Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide (LSD)

Pharmacodynamics is defined as the effect that the drug has on the body. LSD is known mostly for it its hallucinogenic and psychoactive effects. The hallucinogenic effects of LSD that most users experience is thought to be mediated by the binding of LSD to serotonin 2A receptors (5-HT 2A receptors). The 5-HT 2A receptor is the main excitatory receptor subtype among the G protein-coupled receptors for serotonin (5-HT), although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. In recreational doses, LSD has been shown to interact with serotonin1A, serotonin-2A, serotonin 2C, serotonin5A, serotonin 5B and serotonin 6 receptors. The hallucinogenic effect of LSD itself is due to fact that LSD is a strong partial agonist at serotonin 2A receptors and largely 5-HT2A specific antagonists block the psychedelic activity of LSD. Exactly how this produces the drug's effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral prefrontal cortex and therefore excitation in this area, specifically in layers IV and V. Chronically LSD may activate dopamine and cyclic AMP regulated phosphoprotein with molecular weight 32kDa (DARPP-32) related pathways typical of other psychoactive drugs like cocaine and methamphetamine. Unlike many other drugs which are measured in milligrams, doses of LSD are measured in micrograms. One single dose of LSD is typically 100-150 micrograms; although psychotropic effects of the drug itself are experienced with a dosage as little as 25 micrograms. From research, it has been determined that the medium lethal dosage of LSD has an approximate range of 200 micrograms per kilograms to more than 1 milligrams per kilogram; even though there are no known deaths attributed to the overdose of LSD. Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the effects of LSD occurs in humans and animals. Tolerance to autonomic and psychological effects of LSD occurs in humans after a few moderate daily doses of LSD. Despite the rapid tolerance to LSD, users usually do not exhibit the typical effects of

drug addiction and dependence. The attenuation of tolerance to LSD is thought to be related to drug induced down regulation of serotonin -2A receptors in the central nervous system. Any adverse reaction to LSD is treated using fast acting benzodiazepines such as diazepam or triazolam. These drugs serve as anxiolytics, which calm the individual without directly blocking LSD binding at serotonin-2A receptor sites. In theory, specific serotonin-2A receptor antagonists such as atypical antipsychotics like clozapine would act to block LSD binding a these receptor sites thereby lessening the psychoactive effects of LSD. There have been some psychiatric complications of LSD reported. Although these effects have never been studied, many of the persons who have ingested LSD in research trials have reported episodes of anxiety or panic (with severe, terrifying thoughts and feelings, fear of losing control, fear of insanity or death , and despair. Other complicated reactions may include temporary paranoid ideation and, as after-effects in the days following LSD experience, temporary depressive mood swings and/or increase of psychic instability.

Pharmacokinetics is defined as what the body does to the drug. In the case of LSD, regardless of how it is administered, it has a very short half- life in the body and only remains a short time in the system. The body detoxifies itself by breaking the LSD down into inactive metabolites which have no therapeutic effect on the body. LSD is typically administered orally. Often absorbed paper, sugar cubes and gelatin cubes are means of transporting LSD. Liquid forms of the drug are also available and can be administered intramuscularly or intravenously. Psychotic effects of the drugs can be experienced at dosage of 20-30 micrograms but only last from 6-12 hours depending on tolerance of the drug, body weight and age. It was demonstrated that with a large meal, plasma concentrations of orally ingested LSD were half as much as on an empty stomach. When a smaller meal was eaten, plasma levels were somewhere between. It was concluded that the amount of the meal, as well as the pH of the stomach and duodenum, will influence the absorption of LSD. LSD has a half- life of 175 minutes and a plasma life of 2.5-4 hours

LSD is shown to bind and induce conformational changes to the structure of DNA helix and is reported to be mutagenic in higher doses in animal models; however no detectable DNA damage or increased incidences of cancers have been observed in humans due to extensive LSD use. The distribution of LSD in the tissue and organ system of the human organism has not yet been defined; however in mice, LSD was found all over the body in ten minutes and most of it was found in the digestive system within 3 hours. In rats, the brain had a lower amount of LSD after a few hours, it was reported however that the blood plasma held a lot of the LSD in it after a few hours than the brain did. Although the distribution of LSD across the tissue and organ system of humans has not yet been discovered, it can be said that within hours the drug is found with the liver of humans. In humans, LSD is metabolized rapidly into some structurally similar metabolites [Fig.1]. It was first established through in vitro studies that LSD is metabolized in humans by some NADH-dependent microsomal liver enzymes to the inactive 2-oxy-LSD and 2-oxo-3-hydroxy LSD. Metabolites were first detected in urine with infrared spectroscopy identified LAE (which

originates from enzymatic N-dealkylation of the diethylamide radical at side chain position 8) and nor- LSD, an N-de-methylated degradation product of LSD. Another metabolite was identified as di-hydroxy-LSD. In a study more LSD metabolites were found in human urine: norLSD, LAE, 2-oxo-LSD, 2-oxy-3-hydroxy-LSD, 13- and 14-hydroxy-LSD as glucoronides, lysergic acid ethyl-2-hydroxyethylamide (LEO), and trioxylated LSD. The major metabolite in urine is 2-oxy-3-hydroxy-LSD (which could not be detected in blood plasma). This means that the body metabolizes the drug through detoxification in a short period of time and forms metabolites. Metabolites of LSD include N-desmethyl-LSD, hydroxy-LSD, 2-oxo-LSD, and 2oxo-3-hydroxy-LSD. These metabolites are all inactive and they are inactive metabolites because they offer no therapeutic effects.

Figure 1: Metabolites with similar structure of LSD

Slideshow info Pharmacokinetics may be simply defined as what the body does to the drug, as opposed to Pharmacodynamics which may be defined as what the drug does to the body. Pharmacodynamics: LSD is primarily a non-selective 5-HT agonist. LSD may exert its hallucinogenic effect by interacting with 5-HT 2A receptors as a partial agonist and modulating the NMDA receptor-mediated sensory, perceptual, affective and cognitive processes. LSD mimics 5-HT at 5-HT 1A receptors, producing a marked slowing of the firing rate of serotonergic neurons. This allows the user to experience not only hallucinogenic effects but also the psychedelic effect that many users experience.

Pharmacokinetics Pharmacokinetics is defined as what the body does to the drug. In the case of LSD, regardless of how it is administered, it has a very short half- life in the body and only remains a short time in the system. The body detoxifies itself by breaking the LSD down into inactive metabolites which have no therapeutic effect on the body.