SCs are categorized as NPS and have toxic effects which have not yet been fully discussed in the literature. These substances mimic the psychedelic effects of the main phytocannabinoids, the delta-9-tetrahydrocannabinol (THC) [88] and are linked to higher degrees of toxicity in smaller doses. The 64 studies included in our systematic review showed a wide range of dosages of serious chemicals or urine tested in relation to toxic effects, adding to the enormous difficulty in homogenizing effects. They exhibit a variety of toxic side effects which have been described in the literature, such as convulsions, disorientation, forgetfulness, psychomotor agitation, nausea, vomiting, paranoia, palpitations, tachycardia, mental confusion, hypertension, etc. [12,14,89].

SCs toxicity has increased with the affinity and specificity of cannabinoid receptors CB1 and CB2, a phenomenon that may explain their neuropsychiatric effects. The endocannabinoid system’s role in regulating excitability is still not fully understood. Cannabis compounds may have antiepileptic properties but also seem to cause convulsions. Depending on the dose that affects the cerebral regions, endocannabinoids may either stimulate or inhibit the release of GABA, possibly through dopaminergic modulation [90].

The neurotoxicity of these components is limited due to the lack of objective data on SCs. Some studies also reported longer-lasting toxic effects in SCs from third generations and potentially fourth generations due to their connection to increasingly powerful CB1 receptors [17], exhibiting more significant toxicity than earlier generations [20,91,92].

In recent years, the public health field has grown more concerned about the NPS, which include SCs and other psychoactive substances, due to the deaths caused by their abuse. As a result, the number of substances available that can lead to fatal or severe intoxications is increasing yearly. In addition, the NPS metabolic pathways and elimination routes are poorly understood, making it challenging to detect and confirm these substances in toxicological case analyses [93]. There is little detail on how SCs’ metabolic degradation occurs. It is challenging to accurately estimate the lethal SCs concentration in postmortem studies due to the substance’s natural degradation in the bloodstream [25].

NPS draw attention to cases of intoxication in emergency departments when delays in diagnosis can be lethal. These substances are consumed more frequently every day, especially in countries where recreational use is prohibited or where users attempt to evade detection in toxicology tests. Current research indicates that due to the increased intensity of psychological effects and increased likelihood of intoxication, SCs expose healthy patients and individuals with epilepsy to higher risks of intoxication or severe adverse effects [29]. Besides the higher affinity for CB1 receptors, the lack of cannabidiol (CBD) in these substances imposes an increased risk of psychoses and schizophrenia [94,95,96].

The toxic effects of SCs can be compared to those of other NPS. Data on the toxicity of other NPS are still scarce in the literature. Among these are cathinones, also known as ’bath salts‘, which are chemically altered synthetic psychostimulants, similar to the cathinones found in the leaves of the khat plant (Catha edulis) [97]. Its toxic effects include clinical complications and severe hemodynamic changes, such as disseminated intravascular coagulation, hyperthermia, arrhythmias, and sialorrhea [98], all of which have been also linked to SCs and may be difficult to differentiate in emergency situations.

Synthetic cannabinoids, interestingly, have a toxicology profile that is quite similar to other synthetic drugs, such as opioids, which have postmortem effects similar to those of SCs. In recent years, the growing number of synthetic opioids, such as fentanyl analogs, has been a source of concern due to their extreme potency, toxicity, and fatality, even at low dosages, as stated by UNODC [1]. Autopsy examinations demonstrated that pulmonary congestion, cardiomegaly, and cerebral edema associated with isotonitazene, followed by metonitazene, were also toxic effects of synthetic opioids [99]. Nonetheless, the toxicity profile observed in SCs differs from other substances directly linked to fatal toxicology cases, such as phenethylamine or phenyl cyclohexyl piperidine (PCP), phencyclidine analogs, and benzodiazepine derivatives. Phenethylamines are well-known amphetamines that include compounds such as 2C, NBOMe, NBOH, benzofurans (for example, Bromo-Dragonfly), and others (6-APB, PMMA) [100,101].

Most minor intoxications just call for symptomatic care and typically do not necessitate hospitalization. Arrhythmias, considerable chest discomfort, convulsions, extreme agitation, or other symptoms of acute intoxication should all be investigated further in a hospital setting. The unexpected effects and absence of a distinct toxidrome to identify SCs from other recreational drugs make management more difficult due to the lack of an antidote for SCs comparable to that for opioid overdose. Different illnesses, such as hypoglycemia, infections, thyroid hyperactivity, head trauma, and mental disorder, must be ruled out in order to make a differential diagnosis. While the use of haloperidol has also been discussed, caution is suggested in cases of nonspecific agitation. Benzodiazepines are typically sufficient to reduce agitation. Failure with benzodiazepines should provoke thought about final airway control. The main objectives are safeguarding the airway, avoiding rhabdomyolysis, and monitoring for either cardiac or cerebral ischemia, in addition to administering intravenous fluids for dehydration [102,103].