The pharmacology of lysergic acid diethylamide: a review

This paper (2008) extensively reviews the pharmacology and psychopharmacology of LSD.

Abstract

“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.”

Authors: Torsten Passie, John H. Halpern, Dirk O. Stichtenoth, Hinderk M. Emrich & Annelie Hintzen

Summary

Introduction

Lysergic acid diethylamide (LSD) is a semisynthetic product of lysergic acid, a natural substance from the parasitic rye fungus Claviceps purpurea. It was synthesized in 1938 and first used in the 1950s for experimental purposes to induce temporary psychotic-like states in normals and later to enhance psychotherapeutic treatments.

Despite its successful and safe use as a psychotherapeutic adjunct and experimental tool, almost no legal clinical research with LSD has occurred since the 1970s. However, interest is increasing for using LSD in brain research.

Though LSD causes no physical damage, many psychiatric complications have been reported. Although the dosage appears mostly unchanged since the 1970s, the number of complications has probably declined since the late 1960s.

Chemistry

LSD is a semisynthetic substance derived from lysergic acid as found in the parasitic rye fungus C. purpurea. It has four isomeric, optically-active LSD isomers, of which d-LSD has psy-choactive properties.

Many derivatives of LSD have been studied, but none have shown a potency comparable to that of LSD.

Psychological Effects

LSD will significantly alter state of consciousness, causing euphoria, enhanced capacity for introspection, and altered psychological functioning. Perceptual changes such as illusions, pseudohallucinations, and synesthesias may also occur.

LSD’s acute psychological effects last between 6 and 10 hours, depending on the dose applied.

Traumatic experiences can have long-lasting effects on LSD users, but under controlled conditions the experience may have positive effects.

Acute Neurocognitive Effects

LSD has several cognitive effects, including impaired coordination, attention, and concentration, decreased performance on learning tasks, and a regression of intellectual functions to an ontogenetically younger state of development.

Toxicological Data

LSD has a different LD 50 in different species. The most sensitive species is the rabbit, and the highest LD 50 was 16.5 mg/kg i.v.

Eight people have accidentally consumed a very high dose of LSD intranasally, but all survived with hospital treatment and without residual effects.

In 1967, a report gave evidence for LSD-induced chromosomal damage. Later studies disproved this evidence and showed that LSD has no teratogenic or mutagenic effects in man.

Somatic Effects

LSD causes mild autonomic changes in rats and cats, including mydriasis, tachycardia, tachypnea, hyperthermia, hypertonia, and hyperglycemia. These changes may be caused by central stimulation of the sympathetic system.

Autonomic changes are reflected in pupillary dilation, heart rate and blood pressure increase, slight blood-sugar elevation, and body temperature increase. Respiration remains generally unchanged, and there is no evidence that LSD alters liver function.

Most somatic effects ascribed to LSD are secondary effects caused by the psychological reaction to the drug. These effects include an exaggeration of the patellar (and other deep tendon) reflexes, positive Romberg’s sign, and mild tremor.

Biochemical Changes

LSD decreased the excretion of inorganic phosphate in normals, suggesting that LSD may act on enzymatic systems to facilitate the binding of phosphate.

LSD induces a slight decrease in creatinine clearance, but no change in calcium clearance or serum calcium levels. Transaminase levels were essentially unchanged as were all other hepatic tests applied.

Changes in Sleep-Waking Cycle and Dreaming

Low doses of LSD applied before or 1 h after sleep onset prolong the first or second rapid eye movement (REM) periods and shorten the following periods. No qualitative changes in sleep as measured on EEG have been found.

Endocrinological Changes

LSD significantly lowers resting plasma prolactin levels in male rats, increases serum growth hormone, and does not alter serum prolactin levels in humans.

Resorption

Upshall and Wailling [89] demonstrated that the amount of food eaten and the pH of the stomach and duodenum influence the absorption of LSD.

Clinical data about different modes of application are shown in Table 5. Hoch found no qualitative differences regarding psychological LSD effects, regardless of the route of administration.

Distribution in the Organism

LSD is distributed across tissue and organ systems in mice, but has not been quantified for the human organism. In rats, a much lower LSD concentration is found compared to blood plasma levels, but disappears from the brain much more rapidly than from blood plasma.

LSD easily passes the blood-brain barrier. The amount of the drug in the brain and cerebrospinal fluid (CSF) of rats and cats is about the same as the unbound form in blood plasma.

Course of Plasma Levels

Aghajanian and Bing found that after administration of 2 g/kg i.v., plasma levels of LSD gradually fell until only a small amount was present.

Metabolism and Excretion

Rats, guinea pigs, and rhesus monkeys all metabolize [14 C]-LSD to 13- and 14-hydroxy-LSD and their glucuronic acid conjugates, 2-oxo-LSD, nor-LSD, and a not further specified naphthostyril derivative. However, the metabolism of LSD in rhesus monkeys is unique.

In humans, LSD is metabolized rapidly into several structurally similar metabolites, including 2-oxy-LSD, 2-oxo-3-hydroxy LSD, nor-LSD, 13- and 14-hydroxy-LSD as glucoronides, and trioxylated LSD. The major metabolite in urine is 2-oxy-3-hydroxy LSD.

Siddik et al. [103] found that rats, guinea pigs, and rhesus monkeys eliminated 14 C-LSD in feces, urine, and expired air over a 96-h period.

Urine concentrations of LSD reach a maximum 4 – 6 hours after administration, and the drug can be detected for up to 4 days.

Detection of LSD in Body Fluids

LSD can be detected in the body in very small amounts by RIA and enzyme immunoassay. A new indirect enzyme-linked immunosorbent assay (ELISA) was used to detect as little as 1 pg of total drug in 25 l blood.

LSD can be detected in blood and urine samples by high-performance thin layer chromatography and different forms of gas chromatography/mass spectrometry. The detection limits are set to approximately 0.4 g/L for LSD and N-desmethyl-LSD, respectively.

Regional Distribution in Brain Tissue

Arnold et al. [119] and Snyder and Reivich [96] found that LSD was unequally distributed in different areas of the brain and that the limbic system contained two to three times more LSD than cortical structures.

Effects on Cerebral Circulation

Sokoloff et al measured cerebral blood flow, vascular resistance, oxygen consumption, and glucose utilization in humans, but found no significant change. They concluded that the effects of LSD may be limited to small areas of the brain.

Neurophysiological Actions

The EEG shows mild and little specific signs of activation after LSD ingestion, including an increase in mean frequency and a progressive desynchronization due to a quantitative decrement of the slow component.

Neurometabolic Effects

The neurometabolic actions of LSD have not been completely studied, but there are some congruent results regarding the results of different studies. The major hallucinogens appear to activate the right hemisphere, influence thalamic functioning, and increase metabolism in paralimbic structures and in the frontal cortex.

Interactions with Receptors

LSD preferentially inhibits serotonergic cell firing while sparing postsynaptic serotonin receptors from upregulation/downregulation. Nonhallucinogenic analogs of LSD show no such preference.

Serotonin is produced by 1000 neurons in the raphe nuclei of the midbrain, and these neurons innervate 500,000 other neurons. They may inhibit sensation, thus protecting the brain from sensory overload.

5-HT is mainly an inhibitory transmitter, but some 5-HT receptors are excitatory ion channels, and some subtypes may have excitatory effects depending upon the G protein coupling within specific neurons.

LSD inhibits firing and serotonin release of 5-HT 1A receptors in the LC, the RN, and the cortex, and also acts as a partial agonist on the postsynaptic 5-HT 1A site. It also has high affinity for other 5-HT 1 subtypes.

LSD is a partial agonist at 5-HT 2A receptors, and also increases cortical glutamate levels. This can lead to an alteration in corticocortical and corticosubcortical transmission.

Gonzalez-Maeso et al. [156] found that 2-HT 2A agonists with hallucinogenic activity induce different G-protein activations in mice, especially in the pertussis toxin-sensitive heterotrimeric G i/o and G a/11 proteins and their coactivation.

LSD interacts with dopaminergic systems and may be involved in psychoactive effects. Time-dependent activation of dopamine and serotonin receptors may be a possible explanation for the enormous range of effects LSD engenders in humans.

Tolerance

Tolerance to the effects of LSD occurs in humans and animals after a few moderate daily doses of LSD.

A recent animal experiment indicated that rats that were previously trained to discriminate LSD from saline had a lower 5-HT 2A receptor density.

Interactions of LSD with Other Substances

Various studies have evaluated drug interactions with LSD. Chlorpromazine (CPZ) has proven to be an incomplete antagonist of LSD, and at high doses, LSD-induced side effects diminish or disappear.

Sedative-hypnotics like diazepam are often used in the emergency room setting for acute presentations of LSD intoxication to help reduce panic and anxiety. Lithium and some tricyclic antidepressants have also been reported to increase the effects of LSD.

Psychiatric Complications

Many reports exist about psychiatric complications following LSD ingestion outside the research setting, but there is a lack of evidence that other complications will routinely occur or persist in healthy persons taking LSD in a familiar surrounding.

Flashbacks are a very rare occurrence that can occur following intense negative experiences with hallucinogens. They are characterized by their replication of elements of previous drug-related experiences and can last for months to a year with considerable morbidity.

Conclusion

LSD is physiologically well tolerated and its mechanisms of action are unclear. However, research in the 1950s and 1960s led to the discovery of serotonin, brain second-messenger systems, and a variety of other research techniques. After advancements in research, LSD research faded, and government funding dried up. Today, LSD is being evaluated for treatment of cluster headache, anxiety provoking end-of-life issues, and post-traumatic stress disorder.