REVIEWS LYSERGIC ACID DIETHYLAMIDE Snezha Zlateva, Petko Marinov, Gabriela Kehayova Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University of Varna ABSTRACT Lysergic acid diethylamide (LSD) is a drug known for its hallucinogenic properties especially at high doses and in recent years has been used as a pharmacological model to study the neurological substrate of psycho- sis, the effect of antipsychotics, and, in recent decades, the possibility of using it as a remedy for some dis- eases is being studied. The purpose of this review is to analyze reference reports published in Pubmed, Web of Science, Scopus, Google Scholar, articles on preclinical and clinical studies related to LSD, history of use, pharmacokinet- ic properties, mechanism of action by activating serotonergic, dopaminergic, glutamate receptor systems, TAAR₁ receptors, amine receptors and effects on the rewarding brain system, pilot preclinical and clinical studies as a therapeutic model for the treatment of depression, anxiety, stress and addictions. We have con- sidered acute psychotic dose-dependent intoxications and chronic psychosis. Keywords: LSD, LSD psychosis, LSAD schizophrenia 5-HT2A, LSD acute intoxications, LSD chronic intoxications CLASSIFICATION HISTORY Lysergic acid diethylamide (LSD) (C20H25N3O) The hallucinogenic properties of the fungus belongs to the class lysergamides or ergoalkaloids. In Claviceps purpurea have been known for millennia. nature, they are found in the fungus Claviceps pur- The fungus Claviceps purpurea (Fries) grows purea growing on cereals, mainly rye. LSD is classi- as a parasite on the pistil of some cereals, mainly on fied as a drug, psychoactive substance, hallucinogen rye. It is currently collected as a poisonous herb from and entheogen/substance for shamanic, mystical and which various alkaloids, nitrogen-containing com- religious purposes. As a drug it is on List I (USA); pounds and ballast substances are isolated. The most Class A (UK); List III (Canada); Annex 1 (Bulgaria). important are the ergoalkaloids: ergotamine, ergo- In Bulgaria, possession, production and trade in LSD sine, ergozinine, ergocristine, ergocristinine, ergo- are prohibited and prosecuted. cryptine, ergocryptinine, ergocornine, ergocorni- nine, ergometrine (ergobazin), ergometrinin (ergo- metrine). An integral part of these alkaloids is lyser- gic and isolysergic acid. In folk medicine it is used Address for correspondence: Gabriela Kehayova to induce abortion and as gynecological remedy. In Faculty of Pharmacy homeopathy, medicines based on it are used to treat Medical University of Varna blood circulation, with paresthesia and gangrene. In 84 Tzar Osvoboditel Blvd medicine they are used as drugs for neuroses and mi- 9000 Varna graines /belergamine and cofergamine/, to stop uter- e-mail: [email protected] ine bleeding, and to strengthen the contraction of the Received: October 23, 2019 uterus /ergot/. Accepted: December 9, 2019 Scripta Scientifica Pharmaceutica, 2019;6(2):7-21 7 Medical University of Varna Lysergic Acid Diethylamide Claviceps purpurea and its hallucinogenic prop- The Hippie Period of LSD erties have been known for centuries. It is believed The mid-20th century, 1960-1980s, were known that it was used in ancient Greece in the so-called as the “hippie period”. They are largely due to the re- Eleusinian Mysteries /annual celebrations dedicated search of psychiatrists F. Leary /USA/ (6) and Stan- to Demeter and Persephone/. The participants drank islav Grof /Czech Republic/ (7). These scientists saw a drink of barley or rye, fell into a mystical trance in LSD a „magic elixir“ expanding consciousness. with bright pictures sent to them by the gods. In the Adherents of this theory became students, musi- Middle Ages, Claviceps purpurea became the cause cians, actors, writers, artists, as well as many hipsters of mass poisoning by falling into the flour. Poisoning and hippies. LSD is associated with groups that dis- with it is called ergotism. Symptoms include muscle agree with the prevailing cultural and political sit- twitching and convulsions, inability to control the uation in the United States and other countries, the body, grimacing, confusion, hallucinations, vomit- psychedelic revolution (8), and the hippie movement ing and diarrhea. They attributed these symptoms to (9). Young people who committed crimes ended up the possession of an evil force. In France, the most in psychiatric clinics and committed suicide. The common epidemic outbreaks of ergotism have been National Survey on Drug Use and Health (NSDUH) described, killing thousands of people (about 50 000 estimates that more than 22 million (9.1% of the US people between 990 and 1130). They called it ergot- population) have used LSD at least once in their lives ism and Holy Fire or St. Anthony‘s Fire, because the (8). LSD was recognized as a drug criminalized in patients were hospitalized in St. Anthony‘s Hospital. 1965 and banned in the early 1970s, both in the Unit- The Salem Witch believed to have been caused by er- ed States and in most countries. gotism (1,2,3). However, lysergic acid diethylamide continued The connection between the consumption of to be studied by psychiatrists, therapists, military flour infected with the fungus was first made by the and intelligence agencies in the following decades German physician W. Thelius in 1596, and later by with varying success (10), and in the last decade there the French physician Dr. Thuillier in 1670. They be- was a renaissance in the study of this substance to lieved that the disease was not infectious, but was due understand brain neurotransmitters and function, as to rye containing ergotoxins. The first microbiolo- well as therapeutic means. gist to observe the fungus now known as C. purpurea Modern Renaissance of Psychedelics as was Louis Rene Tulasne in 1853, who suggested that Medicines it produced ergo-alkaloids, not rye itself. Scientific interest in serotonergic psychedel- Synthesis of LSD Lysergic Acid Diethylamide ics has increased dramatically over the last decade The chemical isolation of ergo-alkaloids took due to the ineffectiveness of available drugs and the place in 1918 and the vasoconstrictor properties of search for alternative approaches, such as transla- ergotamine were proved. In 1938, the Swiss chemist tional psychedelic biomedicine for patients. Pre- Albert Hoffmann (later called the „father of LSD“) clinical and clinical pilot studies with LSD, psilo- synthesized lysergic acid diethylamine, or LSD-25, cybin and mescaline, in combination with psycho- from ergot alkaloids in the Sandoz laboratories in therapy in volunteers (11, 12, 13), reported good re- Switzerland. Hoffmann himself tried the newly syn- sults in the treatment of mood disorders (14), anxiety thesized substance and described his first experience (11,15,16), depression (12,16,17), post-traumatic stress with LSD as „a journey into the universe of the soul, disorder, cancer and fear of impending death (12,17), waves of immeasurable happiness flowing through increased emotional empathy in healthy volunteers the body.“ In his memoirs he writes: „I have experi- (18), functional neurological disorders (19), inflam- enced the grace of God“ and the feeling that „God is matory diseases (11), as well as addiction to tobacco, in everything“ (4). It was initially thought to be an ef- alcohol (11,12,14,16,17,20,21) and other drug addic- fective drug for treating schizophrenia and was used tions such as cannabis, stimulants and opiates (13). in the mentally ill (5). The potential antidepressant, anxiolytic and anti-addictive effects (17,20,22,24) have been stud- 8 Scripta Scientifica Pharmaceutica, 2019;6(2):7-21 Medical University of Varna Snezha Zlateva, Petko Marinov, Gabriela Kehayova ied. The putative mechanisms include acute desta- ed and perforated) is divided into about 1/4 squares, bilization of the brain network (serotonin, dopa- called sections, and soaked in a dilution of lysergic mine and glutamate neurons) resulting in its recov- acid diethylamide. A separate section usually con- ery (11,23,25), as well as changes in the expression of tains between 30-100 µg LSD, and the variations are genes that contribute to synaptic plasticity, providing wide depending on the skills of the chemist. physiological evidence that these compounds cause It is also possible to take it in the form of gelatin. permanent changes in the brain (15,25-27). They are known as „window glass“. Gelatin LSD is Many of these studies are at an advanced stage, made by mixing liquid LSD with gelatin and forming but no study to date has shown sufficient efficacy it into small, thin squares. The benefit of this method (17,19). For example, a study of 536 volunteers with is that less of the LSD is exposed to the sun and air, chronic alcoholism treated with controlled LSD in- which breaks down lysergic acid diethylamide. One take showed OR, 1.96; 95% CI, 1.36-2.84; p = 0.0003 square of gelatin usually contains 50-150 µg of LSD. (28). Another study of 343 respondents addicted to Liquid LSD is soluble in water and other sol- alcohol, assessed as severely addicted, and using me- vents, although liquid LSD is usually soluble in eth- dium and high doses of LSD or psilocybin at home, yl alcohol or water. Liquid LSD is used for placement showed that 83% of them, after that, no longer met on blotting paper to form labels, but can also be used the criteria for severe alcohol dependence and re- for intravenous administration. One drop of a pow- duced drinking (29). A recent online study in the erful LSD liquid can be 50 times the normal dose, al- United States of 444 cannabis, stimulant and opiate though it is usually diluted to the point where one addicts found that drug addiction was estimated to be drop equals approximately one dose. This varies 79% severe before psychedelic use, and after LSD and considerably from batch to batch and is sometimes a psilocybe use at home, the severity score dropped to weak dose, while other times it is a very strong dose.