Preliminary data from the NPS.Finder® web crawling activities

After about 18 months of operation, the number of substances identified by the web crawler activities was 5922. By the time of writing, some 4204 unique NPS molecules were included in the database and 1718/5922 (29.01%) remaining molecules resulted to be false positives/duplicates. Most popular NPS mentioned in the psychonauts' fora included: psychedelic phenethylamines (1262; 30%); synthetic cannabimimetics (1248; 29.7%); synthetic opioids (460; 10.9%); GABA-A/GABA-B receptor agonists (172; 4.1%); synthetic cathinones (171; 4.1%); prescribed/OTC medicinal compounds (157; 3.7%); novel stimulants (82; 1.9%); novel psychedelics (38; 0.9%) and PCP/ketamine-like compounds (36; 0.8%).

Synthetic cannabinoids/cannabimimetics (SC)

Whilst low-dosage levels of synthetic cannabinoids (SC) produce similar psychoactive effects to cannabis/THC, with higher dosages auditory/visual hallucinations, anxiety and intense feelings of paranoia often occur (Winstock and Barratt, Reference Winstock and Barratt2013a; Wessinger et al., Reference Wessinger, Moran, Seely, Campolongo and Fattore2015; Bonaccorso et al., Reference Bonaccorso, Metastasio, Ricciardi, Stewart, Jamal, Naasir-Ud-Dinn, Theleritis, Ferracuti, Ducci and Schifano2018). Other psychiatric and neurological effects include: behavioural dyscontrol and agitation (Brakoulias, Reference Brakoulias2012); mood swings (Celofiga et al., Reference Celofiga, Koprivsek and Klavz2014); suicidal ideation, suicide attempts (Glue et al., Reference Glue, Al-Shaqsi, Hancock, Gale, Strong and Schep2013); panic attacks; thought disorganisation and agitated/excited delirium (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2017). A florid/acute/transient psychosis; relapse/worsening of a pre-existing psychosis and bipolar disorder (Oluwabusi et al., Reference Oluwabusi, Lobach, Akhtar, Youngman and Ambrosini2012; Ustundag et al., Reference Ustundag, Ozhan Ibis, Yucel and Ozcan2015) and the persistent psychotic disorder ‘spiceophrenia’ (Papanti et al., Reference Papanti, Schifano, Botteon, Bertossi, Mannix, Vidoni, Impagnatiello, Pascolo-Fabrici and Bonavigo2013; Schifano et al., Reference Schifano, Papanti, Orsolini and Corkery2016) have all been described. With synthetic cannabinoids, similar to what being described for a range of remaining NPS (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015), the total or partial recurrence of perceptual disturbances that appeared during previous hallucinogenic intoxications, typically known as Hallucinogen-Persisting Perception Disorder (HPPD), may occur (Martinotti et al., Reference Martinotti, Santacroce, Pettorruso, Montemitro, Spano, Lorusso, di Giannantonio and Lerner2018) (Table 1).

Table 1. Main categories of Novel/New Psychoactive Substances (NPS) and their effects

DXM, dextromethorphan, SC, synthetic cannabinoids, HPPD, hallucinogen-persisting perception disorder.

The intoxication/acute toxic effects of SCs appear to be more akin to those experienced with sympathomimetic/stimulant drug use (Wood and Dargan, Reference Wood and Dargan2012; Naviglio et al., Reference Naviglio, Papanti, Moressa and Ventura2015). Typical medical untoward effects include: vomiting/nausea; hypertension and tachycardia; tachypnoea/dyspnoea; hyperglycaemia; mydriasis (Hermanns-Clausen et al., Reference Hermanns-Clausen, Kneisel, Szabo and Auwärter2013; Winstock and Barratt, Reference Winstock and Barratt2013b; Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015); nystagmus; seizures (Hopkins and Gilchrist, Reference Hopkins and Gilchrist2013); encephalopathy (Louh and Freeman, Reference Louh and Freeman2014); coma and stroke (Mir et al., Reference Mir, Obafemi, Young and Kane2011; Freeman et al., Reference Freeman, Rose and Myers2013; Rose et al., Reference Rose, Guerrero and Mokin2015). Ultimately, deaths have been associated with the use of synthetic cannabinoids, either on their own or in combination (Corkery et al., Reference Corkery, Claridge, Loi, Goodair and Schifano2014; Tait et al., Reference Tait, Caldicott, Mountain, Hill and Lenton2015; Trecki et al., Reference Trecki, Gerona and Schwartz2015; Angerer et al., Reference Angerer, Jacobi, Franz, Auwärter and Pietsch2017; Maeda et al., Reference Maeda, Kikura-Hanajiri, Kawamura, Nagashima and Yoshida2018; Olsen, Reference Olsen2018; Paul et al., Reference Paul, Simms, Amini and Paul2018). These may result from direct lethality of the molecule; behavioural dyscontrol or suicide (Rosenbaum et al., Reference Rosenbaum, Carreiro and Babu2012; Shanks et al., Reference Shanks, Dahn and Terrell2012; Patton et al., Reference Patton, Chimalakonda, Moran, McCain, Radominska-Pandya, James, Kokes and Moran2013; Lászik et al., Reference Lászik, Törő, Vannai, Sára-Klausz, Kócs, Farkas, Keller and Róna2015) (Table 1).

Finally, SC long-term use can give rise to dependence/tolerance phenomena (Gunderson et al., Reference Gunderson, Haughey, Ait-Daoud, Joshi and Hart2012; Spaderna et al., Reference Spaderna, Addy and D'Souza2013); a withdrawal syndrome, characterised by: profuse sweating, tachycardia, tremor, diarrhoea, headache, drug craving, feelings of emptiness/depression, anxiety, irritability, mood swings and insomnia/nightmares has been described (Macfarlane and Christie, Reference Macfarlane and Christie2015) (Table 1).

New synthetic opioids (NSOs)

New synthetic opioids (NSOs) emerged in recent years as part of the alarming worldwide opioid crisis (Van Amsterdam and van den Brink, Reference Van Amsterdam and van den Brink2015; CDC, 2016, 2018; Armenian et al., Reference Armenian, Vo, Barr-Walker and Lynch2017; EMCDDA, 2017; Lucyk and Nelson, Reference Lucyk and Nelson2017; Prekupec et al., Reference Prekupec, Mansky and Baumann2017; Suzuki and El-Haddad, Reference Suzuki and El-Haddad2017; Drummer, Reference Drummer2018; Graddy et al., Reference Graddy, Buresh and Rastegar2018). NSOs are a large group of narcotic analgesic drugs having structural similarities, but much greater potency of action and receptor affinity, with respect to morphine (Tracy et al., Reference Tracy, Wood and Baumeister2017; Marchei et al., Reference Marchei, Pacifici, Mannocchi, Marinelli, Busardò and Pichini2018; Solimini et al., Reference Solimini, Pichini, Pacifici, Busardò and Giorgetti2018). This group includes compounds which were originally synthesised by pharmaceutical companies but never commercialised and then diverted into the illegal market, e.g. benzamide (U-47700, U-49900, AH-7921); acetamide (U-50488, U-51754); piperazine derivatives (MT-45) (Zawilska, Reference Zawilska2017) and several illicitly manufactured fentanyl analogues, e.g. acetylfentanyl; carfentanyl; furanylfentanyl; 3-methylfentanyl; sufentanyl; etc. (Armenian et al., Reference Armenian, Vo, Barr-Walker and Lynch2017; Suzuki and El-Haddad, Reference Suzuki and El-Haddad2017; Marchei et al., Reference Marchei, Pacifici, Mannocchi, Marinelli, Busardò and Pichini2018). These molecules may be used alone; as adulterants in heroin; or as constituents of other illicit products or counterfeit medications (Prekupec et al., Reference Prekupec, Mansky and Baumann2017; Abdulrahim et al., Reference Abdulrahim and Bowden-Jones2018).

NSOs' toxicity includes drowsiness, sedation, disorientation, slurred speech, confusion, dizziness, nausea, miosis, slowed breathing and respiratory depression to coma (Suzuki and El-Haddad, Reference Suzuki and El-Haddad2017). Conversely, NSOs' psychotropic effects include sedation; euphoria; feeling of relaxation; mood lift, dysphoric and dissociating effects (Solimini et al., Reference Solimini, Pichini, Pacifici, Busardò and Giorgetti2018) (Table 1).

Due to their high potency, their continued use (or abuse) may induce tolerance, with the risk of overdose and death being elevated. Physical dependence and addiction may rapidly rise, and withdrawal symptoms occur if their use is rapidly reduced or suddenly stopped. These include symptoms similar to the traditional opioid withdrawal, such as restlessness, agitation, muscle and bone pain, insomnia, diarrhoea, vomiting and cold flashes with goose bumps (Suzuki and El-Haddad, Reference Suzuki and El-Haddad2017; Zawilska, Reference Zawilska2017).

Other compounds classified among NSOs are desomorphine (‘krokodil’), mitragynine and 7-hydroxymitragynine (alkaloids found in ‘kratom’/Mitragyna speciosa; Liu et al., Reference Liu, Wheeler, Venkataramanan, Rymer, Pizon, Lynch and Tamama2018; Corkery et al., Reference Corkery, Streete, Claridge, Goodair, Papanti, Orsolini, Schifano, Sikka, Korber and Hendricksin press) and salvinorin A, with its analogue herkinorin, which are the main Salvia divinorum components. Salvinorin A psychoactive effects include perceptual disturbances, psychosis, irritability and anxiety (Ventura et al., Reference Ventura, Carvalho and Dinis-Oliveira2018) (Table 1).

Ketamine-like dissociatives

Ketamine and phencyclidine (PCP) were both originally developed as general anaesthetics for veterinary and human use, but soon became street drugs. Despite the strong dissociative effects on post-operative patients, ketamine is used as anaesthetic mostly in veterinary practice, but also in emergency medicine (Baumeister et al., Reference Baumeister, Tojo and Tracy2015). Ketamine (‘special K’) can be injected, snorted, smoked or administered rectally, at a dosage range of 25–300 mg, inducing feelings of relaxation, dissociation, depersonalisation and psychotic experiences, with hallucinations lasting even longer than the anaesthetic effects.

Ketamine intoxication may include cardiovascular and respiratory symptoms and, due to its anaesthetic and dissociative effects, related risks may include trauma, drowning, death from hypothermia and traffic accidents (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015) (Table 1). The ‘K-hole’, which may result after the ingestion of large dosages of ketamine, is a typical out-of-body/near-death experience, with the user becoming trapped in a state of detachment from his/her physical presence. Residual symptoms, such as flashbacks and perceptual distortions, may follow.

Long-term ketamine use may present with both urological (‘K-bladder’) and intestinal (‘K-cramps’) symptoms (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015). Compared with ketamine, PCP (‘angel dust’) appears to determine much wider and unstable range of symptoms, with cerebrovascular accidents and cardiac arrest occurring (Baumeister et al., Reference Baumeister, Tojo and Tracy2015). Chronic use of PCP may impair memory and thinking, and determine mood shifts, anxiety and suicidal thoughts (DEA, 2013) (Table 1).

Further related dissociatives recently entered the market (Wallach et al., Reference Wallach, Kang, Colestock, Morris, Bortolotto, Collingridge, Lodge, Halbertstadt, Brandt and Adejare2016), including 4-MeO-PCP (Morris and Wallach, Reference Morris and Wallach2014); the 1,2-diarylethylamines (e.g. diphenidine, ephenidine, methoxydiphenidine and various analogues such as fluorolintane and N-ethyl-lanicemine) and the β-keto-arylcyclohexylamines (e.g. methoxetamine, deschloroketamine and 2-fluoro-2-deschloroketamine) molecules (Wallach and Brandt, Reference Wallach and Brandt2018). They primarily act as uncompetitive antagonists at glutamatergic NMDA receptors, but may also bind at opioid and monoaminergic receptors (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015). Their effects are diverse and dose-dependent, generally inducing a mind-altering state, with sensory hallucinations, tactile distortions, euphoria, derealisation and depersonalisation (Wallach et al., Reference Wallach, Kang, Colestock, Morris, Bortolotto, Collingridge, Lodge, Halbertstadt, Brandt and Adejare2016; Tracy et al., Reference Tracy, Wood and Baumeister2017) (Table 1).

Novel stimulants and novel psychedelics, including psychedelic phenethylamines

Novel stimulant and novel psychedelic compounds include phenethylamines, cathinones, piperazines, tryptamines, pipradrols/piperidines, aminoindanes, benzofurans and amphetamines; all of these present with varying levels of stimulant, entactogenic and hallucinogenic effects. They exert an inhibitory action on the monoamine reuptake, increasing the quantity of noradrenaline/NA, dopamine/DA and serotonin/5-HT in the synaptic cleft (Miliano et al., Reference Miliano, Serpelloni, Rimondo, Mereu, Marti and De Luca2016). Consistent with their pharmacological profile, those molecules that present with high serotonin:dopamine ratios may be considered analogous to entactogenic substances, such as MDMA. Conversely, high dopamine:serotonin ratios might predict a strong stimulant experience. Furthermore, high or low affinity to modulation of noradrenergic systems might be anticipated to be associated with varying sympathetic nervous system activation, whereas activation of 5-HT2A/1A receptors would more likely predict hallucinogenic effects (Baumeister et al., Reference Baumeister, Tojo and Tracy2015) (Table 1).

Presenting with structural similarities to amphetamines (Feng et al., Reference Feng, Battulga, Han, Chung and Li2017), synthetic cathinones (EMCDDA, 2017) are mostly inhibitors of the serotonin (SERT), dopamine (DAT) and noradrenaline (NET) transporters. These molecules can be further sub-categorised as: (1) cocaine/MDMA-like (3,4-methylenedioxy-N-alkylated cathinones e.g. butylone): these act as inhibitors at SERT, DAT and NET and as serotonin releasers; (2) methamphetamine-like (N-alkylated or ring-substituted cathinones e.g. buphedrone): these act as inhibitors at SERT, DAT and NET and as dopamine releasers and (3) pyrovalerone-like cathinones (N-pyrrolidine cathinones e.g. MDPV (3,4-methylenedioxypyrovalerone)): these are very potent at DAT and do not induce any monoamine substrate release (Simmler et al., Reference Simmler, Buser, Donzelli, Schramm, Dieu, Huwyler and Liechti2013).

Apart from mephedrone (Dargan et al., Reference Dargan, Albert and Wood2010; Winstock, Reference Winstock2010; Winstock et al., Reference Winstock, Mitcheson, Ramsey, Davies, Puchnarewicz and Marsden2011; Freeman et al., Reference Freeman, Morgan, Vaughn-Jones, Hussain, Karimi and Curran2012; Prosser and Nelson, Reference Prosser and Nelson2012; Karila et al., Reference Karila, Megarbane, Cottencin and Lejoyeux2015, Reference Karila, Billieux, Benyamina, Lançon and Cottencin2016; De Sousa Fernandes Perna et al., Reference De Sousa Fernandes Perna, Papaseit, Pérez-Mañá, Mateus, Theunissen, Kuypers, de la Torre, Farré and Ramaekers2016), the psychopathological consequences of most cathinones have not been fully studied. With mephedrone, low mood, loss of appetite, difficulty sleeping, levels of paranoid ideation, cognitive impairment, changes in perception, agitation, hallucinations, delusions, amnesia, confusion, violence and suicidal thoughts have been reported (Kehr et al., Reference Kehr, Ichinose, Yoshitake, Goiny, Sievertsson, Nyberg and Yoshitake2011; Capriola, Reference Capriola2013; Herzig et al., Reference Herzig, Brooks and Mohr2013; John et al., Reference John, Thomas-Rozea and Hahn2017; Lovrecic and Lovrecic, Reference Lovrecic and Lovrecic2017; Homman et al., Reference Homman, Seglert and Morgan2018; Kaizer-Będkowska and Kucia, Reference Kaizer-Będkowska and Kucia2018). Users reported as well positive effects e.g. euphoria, improved psychomotor speed, alertness and talkativeness (Dargan et al., Reference Dargan, Albert and Wood2010; Cheng et al., Reference Cheng, Yeo, Brown and Regan2012; Mdege et al., Reference Mdege, Meader, Lloyd, Parrott and McCambridge2017). Cathinone-induced acute intoxication may include symptoms of the serotonin syndrome, associated with aggression and hyperthermia, psychotic disorders, catatonia and excited delirium syndrome (Otachbachi et al., Reference Otachbachi, Cevik, Bagdure and Nugent2010; Penders and Gestring, Reference Penders and Gestring2011; Mugele et al., Reference Mugele, Nanagas and Tormoehlen2012; Penders et al., Reference Penders, Gestring and Vilensky2012; Warrick et al., Reference Warrick, Wilson, Hedge, Freeman, Leonard and Aaron2013; Hohmann et al., Reference Hohmann, Mikus and Czock2014; Denysenko et al., Reference Denysenko, Freudenreich, Philbrick, Penders, Zimbrean, Nejad, Chwastiak, Dickerman, Niazi, Shim and Soellner2015; Weaver et al., Reference Weaver, Hopper and Gunderson2015). Other acute intoxication issues included dehydration, hypertension, tachycardia, kidney and liver impairment, electrolyte imbalance, metabolic toxicity, cerebral oedema and death (Borek and Holstege, Reference Borek and Holstege2012; Adebamiro and Perazella, Reference Adebamiro and Perazella2013; Imam et al., Reference Imam, Patel, Mahmoud, Prakash, King and Fremont2013). Suicides by hanging and deaths from firearm injuries have frequently been reported (Marinetti and Antonides, Reference Marinetti and Antonides2013; Barrios et al., Reference Barrios, Grison-Hernando, Boels, Bouquie, Monteil-Ganiere and Clement2016), as well as deaths from toxicity (Corkery et al., Reference Corkery, Goodair, Claridge, Corazza and Roman-Urrestarazu2018b). Although the long-term effects of synthetic cathinones' use are largely unknown, they may include insomnia, depression, anxiety, psychosis and dependence (Capriola, Reference Capriola2013).

Phenethylamines are synthetic compounds available in tablets, capsules and powder. They act on serotoninergic receptors, hence leading to psychedelic effects, but some of them inhibit the NA/DA reuptake as well. 3,4-Methylenedioxy-methamphetamine (MDMA, ‘ecstasy’) is one of the most popular drugs among youngsters/clubbers, because of its stimulant effects. Recently the emergence of a range of other psychedelic phenethylamines, including the 2-C and 2-D series drugs; the benzodifurans (e.g. 3-C-bromo-dragonfly) and others (e.g. 4-MTA, 6-APB, 4,4′-DMAR and PMA), has been reported (Miliano et al., Reference Miliano, Serpelloni, Rimondo, Mereu, Marti and De Luca2016). Their psychoactive effects are dose-dependent, ranging from stimulant effects at lower doses to hallucinogenic and entactogenic effects at higher doses. Phenethylamines' intake may be associated with loss of appetite, tachycardia, hypertension, anxiety, nausea, headache, dizziness, skin irritation, hyperthermia, convulsions, respiratory deficits, liver/kidney failure and death (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015). Psychotic symptoms are associated with a high dosage intake (Baumeister et al., Reference Baumeister, Tojo and Tracy2015) (Table 1).

The lead compound in piperazines, N-benzylpiperazine (BZP), has a typical central nervous system stimulant structure. Structurally similar to amphetamine and initially developed as an antidepressant, BZP triggers the release of DA and NA whilst inhibiting the uptake of DA, NA and 5-HT (Miliano et al., Reference Miliano, Serpelloni, Rimondo, Mereu, Marti and De Luca2016). Piperazines' toxicity causes hallucinations, seizures, hyponatraemia, serotonin syndrome, renal failure and ultimately death (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015) (Table 1).

Tryptamines, with the most common molecule being the lysergic acid diethylamide/LSD, are a group of monoamine alkaloids very similar to the endogenous neurotransmitter serotonin. They act both as 5-HT2A receptor agonists and serotonin reuptake inhibitors. A large range of novel tryptamines, including 5-MeO-AMT, 5-MeO-DALT, 4-HO-DALT, 5-MeO-DIPT and 5-MeO-DMT, have appeared on the drug scene (Miliano et al., Reference Miliano, Serpelloni, Rimondo, Mereu, Marti and De Luca2016). Some of them are found in nature, e.g. Delosperma species plants (containing dimethyltryptamine/DMT; 5-MeO-DMT); hallucinogenic fungi (psilocin; 4-OH-DMT) and amphibians (bufotenin) (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015). The predominant clinical effects of tryptamines consist of visual hallucinations, alterations in sensory perception, distortion of body image, depersonalisation, marked mood lability and anxiety/panic. Untoward effects include agitation, tachyarrhythmia and hyperpyrexia. There are small numbers of tryptamine-related fatalities (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015) (Table 1).

Prescription and OTC drugs

Over the past decade, the recreational use of several psychoactive pharmaceuticals has emerged in the NPS scene, including antidepressants; antipsychotics; gabapentinoids; Z-drugs and designer benzodiazepines and OTC drugs (Schifano et al., Reference Schifano, Orsolini, Papanti and Corkery2015, Reference Schifano, Chiappini, Corkery and Guirguis2018).