Lysergic Acid Diethylamide (LSD, Entactogen) Toxicity

Article Author:
Maximo Baquiran
Article Editor:
Yasir Al Khalili
Updated:
5/4/2020 7:29:22 PM
PubMed Link:
Lysergic Acid Diethylamide (LSD, Entactogen) Toxicity

Introduction

D-lysergic acid diethylamide, or LSD, is a compound of the lysergamide class known for its powerful psychedelic effects on humans. Although first synthesized in 1938 by Albert Hofmann in an attempt to create a central nervous system stimulant, it was not until 1943 when Hofmann discovered the molecule’s subjective effects on the human body after accidental absorption through the skin. Only a few days later, on the 19 of April 1943, reports suggest Hofmann ingested around 250 micrograms of the drug, marking the very first intentional “LSD trip.” While Hofmann, and countless others afterward, who report ingesting the drug at various dosages, indicate a wide variety of effects, a common denominator of sorts is the absolute profundity of the experience that the drug seems to elicit in users.

A substance of significant pharmacological and clinical interest, LSD remains as the most researched hallucinogen. It was famously examined by the CIA in the 1950s when the research program MK-ULTRA was implemented to investigate potential methods and pharmacological agents to aid in the development of “truth serums.” Further research centered on the substance’s mechanism of action in the body was conducted, and the early belief that it had serotonergic properties was eventually confirmed. Specifically, the drug acts as a partial agonist at the 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT6 receptors.[1]  The threshold dose of LSD is commonly accepted to be 15 micrograms, while a relatively heavy dose at the opposite end of the accepted spectrum is around 300 micrograms. As the dosage increases beyond this arbitrary setpoint, reports suggest an increase in the intensity of the drug’s effects. This dosing brings up an all-important question that applies to any substance under scrutiny: pharmacologically speaking, what is the drug’s toxicity? Interestingly, in the case of LSD, no deaths can be attributed to its direct effects.

Etiology

LSD possession became illegal in the United States on October 24, 1968, in an amendment of the Federal Food, Drug, and Cosmetic Act of 1938. The final study of LSD approved by the FDA took place in 1980. LSD currently sits on a shortlist of schedule I drugs, along with other hallucinogens and stimulants such as dimethyltryptamine (DMT), gamma-hydroxybutyrate (GHB), heroin, marijuana, methylenedioxy-methamphetamine (MDMA), mescaline, and psilocybin. Because of the controversy surrounding the substance, clinical trials have been difficult to organize.

Alexander Shulgin, in his work, “Tryptamines I Have Known and Loved (TiHKAL),” detailed the synthesis of LSD from lysergic acid (interestingly classified itself as a schedule III controlled substance). He describes LSD as “a fragile molecule…free from air and light exposure; it is stable indefinitely.” Shulgin goes on to detail three groups of LSD analogs that have been synthesized; the first group kept the diethylamide group unchanged, with alterations made in the pyrrole ring, and included ALD-52, MLD-41, BOL-148, 1-hydroxymethyl-LSD, 1-dimethyl aminomethyl-LSD, 2-iodo-LSD. The other group of analogs had both 1-substituents, and amide alkyl group variations, and included LAE-32, ergonovine, methergine, DAM-57, LSM-775, and others. The third group included LSD analogs that had structural modifications at the 6-position in the “D-ring” and were labeled as constituents of the “LAD series.” ETH-LAD, AL-LAD, and PRO-LAD were considered significant, according to Shulgin, and earned separate entries in his book.

A study published in 2016 by De Gregorio et al. analyzed the therapeutic potential of novel antipsychotics through the model of LSD-induced psychosis. Their paper includes a summary of experiments performed throughout the years that highlighted the interactions of LSD with serotonergic, dopaminergic, glutamatergic, and trace amine-associated receptor (TAAR) systems. The summary shows that LSD is not only active at the 5-HT1A, 5-HT2A, and 5-HT2C serotonergic receptors and serotonin transporter (SERT), but also active at the D1, D2, D4 dopaminergic receptors, the NMDA, mGlu2/mGlu3 glutamatergic receptors, and the TAAR1 receptor.[2]

LSD is most commonly ingested orally in the form of blotter, perforated sheets of paper often decorated with abstract artwork that can subdivide into smaller pieces with the substance uniformly laid across the sheet. LSD has a bioavailability of 71%, a threshold dose of 15 micrograms, and a duration of action of 8 to 12 hours, with residual effects sometimes lasting anywhere from 12 to 48 hours.[3] It is often known as a “club drug,” but many users report preferring to ingest the drug in a highly controlled, comfortable setting, such as within a home.

Epidemiology

A 2013 study conducted by Krebs and Johansen sought to estimate s lifetime prevalence of psychedelic use. They defined psychedelics as either LSD, psilocybin, mescaline, and peyote, and described prevalence by age category from a retrospective U.S. population survey. The study cited was the 2010 National Survey on Drug Use and Health (NSDUH). This survey takes place annually to estimate general substance use and potential correlations with mental health indicators from a randomly selected group of individuals aged 12 and up. In the 2010 survey, 23 million U.S. residents reported using LSD at least once (23 million, 95% CI: 22 to 25 million). Use amongst residents in the 50 to 64 year age group was similar to the usage rate amongst those in the 21 to 49 year age group. Interestingly, the rate of lifetime psychedelic use was largest amongst those aged 30 to 34 years; recreational LSD use first became widespread during the 1960s and ‘70s.[4]

Rickert et al. looked at prevalence and risk factors for LSD use among young women in a study first published in 2003; 904 sexually active adolescent and young adult women aged 14 to 26 years took the survey at university-based outpatient reproductive health clinics between April and November of 1997. Out of 904 participants, 119 (13%) reported using LSD at least once, and 536 (58%) reported using marijuana at least once. Further analyses showed that the typical female LSD or marijuana user presented with a distinct profile: women who reported alcohol intoxication at least ten times in the past year, smoked at least half a pack of cigarettes within the same timeframe, and those who identified themselves as being relatively “high-sexual-risk takers” were more likely to have used LSD or marijuana before. LSD users, in contrast to nonusers, however, were more likely to be of white ethnicity, present under the age of 17, and were more likely to report a history of physical abuse, as well as severe depressive symptoms.[5]

Toxicokinetics

Dolder et al. analyzed the pharmacokinetics and pharmacodynamics of LSD in a study first published in 2017. The analysis occurred in two studies: in one newly performed study, 100-micrograms of LSD was dosed orally to 24 healthy subjects; in the other study, which was a retrospective analysis, 16 subjects received 200-micrograms orally. Blood sampling was performed, and analysis of plasma LSD concentrations, subjective moods of the subjects, and vital signs were also done. Mean peak plasma concentrations of 1.3 ng/mL were observed 1.4 hours after administering the 100-microgram dose was administered, and a mean Cmax value of 3.1 ng/mL was attained 1.5 hours after administration of the 200-microgram dose. The present study showed that the plasma half-life of LSD was 2.9 hours, comparable to the result after IV administration of 2mcg/kg found in a separate study. In the-100 microgram dose group, the researchers found the time of onset to be 0.8 +/- 0.4 hours (range 0.1 to 1.7 hours) and 9.0 ± 2.0 hours (range 6.1 to 14.5 hours); the mean effect duration was measured as  8.2 +/- 2.1 h (range 5 to 14 hours); time to peak drug effect was 2.8 +/- 0.8 hours (range 1.2 to 4.6 hours). For the 200-microgram dose group, the following values were obtained: for time of onset and offset, 0.4 +/- 0.3 h (range 0.04 to 1.2 hours) and 11.6 +/- 4.2 hours (range 7.0 to 19.5 hours); mean effect duration was 11.2 +/- 4.2 hours (range 6.4 to 19.3 hours), and time to peak effects was 2.5 +/- 1.2 hours (range 0.8 to 4.4 hours). The researchers found vitals such as systolic blood pressure, heart rate, and core body temperature to be elevated after LSD administration in both groups.[3]

History and Physical

Patients under the influence of LSD will most likely present to a clinical setting after experiencing what is colloquially referred to as a “bad trip.” Others may present after ingesting the substance unknowingly, or perhaps in exceedingly large doses.

Obtaining a quality history and physical will be dependent on the alertness and orientation of the presenting patient, which will vary based on just how altered the patient’s perception appears. If the patient is unable to provide a thorough history, clinical staff should contact any friends or family to assist in history taking. Clinicians should focus history taking on the following: chief complaint(s); dosage of substance; timing and place of dosage; patient’s knowledge of the substance; prior experience with substance; associated symptoms, or concomitant substance use; standard review of systems.

The following may appear on the physical exam:

  • Vitals: temperature, which may be normal; blood pressure, can be increased; heart rate, often high; respiratory rate, can be elevated; oxygen saturation, normal in most cases.
  • General: alertness and orientation may be off from baseline; patients can be diaphoretic, and appear disheveled in appearance; loss of appetite
  • HEENT: mydriasis, xerostomia, nystagmus
  • Respiratory: increased respiratory rate
  • Cardiovascular: increased heart rate and blood pressure
  • Skin: hyperhidrosis
  • Neurologic: impaired coordination
  • Psychiatric: auditory and visual hallucinations, panic, psychosis, paranoia, synesthesia, time perturbations, emotional lability, aggression, depersonalization, suicidal ideation, religiosity, depression

Evaluation

The diagnosis of LSD intoxication is clinical. As such, a thorough history and physical requires emphasis; this is not to say other testing modalities are not necessary. In complicated cases, coagulation studies and serum electrolytes should be obtained, especially when seizures are present, or neuroleptic malignant syndrome is suspected. Imaging studies are warranted to rule out other diagnoses. Electrocardiography is appropriate to evaluate tachycardias, bradycardias, and other arrhythmias, not necessarily caused by LSD itself, but possibly from co-ingestion with other potent stimulants, such as MDMA.

Any routine drug test does not detect the substance. Although, a recent study in 2015 by Dolder et al. sought to quantify LSD and its main metabolite, 2-oxo-3-hydroxy LSD (abbreviated as O-H-LSD) in the serum, as well as in urine samples, primarily in the emergency setting. Their methods were found to be both accurate and precise in quantifying the expected concentrations in subjects intoxicated by LSD, but their approach has not found wide adoption in clinical settings.[6]

Berg et al. used ultra-performance liquid chromatography to determine concentrations of LSD in serum in a 2013 study. Concentrations of 1.5 to 5.5 ng/mL were present 24 hours after patients ingested 300-microgram doses of the substance. Due to the level of complexity surrounding the methods, this method is also not adopted to an appreciable degree.[7]

Treatment / Management

Treatment of LSD toxicity is mainly supportive. Autonomic symptoms require symptomatic treatment.

The Substance Abuse and Mental Health Services Administration (SAMHSA) published protocols for improving treatment for patients under the influence of, or withdrawing from specific substances in a 2006 update. For hallucinogenic toxicity, the recommendation is to provide a quiet environment for the patient, one that is preferably free from external stimuli, and also to provide direct one-to-one supervision to ensure the patient does not cause any harm, whether it is self-harm or harm to others. The guidelines also state that a low dose of a benzodiazepine may be indicated in some cases for control of anxiety. Individuals who have taken large doses of LSD are at risk for residual psychotic symptoms and are therefore managed with antipsychotic drugs if symptoms manifest and persist.

Differential Diagnosis

Other drugs of abuse require consideration in the differential of LSD intoxication, such as:

  • 3,4-Methylenedioxymethamphetamine (MDMA)
  • 3,4-Methylenedioxyamphetmine (MDA)
  • N,N-dimethyltryptamine (DMT)
  • Psilocybin
  • Phencyclidine (PCP)
  • Cocaine, and other amphetamines
  • Ethanol
  • Benzodiazepines
  • Barbiturates
  • Gamma-hydroxybutyrate (GHB)

Psychiatric conditions, such as psychosis and schizophrenia, should be considered in the differential. Infections and tumors within the central nervous system should also be in the differential, depending on the clinical presentation. The altered mental status that can manifest from LSD intoxication must be distinguished from other causes, such as from various electrolyte abnormalities.

Prognosis

The prognosis is generally favorable in patients presenting under the influence of LSD, provided the exclusion of other diagnoses, and no complications arise. Since treatment is primarily supportive, as long as the clinical staff follows the treatment recommendations provided by the Substance Abuse and Mental Health Services Administration (SAMHSA), the expectation is for quality outcomes.

Complications

Complications from LSD intoxication can arise in a few places. One such place is the environment in which the patient ingested the substance. If the scene was not safe, and the patient caused accidental harm to his or her self, or others, this can lead to a myriad of complications, such as trauma.

Persistent psychotic symptoms can manifest in those who ingest large doses of LSD. Patients often refer to their "trips" as life-altering experiences, and those who experience particularly profound departures from reality may have a difficult time adjusting long after the drug's effects have worn off.

Hallucinogen persisting perception disorder is a potential complication of hallucinogen intoxication. It is a diagnosis defined in DSM-5 as a disorder in which patients not currently intoxicated by a hallucinogenic agent experience perceptual symptoms that first manifested during prior hallucinogenic experiences. These symptoms must result in clinically significant distress and impair normal social and occupational functions. Clinicians must also not attribute them to another medical condition or psychiatric diagnosis. Reports have shown these symptoms to include mainly visual disturbances, such as geometric hallucinations, halos surrounding objects, alterations in motion-perception, floaters, and flashbacks to images seen during the prior drug experience.[8]

Autonomic complications arise when there is a failure to treat symptoms of hypertension, hypotension, arrhythmias, and hyperthermia.

Deterrence and Patient Education

Education about the risks of drugs of abuse, such as LSD, must be continually emphasized to reduce the risk of accidental ingestion and overdose. Patients often experiment without knowledge of the substances they ingest, and this understandably leads to many negative experiences and potentially unnecessary hospitalizations. Since LSD is a schedule I substance, education about the ramifications of possessing and distributing such substances should also be emphasized, along with the substance's mechanism of action and subjective effects to reduce instances of overdoses.

Enhancing Healthcare Team Outcomes

Patients arriving at the emergency department with drug intoxication present unique challenges to the providing healthcare team. Since the differential diagnosis of LSD intoxication, let alone any drug intoxication, is an exhaustive list, a strong emphasis on obtaining a thorough history and physical exam is of paramount importance. This process starts with EMTs and paramedics, if applicable, the physicians and nurses, and the pharmacists preparing drugs, since the administration of a drug to control a patient's autonomic symptoms can interact, sometimes fatally, with the substances already present in their serum. Although LSD is one of the most well-known illegal drugs, numerous drug analogs have been "designed" to offer many of the same effects of the substances currently outlawed by the government, that many individuals like those on a healthcare team do not have sufficient knowledge of these. Education about current and past designer drugs may be of great benefit to those working in healthcare when the source of intoxication is under question, or completely unable to be elucidated.


References

[1] AGHAJANIAN GK,BING OH, PERSISTENCE OF LYSERGIC ACID DIETHYLAMIDE IN THE PLASMA OF HUMAN SUBJECTS. Clinical pharmacology and therapeutics. 1964 Sep-Oct;     [PubMed PMID: 14209776]
[2] De Gregorio D,Comai S,Posa L,Gobbi G, d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology. International journal of molecular sciences. 2016 Nov 23;     [PubMed PMID: 27886063]
[3] Dolder PC,Schmid Y,Steuer AE,Kraemer T,Rentsch KM,Hammann F,Liechti ME, Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects. Clinical pharmacokinetics. 2017 Oct;     [PubMed PMID: 28197931]
[4] Krebs TS,Johansen PØ, Over 30 million psychedelic users in the United States. F1000Research. 2013;     [PubMed PMID: 24627778]
[5] Rickert VI,Siqueira LM,Dale T,Wiemann CM, Prevalence and risk factors for LSD use among young women. Journal of pediatric and adolescent gynecology. 2003 Apr;     [PubMed PMID: 12742139]
[6] Dolder PC,Liechti ME,Rentsch KM, Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases. Analytical and bioanalytical chemistry. 2015 Feb;     [PubMed PMID: 25542574]
[7] Berg T,Jørgenrud B,Strand DH, Determination of buprenorphine, fentanyl and LSD in whole blood by UPLC-MS-MS. Journal of analytical toxicology. 2013 Apr;     [PubMed PMID: 23423312]
[8] Orsolini L,Papanti GD,De Berardis D,Guirguis A,Corkery JM,Schifano F, The     [PubMed PMID: 29209235]