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LSD Pharmacology

LSD is an ergoline derivative. It is commonly produced from lysergic acid, which is made from ergotamine, a substance derived from the ergot fungus on rye, or from ergine (lysergic acid amide), a chemical found in morning glory and hawaiian baby woodrose seeds. It is theoretically possible to manufacture LSD from morning glory or hawaiian baby woodrose seed. LSD is a chiral compound with two stereocenters at the carbon atoms C-5 and C-8, so that theoretically four different optical isomers of LSD could exist. LSD, also called (+)-D-LSD, has the absolute configuration (5R,8R). The C-5 isomers of lysergamides do not exist in nature and are not formed during the synthesis from D-lysergic acid. However, LSD and iso-LSD, the two C-8 isomers, are rapidly interconverting in the presence of base. Non-psychoactive iso-LSD which has formed during the synthesis can be removed by chromatography and can be isomerized to LSD.

Stability

“LSD,” writes the chemist Alexander Shulgin, “is an unusually fragile molecule.” It is stable for indefinite amounts of time if stored, as a salt or in water, at low temperature and protected from air and light exposure. Two portions of its molecular structure are particularly sensitive, the carboxamide attachment at the 8-position and the double bond between the 8-position and the aromatic ring. The former is affected by high pH, and if perturbed will produce isolysergic acid diethylamide (iso-LSD), which is biologically inactive. If water or alcohol adds to the double bond (especially in the presence of light), LSD converts to “lumi-LSD”, which is totally inactive in human beings, to the best of current knowledge. Furthermore, chlorine destroys LSD molecules on contact; even though chlorinated tap water typically contains only a slight amount of chlorine, because a typical LSD solution only contains a small amount of LSD, dissolving LSD in tap water is likely to completely eliminate the substance.

A controlled study was undertaken to determine the stability of LSD in pooled urine samples. The concentrations of LSD in urine samples were followed over time at various temperatures, in different types of storage containers, at various exposures to different wavelengths of light, and at varying pH values. These studies demonstrated no significant loss in LSD concentration at 25 degrees C for up to 4 weeks. After 4 weeks of incubation, a 30% loss in LSD concentration at 37 degrees C and up to a 40% at 45 degrees C were observed. Urine fortified with LSD and stored in amber glass or nontransparent polyethylene containers showed no change in concentration under any light conditions. Stability of LSD in transparent containers under light was dependent on the distance between the light source and the samples, the wavelength of light, exposure time, and the intensity of light. After prolonged exposure to heat in alkaline pH conditions, 10 to 15% of the parent LSD epimerized to iso-LSD. Under acidic conditions, less than 5% of the LSD was converted to iso-LSD. There was also demonstrated that trace amounts of metal ions in buffer or urine could catalyze the decomposition of LSD and that this process can be avoided by the addition of EDTA.

Pharmacodinamical

LSD’s secondary effects normally last from fifty-two to seventy-five hours, though as Sandoz’s prospectus for “Delysid” warned, “intermittent disturbances of affect may occasionally persist for several days.” Contrary to early reports and common belief, LSD effects do not last longer than significant levels of the drug in the blood. Aghajanian and Bing found LSD had an elimination half-life of 175 minutes, while, more recently, Papac and Foltz reported that 1 µg/kg oral LSD given to a single male volunteer had an apparent plasma half-life of 5.1 hours, with a peak plasma concentration of 1.9 ng/mL at 3 hours post-dose. Notably, Aghajanian and Bing found that blood concentrations of LSD matched the time course of volunteers’ difficulties with simple arithmetic problems.

Some reports indicate that administration of chlorpromazine (Thorazine) or similar typical antipsychotic tranquilizers will not end an LSD trip, it will rather become less intense or the side effects of the medication will immobilize and numb the patient. While it also may not end an LSD trip, the best chemical treatment for a “bad trip” is an anxiolytic agent such as diazepam (Valium) or another benzodiazepine. Some have suggested that administration of niacin (nicotinic acid, vitamin B3) could be useful to end the LSD user’s experience of a “bad trip”. The nicotinic acid in niacin as opposed to niacinamide, will produce a full body heat rash, due to widening of peripheral blood vessels. The effect is somewhat akin to a poison ivy rash. Although it is not clear to what extent the effects of LSD are reduced by this intervention, the physical effect of an itchy skin rash may itself tend to distract the user from feelings of anxiety. The rash itself is temporary and disappears within a few hours. It is not clear how effective this method would be for people having serious adverse psychological reactions.

Receptor Affinity of LSD

LSD affects a large number of the G protein coupled receptors. The graph below (Ray, 2010) shows the affinity for forty-two receptors, arranged in order of decreasing affinity (click the image to enlarge).

LSD Receptors Affinity

As explained by Ray (2010), “The black vertical bar represents a 100-fold drop in affinity relative to the receptor with the highest affinity. As a rule of thumb, this is presumed to be the limit of perceptible receptor interaction. Receptors to the right of the black bar should be imperceptible, while receptors to the left of the black bar should be perceptible, increasingly so the further left they are” (p. 14).

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