The Pharmacology of Lysergic Acid Diethylamide : a Review

Torsten PASSIE, John H. HALPERN, Dirk O. STICHTENOTH, Hinderk M. EMRICH, Annelie HINTZEN

CNS Neuroscience & Therapeutics, 2008, 14, 295-314.

Doi: 10.1111/j.1755-5949.2008.00059.x

 

Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called “experimental psychosis” by altering neurotransmitter system and in psychotherapeutic procedures (“psycholytic” and “psychedelic” therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

Keywords : LSD; Psychopharmacology; Pharmacology;Pharmacokinetics; Mechanism of action; Hallucinogen; Psychedelic

 

Introduction

Lysergic acid diethylamide (LSD) is a semisynthetic product of lysergic acid, a natural substance from the parasitic rye fungus Claviceps purpurea. Albert Hofmann, a natural products chemist at the Sandoz AG Pharmaceutical Company (Basel, Switzerland) synthesized it in 1938 while searching for pharmacologically active derivatives of lysergic acid. He accidentally discovered its dramatic psychological effects in 1943. Though he synthesized many lysergic acid derivatives, none had LSD’s unique spectrum of psychological effects. During the 1950s LSD (Delysidc Sandoz) was introduced to the medical community as an experimental tool to induce temporary psychotic-like states in normals (“model-psychosis”) and later to enhance psychotherapeutic treatments (“psycholytic” or “psychedelic” therapy) [1,2].

Toward the end of the 1960s, people began using LSD for recreational and spiritual purposes, [3] leading to the formation of a “psychedelic movement” during the international student protests of that era [4,5]. Though the protest movement declined, the use of LSD continued. It is still a major hallucinogen, illegally used worldwide. The National Survey on Drug Use and Health [6] has, for example, reported LSD as a major drug of abuse in every annual survey since the 1970s.

Despite LSD’s successful and safe use as a psychotherapeutic adjunct and experimental tool (cf. Ref. [7] and the retrospective surveys of Cohen [8] and Malleson [9]), almost no legal clinical research with LSD has occurred since the 1970s. Exceptions include the continued use in psychotherapy by Hanscarl Leuner at G¨ ottingen University (Germany) and by a limited number of psychotherapists in Switzerland from 1988 to 1993 [10,11]. Today, interest is increasing for using LSD in brain research, treatment of cluster headache [12], and as an aid in the psychotherapeutic treatment of the terminally ill [13,14].

Though no physical damage results from the use of LSD, many psychiatric complications have been reported, with a peak occurring at the end of the 1960s [15,16]. Although the dosage appears mostly unchanged since the 1970s [16], the number of complications has probably declined since the late 1960s and early 1970s because today there may be better-informed users, better mental preparation and attention to surrounding conditions, and reduction in dosage weight (although one report claims LSD dosage has remained fairly constant since the 1970 [16]).

Due to the widely dispersed (across time and languages) experimental literature concerning the pharmacological properties of LSD, old and new data are together reviewed here. It should be noted that the characterization of the complex effects on the human psyche are not the focus of this review [17–19].

Chemistry

LSD is a semisynthetic substance derived from lysergic acid as found in the parasitic rye fungus C. purpurea. The molecule consists of an indole system with a tetracyclic ring (C20H25ON3) (see Figure 1). Carbons 5 and 8 are asymmetric: therefore, four isomeric, optically-active LSD isomers are possible and known. These are d- and l-LSD and d- and l-isolysergic acid diethylamide. Only the d-LSD isomer has psychoactive properties. D-LSD crystallizes from benzene in pointed prisms. It is water-soluble and its melting point is 83◦C. LSD is usually stabilized in solution as its tartrate salt. The molar mass is 323.42 g/mol.

A great number of homologs and analogs of LSD has been studied [20–23]. These derivatives consist of variations of substituents on the amide group, sometimes accompanied by substituents on the indolic pyrrole ring. Except for derivates substituted at the N-6 [24], no other derivate has shown a potency comparable to that of LSD [25].

(…)

CNS-14-295