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Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by “old” and “new” synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids.

Keywords: cannabinoids; dissociatives; hallucinogens; ketamine; MDMA; methamphetamine; methoxetamine; neuroinflammation; neurotoxicity; NPS



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Good post but it looks like most that report neurotoxicity are drugs like meth and mdma. This is what the section on hallucinogens says. The only “hallucinogens” they really list are ketamine and methoxetamine.


  Toxic Effects of Hallucinogen and Dissociative Drugs   Top

Preclinical studies

Studies in vitro have demonstrated that both acute and prolonged exposure to hallucinogen phenethylamines (2.4–100?μM) inhibit neuronal activity in rat primary cortical cultures (Zwartsen et al., 2018). Similarly, studies in users have demonstrated toxic effects of serotoninergic hallucinogens, including the newest ones, which have been frequently associated with acute serotonin syndrome, hyperthermia, seizures, hyponatremia and sympathomimetic toxicity (Hill and Thomas, 2011). Degree of symptoms can range from mild to severe; complications may include seizures and extensive muscle breakdown. Animal studies have described the behavioral components of the serotonin syndrome induced by hallucinogen drugs which include lateral head weaving, hind limb abduction, backward locomotion, and lower lip retraction (Halberstadt and Geyer, 2011; Gatch et al., 2017).

Ketamine is a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors that induces dissociative anesthesia and analgesia at clinical doses; however, at recreational doses of subanesthetic levels, ketamine may produce an intense psychedelic experience. Accordingly, although present on the drug market for long time, ketamine continues to be abused worldwide, and its consumption among adolescents is particularly worrying. A study in Cynomolgus monkeys has shown that repeated parenteral administrations of a recreational dose of ketamine (1 mg/kg) induce neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex, that lead to irreversible deficits in brain functions (Sun et al., 2014). In line with this, repeated parenteral administrations of sub-anesthetic doses of ketamine (5–50 mg/kg) increased cell death in hippocampal cornu ammonis area 3, caused irreversible changes in both brain structure and function in young adult mice (Majewski-Tiedeken et al., 2008) and induced apoptotic and necrotic neuronal cell death in the perinatal rhesus monkey (Slikker et al., 2007).

Methoxetamine is an NPS structurally related to ketamine and phencyclidine, designed to mimic the psychotropic effects of its parent compounds (Zanda et al., 2016) and increasingly available on the Internet as ‘legal ketamine’ (EMCDDA, 2014). Methoxetamine acts as a NMDA receptor antagonist, but also potently inhibits neuronal activity and alters monoamine metabolism in in vitro models (Hondebrink et al., 2018). Moreover, acute repeated parenteral administration of methoxetamine (0.125–5 mg/kg) considerably stimulates the mesolimbic dopaminergic transmission in rats (Mutti et al., 2016), and affects brain functions and behavior in rodents (Zanda et al., 2017). A recent study in mice (Ossato et al., 2018) found that acute parenteral administration of methoxetamine (0.01–30?mg/kg) induced alterations in sensory function processing that resembled those reported by users (Kjellgren and Jonsson, 2013) and persisted for hours when methoxetamine was administered at high doses. Moreover, another recent study in rats found that repeated parenteral administrations of methoxetamine (0.1–0.5 mg/kg) induced persistent behavioral abnormalities in tests used to evaluate anxiety-like states and recognition memory (Costa et al., 2019). The same investigation also demonstrated that methoxetamine induced persistent damage of dopaminergic fibers and neurons in the nigrostriatal and mesocorticolimbic systems as well as of serotonergic fibers in the nucleus accumbens core (Costa et al., 2019). [Table 3] provides further details about the toxic effects of hallucinogen and dissociative drugs demonstrated by preclinical studies from the past 3 years.

NeuralRegenRes_2020_15_5_802_268895_t6.j Table 3: Overview of the toxic effects of hallucinogen and dissociative drugs demonstrated in studies from the past 3 years

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Human studies

In 2007, tryptamine derivatives were listed as ‘narcotics’ or ‘designated substances’ and were quickly replaced on the online drug market by cathinones, phenethylamines, and piperazines. Yet, several novel tryptamines continue to appear on the online drug market as ‘legal highs’, which include AMT, 5-MeO-AMT, 4-HO-DALT and 5-MeO-DALT [Figure 2]. In addition to visual and auditory hallucinations, these drugs may induce agitation, tachyarrhythmia, hyperthermia and death (Wood and Dargan, 2013).

NeuralRegenRes_2020_15_5_802_268895_f2.j Figure 2: Chemical structures of some hallucinogen/dissociative substances used as recreational drugs.
AMT: α-Methyltryptamine; 5-MeO-DALT: N-allyl-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]prop-2-en-1-amine; 25I-NBOMe: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine.

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According to the EMCDDA (2015), some phenethylamines with hallucinogenic properties are very popular in the current drug market, including the so-called 2C series (e.g., 2C-B/‘Nexus’) and the NBOMe series drugs (e.g., 25I-NBOMe, [Figure 2]). Their use has been associated with serotonergic and sympathomimetic toxic effects, including vomiting/diarrhea, metabolic acidosis, mydriasis, convulsions, thrombocytopenia, renal failure, hyperthermia and coma (Schifano et al., 2017). Fatalities and hospitalizations have been reported following use of 25I-NBOMe and symptoms of acute toxicity included tachycardia, hypertension, agitation/aggression and seizures, while laboratory tests detected elevated level of creatinine kinase, leukocytosis and hyperglycaemia (Suzuki et al., 2015). Rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction. Slightly different from 25I-NBOMe, 25C-NBOMe was found to induce aggression, unpredictable violent episodes, dissociation and anxiety (Lawn et al., 2014). Although studies on the pharmacology of hallucinogenic phenylethylamines from the 2C series are still scarce, it has been demonstrated that they may act either as agonists or antagonists of G-protein-coupled serotonin and α-adrenergic receptors (Villalobos et al., 2004; Fantegrossi et al., 2008) and some of them (i.e., 2C-C, 2C-D, 2C-E, and 2C-I) were found to act as full agonists at 5-HT2A/2C receptors (Eshleman et al., 2014).

Use of methoxetamine by humans has been recently associated with acute neurological (Elian and Hackett, 2014; Fassette and Martinez, 2016) and cerebellar toxicity (Shields et al., 2012), including psychomotor agitation and altered motor coordination (Craig and Loeffler, 2014). Case reports described intoxicated patients with hypertension and tachycardia following use of methoxetamine (Thornton et al., 2017), ketamine (Kalsi et al., 2011), phencyclidine (Akmal et al., 1981) or methoxylated phencyclidine analogs (Bäckberg et al., 2015). Induction of gastrointestinal and urinary toxicity by ketamine have also been described (Wei et al. 2013). [Table 3] provides further details about the toxic effects of hallucinogen and dissociative drugs demonstrated by clinical studies from the past 3 years.

Due to the numerous medical issues associated with the use of new hallucinogen and dissociative drugs, being aware of the toxicity of these compounds is of primary importance for health professionals. Since it is not always possible to know the exact compound(s) consumed, management of toxicity should be based on clinical symptoms that an individual presents with and training of medical staff should focus on the management of the pattern of toxicity, rather than on the specific drug(s) used. This view is supported by a recent study revealing that physicians and nurses have less confidence in managing acute toxicity related to the use of NPS compared with classical recreational drugs (Wood et al., 2016).

Edited by dasitmane
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  • 3 weeks later...
4 hours ago, hope1 said:

MDMA was the precursor to my HPPD. Mushrooms finished me off.

MDMA was the precusor to my HPPD too. Nutmeg finished me off and SSRIs were the cherry on the staticake.

Weirdly enough, LSD, mushrooms and DMT ease most of my symptoms except for the visual snow.

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On 1/16/2020 at 11:37 PM, dasitmane said:

Good post but it looks like most that report neurotoxicity are drugs like meth and mdma. This is what the section on hallucinogens says. The only “hallucinogens” they really list are ketamine and methoxetamine.

It is important that neurotoxicity, including that from hyperactivity (regardless of being glutamate or other neurotransmitters), involves the accumulative effect - that is, total toxic burden at the time.  The visual from LSD are attributed largely to one class of serotonin receptor which caused visual processing to go on overdrive, not to mention other effects such as 'ego-loss'.  So while LSD is less damaging than crack and meth, it still can add to the burden.  MDMA is essentially an immediate acting SSRI without sedating effects.  So the increased serotonin can be toxic.

For example, pollution and anxiety both increase toxic burden.  So, theoretically it would be safer to use recreational drugs while calm and happy and in clean mountain air ... rather than while stressed and in a polluted place.  [Disclaimer: this isn't a recommendation, lol.]  It is kind of like the proverbial 'straw that brakes the camels back'.

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