long thought that the Diethylamide moiety of LSD is key to its long residence time within the serotonin receptor; however the image was able to distinguish an extracellular domain of the serotonin receptor which folds over the top of the serotonin receptor when LSD is bound; forming a lid and refusing LSD’s ability to dissociate. The “EL2” lid along with the specific interactions of LSD’s diethylamide group binding to helices III, V, VII of the 5-HT2B receptor provide explanations into LSD’s intense and long lasting effects.

Introduction

Hallucinogens take many forms and have had a place in human history since the beginning of time. It is within recent decades that society has determined hallucinogens to have no recreational or medicinal value and that they pose a threat to our security. Thankfully, due to scientific advancements; neurologist and psychologist consider us to be in a mental health renaissance, and once again hallucinogens place in society is being questioned. LSD, more formally known as Lysergic Acid Diethylamide-25, was first synthesized by a Swedish chemist named Albert Hoffman in 1938. The project initially sought to further expand the arsenal of Lysergic Acid derivatives partially synthesized from the ergot fungus, where they act as a vasoconstricting agent and thus are used in the treatment of migraines.

LSD-25 was the 25th product of this project and is where its name is derived. It was not until 1943 when Albert Hoffman unknowingly ingested a trace amount of LSD and had slight, but pronounced effects. Three days later, Albert Hoffman intentionally ingested 250ug of LSD-25, a dose he initially expected to be the threshold, and experienced the first “acid trip” as he rode his bike home; a ride forever remembered as Bicycle Day.

To further understand LSDs short history in society, it must be known that although the initial intent was to derive more migraine medications, LSD was patented by Sandoz Laboratories in 1947 as a psychiatric drug. The government even had personal interest in the 1950s, where the CIA conducted project MK-ULTRA to try and attain complete mind control and or a truth serum for use in chemical warfare. The patent held by Sandoz Laboratories expired in 1963 which led to wide scale production and distribution which helped flourish the 1960s “anti-establishment” movement led by the Hippies. This movement was the nail in the coffin for President Nixon to develop the Controlled Substance Act of 1970, which categorized drugs based on their addiction potential, safety, and potential medical applications. In this act LSD was placed in the highest category, schedule I which is shared with Heroin as having high potential for addiction and no medical value. Understanding serotonergic interactions is an important goal for pharmaceuticals to achieve, as they are known to be involved in a diverse range of biological functions. In the CNS these processes include, but are not limited to, modulating mood, cognition, learning, memory, aggression, feeding behavior, sleep, and pain processing. In the PNS, they have been attributed to mediating smooth muscle contraction, platelet aggregation, gastrointestinal function.

Lastly there are the release of numerous neurotransmitters and hormones regulated through the serotonergic receptors and thus a true understanding of their mechanism would aid future medicine.

Pharmacodynamics

LSD works on serotonergic receptors that are found both in the Central Nervous System as well as the Peripheral Nervous System. More specifically, LSD acts among the 5-HT (5-hydroxytryptamine) family of G protein-coupled receptors (GCPR) as non-selective agonist at seven of the subclass receptors. LSD is also an atypical serotonergic hallucinogen as it also ensues action through the dopamine D1-D5 receptors and Adrenergic Receptors. One of the most basic rules of both chemistry and biology is that the structure is one of the largest influencers of a molecules function. In this context, it is important to compare structures of the endogenous neurotransmitters serotonin and dopamine, to that of the hallucinogen agonists. Serotonin shares a much more similar backbone to LSD than dopamine due to dopamine lacking the Indole ring. Because of this, LSD’s interactions with the serotonin receptor are more pronounced and have been studied more in depth than that of the dopamine receptor, and is the reason the rest of the paper will focus on LSD’s interactions with the 5-HT serotonin receptor. GCPR’s typically are found in either their Gs (stimulatory) or Gi (Inhibitory) pathways. However there is also the Gq (Independent) pathway which is the preferred pathway of the 5HT receptors. In this cascade, a ligand binds which activates the GCPR through a conformational change that allows the exchange of GDP for GTP on the alpha subunit. This subunit is mobilized when GTP is attached and works on its effector enzyme, Phospholipase C (PLC) which allows the hydrolysis of PIP2 to DAG and IP3. IP3 dissociates from the membrane and acts as ligand at the endoplasmic reticulum to release calcium. Both calcium and DAG are important intermediates, as DAG will activate Phospho Kinase C (PKC) which works on its own to phosphorylate other enzymes which have an array of effects depending on the enzyme being effected. As well as calcium which acts as a secondary messenger to initiate and alter further cellular responses. EL2 Lid on 5-HT2B It has been long thought that the Diethylamide moiety is responsible for LSDs unique characteristics as well as its long residence time within the receptor.

In January of 2017 the first image of the 5HT2B receptor was successfully documented and was able to compare the conformational changes induced when LSD and ergotamine, a popular antimigraine agent which works through vasoconstriction in the brain. It was found that when LSD is bound to the 5HT-2B receptor, an extracellular domain of the receptor folds over LSD and refuses its ability to associate, known as extracellular loop 2 (EL2). This helps explain why LSD has a half-life of 3. 6 hours, yet the hallucinogenic trips are known to last 8-16 hours. The X-ray crystallography was able to show the L209 side chain of the receptor acted as a latch, to fold over LSD. To further the theory of the EL2 lid increasing LSDs residence time, a L209 mutation to alanine on a receptor showed a tenfold decrease in LSDs residence time. This lid was not observed in ergotamine, most likely due to the massive sterics associated with its structure. Further experimentation on the EL2 lid was able to demonstrate that not only did it affect LSDs residence time within the receptor; it also enforced stronger interactions among LSD and the binding pocket of the 5HT-2B receptor by constraining the conformation of the receptor. Through calcium flux assays and Phosphoinositide hydrolysis assays, it was noted that Gq induced calcium flux and PI hydrolysis was not affected by the mutant lid. Instead it was found through Bioluminescence Resonance Energy Transfer (BRET) that B-arrestin recruitment was reduced in the L209 mutant. Functional Selectivity of B-Arrestin Pathway Arrestins are important modulators of GCPRs for regulating signal transductions. As explained in the previous section, B-arrestin recruitment is favored among the LSD-5HT interaction in a process known as functional selectivity, or biased agonism.

Arrestins work by acting as a scaffolding protein that binds to the cytoplasmic side of the G protein, inhibiting the exchange of GDP for GTP and thus the activation of the alpha subunit. This is a process known as desensitization which prevents the receptor from continuing down its signalling cascade. Arrestins work secondly, by mediating the recruitment of clathrin and the AP2 adaptor, promoting the internalization of the receptor in a process of endocytosis. The receptors can either be directed then to the lysosome for degradation, or held in the cytoplasm until they are further needed, where they will then be recycled back to the cell membrane. Receptor endocytosis is not as black and white as it sounds, there is still further properties to its regulation such as compartmentalizing receptor signaling, and de-phosphorylating it to further resensitize the receptor. Because of this B-arrestins are key to the function and life cycle of GCPRs. However research into B-arrestins mechanism is still young, and it has been proposed that arrestins may have their own downstream signalling cascade for cell regulation.

Favoring Biased Agonism of B-Arrestin

Although LSD is illegal, there is a huge gray area in pharmaceutical regulations and the allowance of derivative chemicals to be sold for research purposes. In layman’s terms this means that by simply altering certain functional groups of a molecule, it has a new name and thus a molecule that was once regarded as illegal can be simply modified into a legal compound. Four LSD derivatives were compared through BRET assays to measure their influence on B-arrestin recruitment. Through this it was found that greater the steric constraint of the LSD analog is, the stronger the B-arresting response, and thus hypothesized to have stronger hallucinogenic effects. In this experiment it was found that (S, S)-Azetidide (SSAz) had the most pronounced B-arrestin recruitment. It should be noted that although the RRaz has a strikingly similar structure to SSAz, it is an isoform that is not favored in its interactions with the Serotonergic receptor.

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History Of Lysergic Acid Diethylamide (LSD) Usage In Society. (2020, March 16). GradesFixer. Retrieved October 30, 2020, from https://gradesfixer.com/free-essay-examples/history-of-lysergic-acid-diethylamide-lsd-usage-in-society/
“History Of Lysergic Acid Diethylamide (LSD) Usage In Society.” GradesFixer, 16 Mar. 2020, gradesfixer.com/free-essay-examples/history-of-lysergic-acid-diethylamide-lsd-usage-in-society/
History Of Lysergic Acid Diethylamide (LSD) Usage In Society. [online]. Available at: <https://gradesfixer.com/free-essay-examples/history-of-lysergic-acid-diethylamide-lsd-usage-in-society/> [Accessed 30 Oct. 2020].
History Of Lysergic Acid Diethylamide (LSD) Usage In Society [Internet]. GradesFixer. 2020 Mar 16 [cited 2020 Oct 30]. Available from: https://gradesfixer.com/free-essay-examples/history-of-lysergic-acid-diethylamide-lsd-usage-in-society/
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