Hallucinogen Toxicity

Updated: Apr 03, 2017
  • Author: Joseph L D'Orazio, MD, FAAEM; Chief Editor: Sage W Wiener, MD  more...
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Overview

Practice Essentials

Hallucinogens comprise a unique collection of substances that are used to induce hallucinations or alterations of consciousness. Hallucinogens are drugs that cause alteration of visual, auditory, or tactile perceptions but are also referred to classes of drugs that cause alteration of thought and emotion.

Naturally occurring hallucinogenic substances have been used worldwide for millennia to induce altered states for religious and spiritual purposes. While these practices still exist, the abuse of synthetic hallucinogens for recreational purposes is much more common today.

Patients under the influence of hallucinogens may exhibit a wide range of behaviors with the potential to rapidly fluctuate from a relaxed, euphoric state to one of extreme agitation and aggression. They should be placed in a calm and relaxed environment. Security personnel, physical restraints, and chemical sedating agents should be prepared and readily available if agitation suddenly develops.

Physical restraints should be used as a bridge to chemical restraint. Benzodiazepines are the first-line agents, and should be administered liberally.

All patients should be evaluated for the presence of emergent medical conditions, including traumatic injuries and cardiac arrhythmias. Special attention should be paid to the patient’s temperature, as many hallucinogenic agents can induce hyperthermia.

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Background

Hallucinogens can be classified and grouped by chemical structure and the compound from which they are derived. Chemically related substances tend to exhibit similar effects. Many other agents can be classified as pseudohallucinogens because they produce psychotic and delirious effects without the classic visual disturbances of true hallucinogens.

There is no perfect method to categorize hallucinogenic substances because many overlap in structure, pharmacology, and clinical features. One system groups hallucinogens into the following families [1] :

  • Indole alkaloids (tryptamines)
  • Piperidines/piperazines
  • Phenylethylamine derivatives
  • Miscellaneous psychoactive substances

Some common indole alkaloids (tryptamines) include dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin. The most common piperidines and piperazine are phencyclidine (PCP), ketamine and benzylpiperazine (BZP). The phenylethylamine derivatives are the broadest group of hallucinogen and incorporate many substances. While 3,4-methylenedioxy-N -methylamphetamine (MDMA [eg, ecstasy]) is likely the most common of the phenylethylamine derivatives, some others include such newer novel synthetics as cathinones (“bath salts”), the 2C family of drugs, as well as their N-o-methoxybenzyl analogs (NBOMe).

A number of naturally occurring hallucinogens can be found in plants and mushrooms and grow in many locations in the United States. Many of these substances have long been used in ritualistic medicine, and some are emerging agents of abuse. Included in these naturally occurring substances are DMT, psilocybin and psilocin, mescaline, salvinorin A, lysergic acid amide (LSA), and atropine and scopolamine.

Ayahuasca

DMT is a naturally occurring tryptamine found in over 65 species of plants, primarily in the South American region. For centuries, DMT-containing plants have been used for religious purposes, as they rapidly induce brief but powerful hallucinogenic effects. DMT is primarily smoked or insufflated, as it is orally inert due to rapid inactivation by intestinal monoamine oxidase (MAO). This inactivation can be overcome by the addition of a monoamine oxidase inhibitor (MAO-I), as is found in the ritualistic brew Ayahuasca.

Over the past decade, DMT use has gained popularity following the publication of the 2001 book DMT: The Spirit Molecule by Dr. Rick Strassman, MD. Of note, DMT ingestion produces significant gastrointestinal distress and universal emesis shortly after ingestion, the development of which is a desired effect in spiritual purgative ritual use.

Bath Salts

"Bath salt" is the informal street name given to designer drugs containing substituted or synthetic cathinone chemicals. These substances are sold in plain sight surreptitiously as innocuous products such as "baths salts" and are marketed under names such as "Bliss," "Ivory Wave," and "Vanilla Sky." "Not For Human Consumption" labels are utilized in an effort to circumnavigate law enforcement. Synthetic cathinone or "bath salt" abuse has emerged over the last decade and gained popularity in large part due to these agents' accessibility and ambiguous legal status. In 2011, The DEA designated methylenedioxypyrovalerone (MDPV), methylone, and mephedrone as Schedule I substances, to make their sale and possession illegal. However, the clandestine production of these substances remains ahead of legislative action to avoid prohibition.

Cathinones are found in the leaves and stems of Catha edulis (khat), a plant native to East Africa and the Arabian Peninsula. Historically, consumption of this naturally occurring cathinione has been through chewing the fresh, unprocessed leaves of the khat plant. Substituted cathinones found in "bath salts" are created in clandestine labs and have effects similar to those of amphetamines and the phenethylamine class.

Abuse of the cathinones has stemmed from the custom of khat chewing in indigenous areas, which dates back thousands of years and remains culturally acceptable in these regions. [2] Currently, substituted cathinones such as MDPV, methylone, or mephedrone are abused by insufflation of the crystalline powder.

Cannabinoids and Synthetic Cannabinoids

Cannabis sativa is the scientific name for the plant commonly known as marijuana. It is used recreationally and medicinally for many conditions. The Cannabis sativa plant contains high levels of tetrahydrocannabinol (THC) and other psychoactive cannabinoids. Although THC is the principal psychoactive component of cannabis, this plant is chemically complex and contains many other cannabinoids, including cannabidiols, cannabinol, and tetrahydrocannabivarin (THCV). The psychoactive effects seen with cannabis use include relaxation, euphoria, and heightened mood.

Synthetic marijuana is a designer class of drugs created to act as a cannabinoid receptor agonist. These synthetic cannabinoids are added to herbal mixtures to facilitate smoking to produce what many term a "legal high" or "herbal high." These products, much like the bath salts, are sold surreptitiously as "herbal incense" and are commonly referred to as "spice." Synthetic marijuana is commonly packaged and marketed under such names as K2, Spice, Bombay Blue, and Black Mamba. The label "Not For Human Consumption" is used to avoid regulation. In 2011, five synthetic cannabinoids [JWH-018, JWH-073, CP-47,497, JWH-200, and cannabicyclohexanol (CCH)] were designated Schedule I by the Controlled Substances Act which made it illegal to manufacture, import, possess, distribute, or use these substances.

Synthetic cannabinoids users typically abuse these substances to avoid illicit drug detection on standardized drug testing. While THC from marijuana abuse is easily detected on a standard urine drug test, most synthetic cannabinoids are not similar in structure to THC and therefore do not trigger positive results on typical urine drug screens. This has led to its popularity in populations with obligatory drug testing (eg, the penal system, psychiatric setting, military, department of transportation, professional athletics)

Antimuscarinic xenobiotics

Atropine and scopolamine are found in a variety of plants, and overdoses can induce hallucinations as well as a variety of more serious effects. Both are found in Datura stramonium (Jimson weed), Atropa belladonna (deadly nightshade), and Mandragora officinarum (mandrake). Scopolamine alone occurs in Hyoscyamus niger (henbane).

Dextromethorphan

Dextromethorphan (DXM) is the antitussive agent found in many over-the-counter cough and cold medicines. DXM’s clinical effects at doses higher than recommended include a euphoric-like effect, alteration of perception, and visual hallucinations. When recreationally abused in high doses, DXM acts like ketamine or PCP, blocking NMDA receptors and causing an altered level of consciousness commonly described as a dissociative state. Clinical effects vary by dose and time; abusers commonly refer to these stages as "plateaus." [3]

The over-the-counter remedies that contain DXM also typically contain other ingredients, such as decongestants, antihistamines, analgesics, and expectorants. Consequently, abusers can unwittingly consume toxic amounts of those other ingredients when abusing DXM.

Ecstasy

This designer hallucinogenic drug is widely abused recreationally as a "club drug" and is found at night clubs, festival, raves, and concerts. While the name "ecstasy" originally referred to MDMA, many drugs are sold as "ecstasy" today. [4] MDMA produces hallucinogenic effects by causing release of serotonin, norepinephrine, and dopamine. Clinical effects of this drug are similar to those of other phenethylamine drugs. The street terms "E," "X," "Molly", and others may also refer to the drug MDMA.

LSD and LSA

LSD was first synthesized in 1938 by Albert Hoffman in an attempt to derive new analeptic agents from extracts of the ergot fungus Claviceps purpurea. It first appeared in the United States in 1949 when it was used as a model to study schizophrenia due to its potent psychotomimetic effects. The applications of LSD quickly broadened to include numerous other medical and clandestine uses, including interrogation and mind-control experiments.

LSD use also was believed to enhance creativity and promote well-being. By the late 1950s, use of LSD had been proposed as a way to achieve intellectual and spiritual awakening and enlightenment. Initial studies in the early 1960s concluded that the drug was safe. By the mid 1960s, reports of increasing illicit abuse and adverse effects in patients treated with LSD led the federal government to begin regulation and restriction of its use.

Overall hallucinogen use is estimated to have remained fairly constant rover the past decade. While LSD is included in national drug trending reports, the accuracy of these for actual LSD use is complicated by novel non-lysergamide hallucinogenic compounds being marketed as LSD.

Natural occurring lysergamides can be easily found in the morning glory species (Ipomoea violacea and Rivera corymbosa) and Hawaiian baby woodrose (Argyreia nervosa), the seeds of which contain these hallucinogenic alkaloids. Both plants and seeds are legal to purchase in the United States for landscaping or decorative purposes, but extraction of the active lysergamide is illegal, as LSA is a Schedule III controlled substance.

Mescaline

Mescaline is a phenylethylamine-derived alkaloid that is found worldwide in a variety of cacti, the best known being the North American peyote cactus. Similar to the mushroom-derived hallucinogens, mescaline in the form of peyote cactus buttons has been used in rituals by many Native Americans for centuries. To achieve the desired effect, 5-10 buttons are chewed and ingested.

NBOMe

This new class of designer research chemicals includes highly potent hallucinogenic serotonin agonists. 25I-NBOMe and 25C-NBOMe are the two most common forms of this drug. "Bomb" or "N-Bomb" is commonly sold on blotter paper and the abuser administers the drug via the buccal or sublingual route, just like LSD. NBOMe is commonly misrepresented as LSD because of their similar routes of administration and effects. While the two drugs are similar, there are numerous reports of fatal overdoses in the US due to NBOMe. [5, 6]

Nutmeg

Nutmeg (seed of the Myristica fragrans tree) is widely available for culinary use. Historically, nutmeg has been used as an abortifacient and to induce menses, albeit ineffectively. In large quantities, nutmeg can produce anticholinergic effects, including visual hallucinations due to activity of the compound myristicin. While often ingested intentionally for hallucinogenic effects, case reports exist where therapeutic misadventures for naturalistic purposes have induced hallucinations. [7]

Phencyclidine and ketamine

PCP and ketamine are piperidine derivatives with potent anesthetic and illusionogenic properties. PCP was developed at Parke-Davis and Company in the late 1950s as a potent and effective dissociative anesthetic. Its use was short-lived, as it produced strong adverse side effects, including emergence reactions with extreme agitation, disorientation, and hallucinations. [8] PCP enjoyed a short use in the veterinary world during the 1960s, during which time it was diverted in pill form throughout the San Francisco region and eventually spread to surrounding states in the form of powder ("angel dust") added to plant substances for smoking.

PCP use has declined nationally over the past three decades, but remains common in certain cities including Philadelphia and Washington, D.C. PCP is most commonly sold as a liquid solvent in which an abuser will dip a cigarette or marijuana joint (a so-called wet, dip, dipper, or sherm)and the product is smoked, producing rapid clinical effects. [8] Because of PCP’s strong volatile solvent smell, it often been referred to as "embalming fluid" or "formaldehyde." This had led to some users to erroneously believe that the clinical effects from abusing formaldehyde are similar. Currently, illicit PCP is not diverted from health-care sources, but rather produced illegally in clandestine labs due to ease of synthesis and readily available precursors. [9]

Ketamine was synthesized in 1962 as a replacement for PCP, and it remains a widely used anesthetic with increasing non-operative usage, including emergency departments and the pre-hospital setting. [10, 11] Ketamine is used recreationally primarily as an insufflated powder. Its effects are dose-dependent and wide-ranging, from mild alteration of sensorium to complete dissociation of consciousness with powerful and sometimes disturbing hallucinogenic experiences known as the "K hole". Ketamine is known for being more psychologically addictive than most psychedelics. It is commonly used at large concerts and clubs. [12]

Psilocin and psilocybin

Psilocin and psilocybin are indole alkaloids that are found worldwide in a variety of mushrooms including the genus Psilocybe and have been used in religious rites for over 6,000 years. Ingesting only a few mushroom caps can produce hallucinogenic affects, but in general large numbers of mushrooms are required.

Psilocybin, the prodrug to psilocin, induces a sense of euphoria, causes visual hallucinations, and can alter spiritual perception (entheogen). The drug was widely studied in the 1960s by Timothy Leary and Richard Alpert in the Harvard Psilocybin Project and has recently gained a renewed interest in its treatment for many disorders including obsessive-compulsive disorder, cluster headaches, drug dependence, and anxiety in advanced-stage cancer.

Salvinorin A

Salvinorin A is a naturally occurring hallucinogen that is found in a variety of plants but is named from Salvia divinorum, or diviner's sage, a member of the mint family. [1] Salvinorin A is unique in that, unlike other known hallucinogenic substances that interact with serotonin (5-HT2 receptors) metabolism, it is the first known naturally occurring kappa-opioid receptor agonist. [13] This substance has been used by the Mazatec Indians in Mexico for ceremonial purposes. While Salvia divinorum and salvinorin A are not classified under the Controlled Substances Act, several states have placed regulatory controls on either or both. [14]

Other designer drugs

This group of drugs refers to psychoactive drugs initially discovered in pharmaceutical or research labs but sold illegally by clandestine labs. Just like other hallucinogens, these drugs can be classified by effect or chemical structure. Most of these drugs belong structurally to the phenylethylamine derivative group. The newer designer drug category is the most rapidly growing and changing group of drugs among the hallucinogens. While this is an ever-changing, some of the common substances include the MDMA congeners (eg, MDA, MDEA, MDPV), the 2C family of drugs (eg, NBOMe, 2CB, 2CI, and Bromodragonfly), and the D series of ring-substituted amphetamines (eg, DOB, DOI, DOM).

This category is likely the most dangerous group of drugs, for many reasons. These drugs are typically made in clandestine labs by amateur chemists, which produces variable results with poor quality control. Oftentimes these clandestine labs may inadvertently produce a drug other than their intended product, although it may be structurally similar. This unknown agent may have untoward effects above and beyond those of the intended drug. Dosing and potency are also common problems with clandestine labs — especially when chemicals are added to blotter paper or organic material, as is done with NBOMe and synthetic cannabinoids, respectively.

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Pathophysiology

Hallucinogenic substances primarily exert their effect on the central nervous system by way of neurotransmitter level manipulation. Stimulating secretion, inhibiting reuptake, or delaying enzymatic breakdown are all mechanisms by which hallucinogens can increase the synaptic concentration of the major neurotransmitters (ie, norepinephrine, serotonin, and dopamine). Small differences in structure affect neurotransmitter levels differently, which leads to the wildly varied clinical effects.

Tryptamines (eg, LSD, psilocybin, DMT) are strong partial agonists at the 5-hydroxytryptamine receptors (5-HT), which stimulate serotonin release. MDMA (ecstasy) enhances presynaptic release and reuptake of serotonin and norepinephrine. [15] JWH-018 (synthetic marijuana, spice, and K2) and other synthetic cannabinoids are cannabinoid receptor (CB1 and CB2) agonists that can exert a secondary effect on the balance of circulating catecholamines. [16]

Although these small differences help to explain the varied hallucinogenic experiences, they can also predict the spectrum of deleterious effects. Serotonin syndrome (serotonin toxicity) can occur with any agent that increases concentrations of serotonin, including LSD, psilocybin, and mescaline. [17] The neurotransmitter dopamine is associated with the reward system of the brain. Substances that stimulate release or inhibit reuptake of dopamine typically exhibit a strong addictiveness, as seen with cathinones (bath salts) and methamphetamines.

Unfortunately, even if structure and mechanism of action are similar, subtle differences in potency can lead to devastatingly different effects, as seen in the psychosis that can occur with the highly potent cannabinoid receptor agonists (eg, spice) that is not routinely associated with low-potency organic tetrahydrocannabinol (marijuana).

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Epidemiology

Frequency

United States

Results from the 2014 National Survey on Drug Use and Health (NSDUH) showed that in 2012, 1.2 million persons aged 12 or older had used hallucinogens within the past year representing 0.4 percent of that population. The percentage of adolescents (aged 12 to 17) in 2014 who were current hallucinogen users was similar to the percentages in 2012 and 2013, but it was lower than the percentages in most years from 2002 through 2011. [18]  

Of hallucinogens on the survey, ecstasy appears to be the most frequently abused, with 609,000 users in 2014. The percentage of users over aged 12 in 2014 was similiar in most years from 2002 to 2013. However, among adolescents, current ecstasy usage was lower than the percentages in most years from 2002 to 2013. [18]

International

Australia reported that in 2014, ecstasy was second only to cannabis as the most commonly used illicit drug with 2.1 million (10.9%) people aged 14 or older having used the drug during their lifetime and 500,000 having done so in the past 12 months, representing 2.5% of the population [19]

In Europe, an estimated 1.8 million young adults (15–34) used ecstasy in 2014 (1.4 % of this age group), with national estimates ranging from under 0.1 % to 3.1 %. [20]

Globally, abuse of ecstasy has been declining, according to many reports. However, the United Nations World Drug Report shows that abuse of ecstasy in Europe is still increasing. The regions with highest prevalence of ecstasy abuse are Australia and Oceania (2.9%), North America (0.9%) and Europe (0.7%). [21]

Mortality/Morbidity

Deaths from drug overdose are currently the leading cause of injury death in the United States and have been rising steadily over the past two decades. [22] While data on mortality directly attributable to hallucinogen abuse is not readily available, many estimate that hallucinogenic drugs are among the drugs with highest mortality, including prescription painkillers, heroin, and cocaine.

The Drug Abuse Warning Network (DAWN), a public health surveillance system that monitored drug-related morbidity and mortality, estimated that 49% of all emergency departments visits are due to drug use or misuse. [23]

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Race-, Sex-, and Age-related Demographics

According to the 2014 NSDUH, rates of illicit drug abuse in the past year among different ethnic groups were as follows [18] :

  • American Indians or Alaska Natives: 24.0%
  • Native Hawaiians or other Pacific Islanders: 21.3%
  • Blacks: 19.5%
  • Whites: 16.9%
  • Hispanics: 15.6%
  • Asians: 8.0%
  • Two or more races: 23.3%

According to the 2014 NSDUH, the rate of illicit drug abuse was higher in males, at 19.8%, than in females, at 13.7%. Males were more likely than females to be abusers of hallucinogens (2.1% vs. 1.1%). [18]

The age group with the highest incidence of hallucinogen use in 2014 was adults 26 year olds and older.  An estimated 0.3 percent of this population were current users of hallucinogens in 2014 which represents 535,000 individuals. Estimates of current hallucinogen use ranged between 0.1 and 0.3 percent from 2002 to 2014, with the 2014 estimate being slightly higher than the estimates in 2003, 2004, 2006, 2008, 2010, and 2011. [18]

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