Hallucinogen Toxicity

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, benzylpiperazine (BZP), and 3-trifluoromethylphenylpiperazine (TFMPP). The phenylethylamine derivatives are the broadest hallucinogen group and incorporate many substances. While 3,4-methylenedioxy-N -methylamphetamine (MDMA; ecstasy, Molly) 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 recreational use. 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, because 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 circumvent regulation.

Synthetic cathinone or "bath salt" use has emerged over the last decade and gained popularity in large part due to these agents' accessibility and ambiguous legal status. In 2011, the Drug Enforcement Administration (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. Since then, additional cannbinoids have been scheduled by the DEA, but it can be difficult for the DEA to keep up with products that contain an evolving variety of cannabinoids.

Cathinones are generally amphetamine-like in structure. Some, with a methylene-dioxy- group—such as methylone and 3,4-methylenedioxypyrovalerone (MDPV)—are MDMA-like and can be considered hallucinogens. Others—such as cathinone, metcathinone, and mephedrone—have clinical effects more akin to amphetamine and methamphetamine

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.

Use 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 sold in the form of crystalline powders, which are taken by insufflation.

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 cannabinoids act as cannabinoid receptor agonists. Many were initially developed as research chemicals designed for studying cannabinoid receptors, and were only later diverted as recreational drugs. These synthetic cannabinoids are added to herbal mixtures to give them the appearance of marijuana and 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" or "K2". 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. Since then, additional cannbinoids have been scheduled by the DEA, but it can be difficult for the DEA to keep up with products that contain an evolving variety of cannabinoids.

Some synthetic cannabinoids users use these substances to elude detection on standardized drug testing. While THC from marijuana use 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). Others use synthetic cannabinoids because they are inexpensive and readily available, which has made these drugs popular among the homeless population in some cities.

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 an 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 used recreationally 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; users 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. Users who take these products for the DXM may unwittingly consume toxic amounts of those other ingredients.

Ecstasy

This designer hallucinogenic drug is widely used recreationally as a "club drug" and is found at night clubs, festivals, raves, and concerts. While the names "ecstasy" and "Molly" originally referred to MDMA, many drugs are sold by those names today, and MDMA is known by other street terms as well, such as "E" and "X". ^[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, but the methylene-dioxy ring makes it more serotonergic than amphetamines that lack this structure. 

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, however, reports of increasing illicit use 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.

Naturally 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, because 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, which the user places against the buccal mucosa or under the tongue, 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 the user 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 usage outside the operating room, including in emergency departments and the pre-hospital setting. ^{[10, 11]}  More recently, ketamine in subanesthetic doses has been studied for use as an antidepressant, particularly in cases that are refractory to standard treatment or accompanied by suicidality. ^{[12, 13]}  In 2019, the US Food and Drug Administration approved (FDA) approved esketamine (Spravato) nasal spray, in conjunction with an oral antidepressant, for use in patients with treatment-resistant depression. ^[14]  Esketamine is the S-enantiomer of racemic ketamine. It is available to prescribers only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

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". Hallucinations from ketamine and PCP are due to agonism at the sigma-receptor (previously classified as an opioid receptor). Ketamine is known for being more psychologically addictive than most psychedelics. It is commonly used at large concerts and clubs. ^[15]

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. ^{[16, 17]}

For more information, see Hallucinogenic Mushroom Toxicity.

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, with the sigma receptor, or with muscarinic receptors—it is the first known naturally occurring kappa-opioid receptor agonist. ^[18] This substance has been used by the Mazatec Indians in Mexico for ceremonial purposes. ^[19] While Salvia divinorum and salvinorin A are not classified under the Controlled Substances Act, several states have placed regulatory controls on either or both. ^[20]

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.

Hallucinogenic substances primarily exert their effect on the central nervous system by way of neurotransmitter level manipulation. Stimulating secretion, inhibiting reuptake, delaying enzymatic breakdown, or directly stimulating or inhibiting neurotransmitter receptors 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 (5-HT) receptors. MDMA (ecstasy) enhances presynaptic release and reuptake of serotonin and norepinephrine. ^[21] JWH-018 and other synthetic cannabinoids are cannabinoid receptor (CB1 and CB2) agonists that can exert a secondary effect on the balance of circulating catecholamines. ^[22]

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. ^[23] 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 but that is not routinely associated with marijuana.

United States

The 2019 National Survey on Drug Use and Health (NSDUH) found that in an estimated 6.0 million people aged 12 or older had used hallucinogens during the year, representing 2.2 percent of that population. Current hallucinogen use was highest in young adults aged 18 to 25 years, 2.4 million of whom (an estimated 7.2% of that population) had used hallucinogens during the year. The NSDUH's category of hallucinogens includes LSD, phencyclidine (PCP), peyote, mescaline, psilocybin mushrooms, MDMA (ecstasy or Molly), ketamine, DMT/AMT/Foxy, and Salvia divinorum.  ^[24]

According to the US Centers for Disease Control and Prevention (CDC), the number of acute poisonings from synthetic cannabinoids rose sharply between 2010 and 2015. Of 456 cases of synthetic cannabinoid intoxication reported to a toxicology case registry during that period, 277 (61%) involved synthetic cannabinoids only. Three deaths were recorded, one with synthetic cannabinoids alone and two with multiple-agent exposures. ^[25]

In March 2018, the Illinois Department of Public Health reported cases of unexplained bleeding in users of synthetic cannabinoids. Subsequent testing showed that the cannabinoids had been adulterated with brodifacoum, a long-acting vitamin K antagonist anticoagulant that is often used as a rodenticide. By late May 2018, the CDC had received reports of 202 cases: 164 from Illinois, 20 from Maryland, and the remainder from Florida, Indiana, Kentucky, Missouri, Pennsylvania, Virginia, and Wisconsin. Five cases were fatal. ^{[26, 27]}

International

Australia reported that in 2014, MDMA 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 ^[28]

In Europe, an estimated 2.3 million young adults (15–34) used MDMA in 2019 (1.9% of this age group), with national estimates ranging from 0.2% in Portugal and Romania to 6.9% in the Netherlands.  ^[29]

The overall prevalence levels of LSD and hallucinogenic mushroom use in Europe have been generally low and stable for a number of years. Among adolescents and young adults (ages 15–34), in 2019 prevalence estimates of less than 1% for both substances were reported with the exception of the Finland (2.0%) and Estonia (1.6%) for hallucinogenic mushrooms, and Finland (2.0%), Estonia (1.7%) and Norway (1.3%) for LSD. ^[29]

Race

According to the 2019 NSDUH, rates of hallucinogen use in the past year among different ethnic groups were as follows ^[30] :

• American Indians or Alaska Natives: >1%
• Native Hawaiians or other Pacific Islanders: >1%
• Blacks: 5.5%
• Whites: 76.3%
• Hispanics: 11.6%
• Asians: 2.3%
• Two or more races: 3.1%

Sex

According to the 2019 NSDUH, 59% of hallucinogen users in the past year were male. ^[30]   In 2020, the European Monitoring Centre for Drugs and Drug Addication (EMCDDA) reported the use of all drugs is generally higher among males. Almost twice as many males (9.1 million) reported lifetime use of MDMA compared to females (4.6 million). ^[29]

Age

In 2019, approximately 86% of hallucinogen users were adults 26 years old and older. ^[30]

 

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. ^[31]  Most of these deaths are due to opioids, and data on mortality directly attributable to hallucinogen use are not readily available.