How is designer drugs used

Consistent with the in vitro findings, psychedelic phenethylamines were shown to induce 5-HT 2A -dependent behaviors in vivo, such as wet dog shakes, back muscle contractions, and a head twitch response Elmore et al.

In addition to interactions with serotonergic receptors, phenethylamine psychedelics have been shown to interact with other monoaminergic targets, including adrenergic, dopaminergic, and histaminergic receptors, monoamine transporters, and MAOs Eshleman et al. However, most of these interactions are weak compared with the potent interactions with serotonergic receptors. Therefore, they most likely have little or no pharmacological relevance to the actions of phenethylamine psychedelics.

Rodent studies have suggested reinforcing effects for NBOMe derivatives that involve the dopaminergic system Custodio et al. Most of the frequently reported adverse effects of phenethylamine psychedelics are shared by psychedelics of other chemical classes, including agitation, hallucinations, drowsiness, confusion, mydriasis, aggression, hyperthermia, hypertension, and tachycardia Dean et al. Moreover, severe adverse effects have been linked to the use of psychedelic phenethylamines, including acute psychosis, seizures, coma, cerebral edema, long-lasting severe neurological impairment, serotonin syndrome, prolonged respiratory failure, renal failure, multi-organ failure, metabolic acidosis, and rhabdomyolysis Bosak et al.

Furthermore, 1- 4-bromofuro[2,3- f ][1]benzofuranyl propanamine Bromo-dragonFLY has been associated with potent vasoconstriction, ischemia, and tissue necrosis in patients, which may be caused by the activation of serotonergic and adrenergic receptors combined with metabolic stability and long-lasting effects Hill and Thomas ; Noble et al.

A remarkable case of mass intoxication with 4-ethyl-2,5-dimethoxyphenethylamine 2C-E and Bromo-dragonFLY among 29 attendees of an esoteric weekend seminar was reported Iwersen-Bergmann et al. Upon the arrival of paramedics, some of the seminar attendees were rolling on the ground and screaming, and others were unconscious or unresponsive. Several attendees exhibited severe delusions and physical symptoms, including generalized seizures, pain, respiratory distress, and tachycardia Iwersen-Bergmann et al.

In some severe cases, the use of psychedelic phenethylamines has even resulted in death Curtis et al. Adverse effects of different phenethylamine designer drugs are mostly comparable. However, a higher incidence of hallucinations, delusions, and single-episode seizures has been observed for NBOMe derivatives compared with 2C derivatives Srisuma et al.

This may be explained by the higher potency of NBOMe derivatives compared with most other phenethylamine psychedelics Braden et al. Several reports have linked severe intoxication to substituted phenethylamines, but the lack of analytical confirmation of the drug prevents the direct attribution of adverse effects to phenethylamines.

For example, a year-old woman was reported to have developed severe headaches, progressive encephalopathy, and quadraparesis within 48 h after taking a liquid form of 2C-B that was synthesized according to a manual on the Internet Ambrose et al. Similarly, a patient presented to an emergency department with hallucinations and agitation that progressed to status epilepticus after using of 4-chloro-2,5-dimethoxyamphetamine DOC.

In addition to the analytically confirmed presence of DOC, however, the toxicology screen was positive for cannabinoids and opioids, thus hampering the attribution of seizure development to DOC Burish et al. Additionally, several fatalities from 2C derivative use have been reported in the media, but the accuracy of this information cannot be verified Dean et al. The core structure of tryptamine designer drugs contains an indole ring that is connected to an amino group by an ethyl side chain, a structural feature that is shared by 5-HT.

DMT as an ingredient in the psychoactive brew ayahuasca and psilocybin that is contained in Psilocybe spp. In addition to naturally occurring compounds, psychedelic properties of various synthetic tryptamines Fig. Similar to other psychedelics, 5-HT 2A receptor agonism plays a key role in mediating the psychedelic effects of naturally occurring and synthetic tryptamine psychedelics Fantegrossi et al.

Although mediating opposing functional effects on 5-HT 2A receptors, the concurrent activation of 5-HT 1A receptors has been suggested to contribute to the qualitative effects of tryptamine psychedelics, distinguishing them from phenethylamine psychedelics Fantegrossi et al.

Some tryptamines are slightly more selective for one or the other receptor subtype Rickli et al. At 5-HT 2B receptors, traditional and novel tryptamine psychedelics have very heterogeneous profiles, with different potencies and efficacies.

Tryptamine designer drugs have been shown to bind to 5-HT 2C receptors but with slightly lower affinity compared with 5-HT 2A receptors Rickli et al. In addition to their primary effects at serotonergic receptors, tryptamines have been shown to bind to various targets in vitro, including adrenergic, dopaminergic, and histaminergic receptors Klein et al.

Furthermore, unlike phenethylamine or lysergamide psychedelics, many tryptamine psychedelics interact with monoamine transporters at pharmacologically relevant concentrations. DMT and other tryptamine psychedelics have been reported to elicit 5-HT efflux, suggesting that they are transporter substrates Blough et al.

In contrast, other tryptamine psychedelics, including psilocin, act as transporter inhibitors that are devoid of substrate activity Rickli et al. In addition to interactions with transmembrane monoamine transporters, substrate activity at the VMAT has been described for tryptamine psychedelics Cozzi et al. Tryptamines are prone to metabolism by MAOs, and MAO inhibitors counteract extensive degradation of tryptamines after oral use Halberstadt et al. Similar to other psychedelics, tryptamine psychedelics alter perception and can induce psychological disturbances in users, including acute psychosis Meatherall and Sharma ; Nichols , ; Shulgin and Shulgin ; Taljemark and Johansson Adverse effects of tryptamine designer drugs include restlessness, disorientation, clouding of consciousness, confusion, hallucinations, amnesia, catalepsy, mydriasis, tachypnea, hypertension, and tachycardia Alatrash et al.

In severe cases, the use of tryptamine designer drugs has resulted in acute renal failure and rhabdomyolysis Alatrash et al. Furthermore, several fatalities after the use of tryptamine designer drugs have been reported Boland et al. Several derivatives of LSD have been described in the scientific literature, and such derivatives are increasingly emerging as designer drugs Fig. Whereas self-reported effects of some LSD analogs are similar to LSD but with slightly weaker or less pleasurable effects, other LSD analogs have been reported to be distinctively less potent or significantly differ from LSD in terms of effects Coney et al.

Additionally, 5-HT 1A receptor activation likely contributes to the qualitative effects of lysergamide designer drugs similarly to LSD and tryptamine psychedelics Fantegrossi et al.

In addition to differences in affinity, LSD-derived designer drugs may activate 5-HT 2A receptors with lower relative potency compared with LSD, but more research is needed to test this hypothesis Brandt et al. Furthermore, unclear are the ways in which the behavioral effects of lysergamide designer drugs in animals translate to humans. Little is known about the adverse effects of lysergamide designer drugs. One case of a year-old male who developed anxiety, hallucinations, restlessness, elevations of blood pressure, palpitations, and tachycardia after ingesting 1P-LSD was reported Grumann et al.

The patient reported that he recently used the stimulant phenmetrazine derivative 3-FPM. The low serum concentrations of 3-FPM that were detected at the time of hospital admission are, however, not expected to result in acute effects Grumann et al.

The symptoms of this 1P-LSD intoxication case are consistent with reported adverse effects of LSD, which is known to potentially cause psychological disturbances and moderately increase body temperature, blood pressure, and heart rate Dolder et al. Acute physiological adverse effects of LSD include difficulty concentrating, imbalance, feelings of exhaustion, dizziness, headache, dry mouth, lack of appetite, and nausea Dolder et al.

Nichols and Grob recently reviewed the risk of LSD toxicity in users, which they concluded was very low Nichols and Grob The few cases of fatality that were attributed to LSD toxicity were either associated with massive overdoses or physical restraint, or they were potentially caused by drugs that remained undetected in the toxicological analysis Nichols and Grob Currently, no evidence suggests that any of the currently available lysergamide designer drugs are significantly more toxic than LSD.

Designer doping agents have become increasingly popular outside of the professional athletic community and include anabolic steroids, peptide hormones, growth factor mimetics, and hormone and metabolic modulators Joseph and Parr ; Poplawska and Blazewicz ; Rahnema et al. Such substances are mainly used for performance and image enhancement, exerting effects through several different mechanisms within the hormone system Graham et al. Adverse effects that are associated with performance-enhancing designer drugs include secondary hypogonadism, gynecomastia, infertility, hypertension, ischemic stroke, cardiotoxicity, hepatotoxicity, and renal failure Rahnema et al.

In addition to substances that are taken to enhance athletic performance and appearance, designer drugs that are taken to enhance sexual performance, such as phosphodiesterase-5 inhibitors with no known safety profile, have also appeared.

These substances may potentially induce visual disturbances or severe drug—drug interactions Venhuis et al. In addition to adverse effects that are associated with specific classes of designer drugs, some general risks are essentially the same as for traditional drugs of abuse. For example, quality assurance is not guaranteed for clandestine designer drugs. A lack of information about purity, mislabeling, pharmaceutical impurities, and hazardous cutting agents can pose a risk for drug users.

A series of patients who presented to a hospital with coagulopathy and bleeding diathesis that were related to long-acting anticoagulant rodenticide adulterants of synthetic cannabinoids exemplifies their potentially fatal consequences Devgun et al.

Potentially severe drug—drug interactions are a risk when more than one substance is used, including prescription medications Contrucci et al. Byproducts and impurities can pose such risks as septum perforation when insufflated or necrotic ulcers and infections when injected Lafferty et al. Hallucinogen-persisting perception disorder has been associated with psychedelics, cannabinoids, and psychostimulants, manifesting in prolonged or reoccurring perceptual symptoms Ikeda et al.

The neurological and psychological changes that are associated with designer drugs can impair safe driving, and driving under the influence can severely jeopardize traffic safety Adamowicz and Lechowicz ; Maas et al.

Designer drugs are often used in combination with other substances, thus hindering precise evaluations of the degree of involvement of individual substances to clinical toxicity in patients. Furthermore, designer drugs may remain undetected by routine drug screenings. Nevertheless, the pharmacological and toxicological profiles of most designer drug classes are similar to their related traditional drugs of abuse. Stimulants primarily act as substrates or inhibitors of monoamine transporters.

Intoxication with stimulants mostly manifests as sympathomimetic adverse effects, the treatment of which is mainly supportive. Benzodiazepines may be given to control agitation, hypertension, and convulsions.

Certain stimulants, including MDMA, have a marked serotonergic profile. Their associated adverse effects, such as serotonin syndrome, can be potentially severe clinical complications. Sedatives, including synthetic opioids and GHB analogs, pose a risk of cardiorespiratory arrest, especially when they are used in combination with other depressants, such as alcohol and benzodiazepines.

Initial patient care should focus on protecting the airways and maintaining breathing and circulation. Naloxone is an effective antidote to opioid toxicity. Dissociative designer drugs act as NMDA receptor antagonists and induce adverse effects that are similar to the dissociative anesthetics ketamine and PCP.

Compared with cannabis, effects of synthetic cannabinoids are less desirable, and adverse effects are more severe. Serotonergic psychedelics alter perception and cognition mainly through 5-HT 2A receptor agonism. In addition to psychological disturbances, psychedelics may induce physical adverse effects, which are usually short-lived. Rarely, designer drug use can lead to severe psychiatric and physical complications and even death. Single-drug use and more precise knowledge of substance identity, potency, and purity can reduce the risks of designer drug use.

Open access funding provided by Medical University of Vienna. The authors thank Michael Arends for proofreading the manuscript. Publisher's Note. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Dino Luethi, Email: ta. Matthias E. Liechti, Email: hc. Archives of Toxicology. Arch Toxicol. Published online Apr 6.

Dino Luethi 1, 2, 3 and Matthias E. Liechti 3. Author information Article notes Copyright and License information Disclaimer. Corresponding author.

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Abstract Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Electronic supplementary material The online version of this article Stimulants Monoaminergic stimulants, such as amphetamine, 3,4-methylenedioxymethamphetamine MDMA , and cocaine, are among the most popular drugs of abuse.

Open in a separate window. Amphetamines In addition to traditional amphetamines that are used both medically and recreationally, several amphetamine designer drugs without approved medical uses have become available. Mechanism of action of amphetamines Most amphetamines are substrate-type monoamine releasers Rothman and Baumann ; Simmler et al.

Adverse effects of amphetamines Numerous studies have reported the adverse effects of amphetamine, lisdexamfetamine, and methamphetamine. Mechanism of action of cathinone and pyrovalerone derivatives Similar to other monoaminergic stimulants, the psychoactive effects of synthetic cathinones are primarily mediated by interactions with monoamine transporters.

Benzofuran and indole derivatives Various analogs of MDMA and its metabolite 3,4-methylenedioxyamphetamine MDA have become available as designer drugs, in which a dihydrobenzofuran, benzofuran, or indole group replaces the benzodioxole group Fig. Mechanism of action of benzofuran and indole derivatives In addition to norepinephrine uptake inhibition, stimulant benzofuran and dihydrobenzofuran designer drugs have moderate-to-high selectivity in inhibiting 5-HT vs.

Adverse effects of benzofuran and indole derivatives Benzofuran designer drugs may cause agitation, insomnia, headache, drowsiness, dry mouth, dry eyes, bruxism, hyperthermia, tachycardia, palpitations, nausea, diarrhea, hot flashes, clonus of the hands and feet, and psychological symptoms, including visual and auditory hallucinations, depression, anxiety, panic attacks, paranoia, and psychosis Jebadurai et al.

Aminoindanes Aminoindane designer drugs Fig. Mechanism of action of aminoindanes Similar to amphetamines, aminoindane designer drugs are monoamine transporter substrates, with relevant affinity for adrenergic, dopaminergic, and serotonergic receptors Iversen et al.

Adverse effects of aminoindanes Self-reported undesirable effects of aminoindane designer drugs include agitation, anxiety, panic attacks, headache, insomnia, hallucinations, and tachycardia Coppola and Mondola a. Piperazines Piperazine designer drugs Fig. Mechanism of action of piperazines Piperazine designer drugs exert mixed effects at monoamine transporters.

Adverse effects of piperazines Adverse effects of piperazine designer drugs are mostly sympathomimetic, including agitation, insomnia, headaches, dizziness, dilated pupils, hyperthermia, tachycardia, nausea, urine retention, and inducible clonus Arbo et al.

Phenidate derivatives Derivatives of the piperidine prescription drug methylphenidate have appeared as designer drugs Fig. Mechanism of action of phenidate derivatives Similar to methylphenidate, methylphenidate-based designer drugs act as potent NET and DAT inhibitors that are devoid of substrate activity Luethi et al. Adverse effects of phenidate derivatives Adverse effects of phenidate derivatives are similar to amphetamines and include agitation, anxiety, hypertension, tachycardia, and palpitations Bailey et al.

Aminorex analogs Various analogs of the anorectic agent aminorex have become available as designer drugs Fig. Adverse effects of aminorex analogs Adverse effects of aminorex designer drugs that have been reported by users on various Internet discussion platforms include agitation, dysphoria, insomnia, amnesia, panic attacks, psychosis, hallucinations, facial spasms, dilated pupils, foaming at the mouth, dry mouth, jaw clenching, elevations of body temperature, sweating, elevations of heart rate, nausea, and restless legs Glanville et al.

Phenmetrazine derivatives Phenmetrazine is a reinforcing stimulant, which was previously used as an appetite suppressant before it was eventually withdrawn from the market Chait et al. Adverse effects of phenmetrazine derivatives Based on their mechanism of action, phenmetrazine designer drugs are expected to elicit stimulatory toxicity that is similar to amphetamines.

Thiophene designer drugs Various analogs of amphetamines and cathinones with a thiophene group that replaces the phenyl ring have appeared as designer drugs Fig. Mechanism of action of thiophene designer drugs MPA is a quasi-equipotent inhibitor of norepinephrine and dopamine uptake and was reported to interact with various serotonergic, adrenergic, dopaminergic, N -methyl- d -aspartate NMDA , and sigma-1 receptors Iversen et al.

Adverse effects of thiophene designer drugs MPA use has been associated with significant acute toxicity and psychotic, cardiovascular, and gastrointestinal symptoms, including agitation, anxiety, confusion, a lower level of consciousness, insomnia, visual hallucinations, elevations of creatine kinase, tachycardia, palpitations, chest tightness, nausea, and vomiting Daveluy et al.

Miscellaneous stimulants Several designer drugs have appeared that do not belong to any classes that are discussed in the previous sections.

Sedatives Synthetic opioids While being essential for pain treatment, the non-medical use of opioids has been a public health threat for centuries and includes the recreational use of illegal substances, the abuse of prescription medications, and drug adulteration with non-pharmaceutical opioids Armenian et al. Adverse effects of synthetic opioids Adverse effects of novel synthetic opioids include typical symptoms of opioid overdose, such as dizziness, a lower level of consciousness, miosis, central nervous system depression, respiratory depression, pulmonary edema, hypoxia, bradycardia, pruritus, nausea, vomiting, constipation, and also such symptoms as agitation, hypertension, and tachycardia Armenian et al.

Designer benzodiazepines In , chlordiazepoxide became the first of several medically approved benzodiazepines that today represent a widely prescribed class of drugs for the treatment of psychiatric and neurological conditions, particularly insomnia and anxiety disorders Longo and Johnson ; Sternbach Mechanism of action of designer benzodiazepines The mechanism of action of most benzodiazepine designer drugs currently remains understudied.

Adverse effects of designer benzodiazepines Despite their depressive actions on central nervous system function and respiration, the isolated use of benzodiazepines is rarely fatal. Dissociatives Arylcyclohexylamine and diarylethylamine designer drugs Dissociative agents are appreciated in medicine because of their unique pharmacological effects.

Mechanism of action of arylcyclohexylamine and diarylethylamine designer drugs Similar to ketamine and PCP, dissociative arylcyclohexylamine and diarylethylamine designer drugs act as relatively selective noncompetitive antagonists at ionotropic glutamatergic NMDA receptors.

Synthetic cannabinoids The endocannabinoid system is involved in various physiological functions, including cognition, behavior, memory, motor control, pain sensation, appetite, cardiovascular parameters, gastrointestinal motility, and immunoregulation Le Boisselier et al.

Adverse effects of synthetic cannabinoids The most common adverse effects of synthetic cannabinoids include agitation, drowsiness, dizziness, confusion, hallucinations, hypertension, tachycardia, chest pain, nausea, and vomiting, which typically have a short duration and require only symptomatic or supportive treatment Forrester a ; Forrester et al.

Psychedelics Serotonergic psychedelics induce alterations of perception and cognitive states in users Nichols , Phenethylamines Derivatives of mescaline comprise a large amount of psychedelic designer drugs Fig. Mechanism of action of phenethylamines Similar to other psychedelics, substituted phenethylamines mainly interact with serotonergic receptors, with the highest affinity for 5-HT 2A receptors Eshleman et al.

The reality of designer drugs is that they are often extremely unpredictable, both in chemical content and in effect. Buying from a drug dealer gives no guarantee that you are receiving the drug you are requesting.

Many poisonings and overdoses have occurred as a result of poor judgment in the use of illegally acquired drugs and abuse of prescription medications. Designer drugs create difficulties for treatment, particularly in the initial acute stages. Without knowing what is causing a person's intoxication , it is difficult to correctly administer appropriate medication. Many designer drugs are also addictive. In recent years, there has been a resurgence of designer drugs sold over the Internet, particularly synthetic versions of Viagra, marijuana and anabolic steroids.

These synthetic versions of recognized drugs carry all the risks of the originals and more. And regardless of promises of "legal" highs, law enforcement agencies increasingly are cracking down on drugs marketed as recognized drugs, regardless of actual chemical content.

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These drugs are also called synthetic drugs, because of their chemical creation, or club drugs, because of their common recreational use in nightclubs. They can also be addictive and many people may need a PHP or another treatment program in order to stop their use.

There are several types of designer drugs and because they are created in mostly illegal labs, their chemical makeups can also range drastically. While these drugs may be popular at dance clubs or music festivals, these altered substances also come with many dangers.

These club drugs, while seemingly harmless for a fun night out, can have devastating results. Designer drugs are so dangerous because their potency and chemical makeup can vary greatly depending on where it was made. These underground chemistry labs are not regulated, and the result can be irregular ingredient amounts as well as the presence of other potentially harmful drugs.

If designer drugs are laced with another drug that the consumer is not aware of, it could lead to overdose. Also, because they lack uniformity, designer drugs can lead to dangerous side effects like hallucinations, dizziness, violent outbreaks, headaches, vomiting, heart complications, and more.

Not to mention the fact that because these drugs are often taken in a party environment, many users will also consume alcohol at the same time that can make these side effects worse or lead to even more health problems. These synthetic drugs can also be addictive.