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LSD - an Overview on Drug Action and Detection

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LSD - an Overview on Drug Action and Detection LSD - An Overview on Drug Action and Detection REFERENCE: Paul BD, Smith ML: LSD - An overview on drug action and detection; Forensic Sci Rev 11:157; 1999. ABSTRACT: LSD is a psychoactive semisynthetic ergot alkaloid. It is so potent that a small dose (",,25ug) may produce a profound hallucinogenic effect. The compound is a controlled substance under the US code of regulations. One of the major adverse effects of LSD is the "flashback" or spontaneous recurrences of hallucinogenic effects that may occur months to years after cessation of the drug. The major concern of LSD abuse is the long duration of action and fatal accidents and suicides during the state of intoxication. Because LSD metabolizes to a number of compounds and detection methods for these compounds in a large number of samples are not well established, most of the methods are aimed at identifying unchanged LSD in urine. After initial screening by an immunoassay method, the presence of LSD in urine is confirmed by a gas chromatographic-mass spectrometric (GC-MS) method. The immunoassay techniques are simple and cost-effective. In confirmation, selective extraction is preferred because it allows detection of the compound at concentrations as low as 50 pg/mL. Recent methods for detection of an LSD metabolite, 2-oxo-3-hydroxy-LSD, by liquid chromatography-mass spectrometry appeared to be promising in some forensic investigations. Key Words: Biochemical and pharmacological actions, LSD, metabolism and excretion, methods of analysis, synthesis. INTRODUCTION LSD was first prepared in 1938 but the pharmacologi- cal studies revealed no unusual effect at that time [33]. It Lysergic acid diethylamide (LSD) is a semisynthetic showed an oxytocic action similar to that of ergonovine. compound derived from structural modifications of natu- In 1943, Stoll and Hoffman synthesized the compound rally occurring ergot alkaloids.Ergot is a rhizomorph of again with the intention of obtaining a compound with Claviceps purpurea, a parasitic fungus that grows on rye analeptic effect because part of the compound showed and wheat, and on other grains in the grass (Gramineae) structural similarities (D-ring with diethylamide) with a family [94]. The alkaloids are also present in the seeds of well-known circulatory stimulant, nikethamide [95]. In morning glory, Rivea corymbosa [32]. Ergot is toxic and the course of these investigations, Hoffman was exposed if appreciable amounts of ergot get into the grain and then to this compound and experienced a remarkable but not into the feed, ergotism may occur. In 994 A.D., ergotism unpleasant state of intoxication that lasted for 2-3 hand killed about 40,000 people in France. Present-day meth- was characterized by intense stimulation of the imagina- ods of ergot production utilize submerged culture fermen- tion and an altered awareness of the world around him tation rather than culti vation on rye or other grains [46,51]. [33]. The ergot alkaloids are hydrolyzed to produce a common An enormous number of articles on chemical, bio- compound, lysergic acid, which is then reacted with chemical, pharmacological, and pharmacokinetic proper- diethylamine to produce the LSD [95]. ties of LSD are available. It is the purpose of this review A resurgence of LSD abuse has been reported among to provide, in short form, an overall background to readers adolescents and college students in the United States [43]. Estimated numbers of LSD use among US children aged Table 1. LSD seizures by the Drug Enforcement Agency a 12-17 years increased from 970,000 in 1996 to 1,174,000 Year Dosage units in 1997, an increase of21 % in one year. According to the Drug Abuse Warning Network (DAWN), the rate of LSD- 1998 b 701,434 related hospital emergencies increased by 13% from 1989 1997 396,183 1996 68,141 to 1990. Approximately 50% of the patients were younger 1995 100,521 than 20 years [60]. Most of them were high school and 1994 302,446 college students who were male Caucasian. Therefore, (J Source: System to Retrieve Information from Drug Evidence LSD is more prevalent in the suburbs than in the inner (STRIDE).The statistics can fluctuate widely due to the presence or cities. The extent of LSD abuse can be estimated from the absence of large seizures. number of doses seized by the U.S. Drug Enforcement b The 1998 figures are preliminary and are significantly high due to one Agency (DEA) during the last five years (Table 1). large seizure of 621 ,390 dosage units. Forensic Science Review • Volume Eleven Number Two • Dec.1999 159 whose main interests are in toxicology. Major emphasis appropriate ergot strains in fermenters [5,12,50]. Whereas will be given to the subject that deals with the analysis of C. paspali of New Guinea strain produced a mixture of d- the drug and its metabolites in biological samples. lysergic acid amide and d-isolysergic acid amide - 90% of the total alkaloids of 1.4 g/L of cultured media, C. paspali I. NATURE OF THE DRUG of Portugal strain produced paspalic acid - 95% of the total alkaloids of 0.55 g/L of the cultured media [50]. d- A. Synthesis Lysergic acid was prepared by alkaline hydrolysis of d- lysergic acid amide, or isomerization of paspalic acid Starting materials for LSD synthesis are the ergot under mild conditions (Figure 1).A second method alkaloids. Most of the alkaloids are produced by different involved production of peptide alkaloids by fermentation strains of Claviceps fungus. In classical preparation, the of suitable ergot strains [51]. Most of the alkaloids were rye grown in the field was artificially infected with se- d-lysergic acid alkylamides which on alkaline hydrolysis lected strains of the fungus [97]. The process was time produced d-lysergic acid [5,50,89,90]. consuming and depended on the climatic conditions.Two The biosynthesis of lysergic acid and other ergot other methods for preparation of the compounds are alkaloids was a fascinating subject to many chemists for available. In the first method, lysergic acid amide and nearly forty years. The basic structure is formed from a paspalic acid were prepared by saprophytic cultivation of molecule ofL-tryptophan and an isoprenoid unit originat- eOOH H HN HN d-Lysergic acid amide Paspalic Acid (natural compound) (natural compound) H. eOOH / i 7 / Isomerization HYdr~ 11 ('NCH, ~11 H 2 d-Lysergic acid /CH2CHJ HN'-..CH,CH, POCI) 12 IJ uv H ) 14 I I HN HN d-LSD Lumi-LSD Figure 1. Synthesis of d-LSD and lumi-LSD from naturally occurring ergot alkaloids. Paul & Smith' LSD - Drug Action and Detection ----- -- ---- - - ---- -------- ------ ----- - ---- 160 ing from R-mevaJonic acid (Figure 2). The intermediate skeleton of the ergot alkaloids. Incorporation of R,S- 4-(3,3-dimethylallyl)-L-tryptophan through a number of mevalonate-2-14C,2-3H and 4-3H at rates of 9-23% into steps of decarboxylation, oxidation, and cyclization is the ergot alkaloids strongly suggested a direct precursor transformed into argoclavine, elymoclavine, and paspalic role of mevalonic acid. The rate of incorporation of the R- acid, and finally through isomerization into d-lysergic isomer, however, was demonstrated to be 100 times more acid [21]. TheN-methyl group at 6-position is introduced efficient than the S-isomer. Although d-lysergic acid is a by L-methionine in one of the steps between 4-(3,3- biosynthetic product of ergot, the major source of this dimethylallyl)-L-tryptophan and argoclavine. The pro- compound is the hydrolysis of d-Iysergic acid amides or posed biosynthesis of lysergic acid was supported by the isomerization of paspalic acid. chemical analysis of isotopic biosynthetic products. When Theoretically, four optical isomers are possible from tryptophan-f-v'C was incorporated into the saprophytic the two asymmetric carbons atoms in the lysergic acid cultures of Claviceps, the amount of 14C in elymoclavine molecule (C-5 and C-8 in Figure 1). Many of the ergot was found to be 10-39% of the original radioactivity. alkaloids are isomeric at the C-8 position, but none of Tryptophan deuterated specifically in the indole ring these alkaloids is isomeric at C-5 [52,92]. Therefore, only showed incorporation of the indole moiety and retention two compounds, d-lysergic acid and d-isolysergic acid, of the hydrogens at C-5, C-6, and C-7, but not that at C-4. are formed after alkaline hydrolysis of the ergot alkaloids. These experiments clearly indicated that the entire tryp- In d-lysergic acid, the C-5 hydrogen atom and the C-8 tophan molecule, wi th the exception of the carboxyl group carboxylic acid are in cis configuration, and in d-isolysergic and the hydrogen at C-4, was incorporated into the basic acid, these two functions are in trans configuration. If J eOOH CH :O~HC'j H _~~FCH2 CH CH 3 3 3 )j: 3 L'.2-Isopentenol pyrophosphate eOOH HOfr 0 5 00 000 + 6 ~ 4 NH2 R-Mevalonic acid L'.3-Isopelltenol pyrophosphate JI "H 1 HN 2 L-Tryptophan CH3 ) HN 4-(3,3-Dimethylall)'I)-L-tryptophan Argoclavine eooH Elymoclavine Paspalic Acid d-Lysergic acid Figure 2. Biosynthesis of d-lysergic acid. Forensic Science Review • Volume Eleven Number Two • Dec. 1999 ----- ---- - -, ----- 161 these two isomers are not separated before preparation of compound d-iso-LSD is not active. The lethal toxicity LSD, both d-LSD and d-iso-LSD are formed. Moreover, (LDso) of LSD was studied in various species [17]. It has a strong base and long reaction time in the hydrolytic step been suggested that LSD toxicity is related more closely may transform some of the d-Iysergic acid to d-isolysergic to brain than to the body weight.
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