SCs abuse has gained great concern due to its increasing popularity and lack of awareness of its hazards as it is regarded by abusers as a natural plant owing to its appearance. Furthermore, insufficient information is known about the long-term consequences of chronic SCs misuse .
The present descriptive study was conducted from October 2019 to January 2021, and it aimed at evaluation of the epidemiologic data of acute and chronic toxicity by SCs in patients presenting at Assiut university hospital and Psychiatric Hospital of ministry of health using medical records and clinical examination to assess the personal experiences and how the participants interpret their experience with SCs use. Also, to describe relationship between different types of violence and SCs abuse.
Regarding the epidemiological data, the current study showed that most users of synthetic cannabinoids were in the adolescence and middle age group (15–< 35) representing 68% of the studied cases, and this in accordance with surveys of substance use in USA where it has found that SCs use is more concentrated in adults aged (19–28 years)  and as well with the finding of Loeffler et al.  who reported that abuse of SCs tended to peak in the adolescence (late teens and early twenties). All cases included in the presenting study were males and this comes in agreement with the results of [5, 53]. This can be explained here by fear from addiction stigma especially with females in our society. Most of the abusers in this study had 12 or less years of education and this is the same found in the study of Cohen et al.  where SC users had fewer years of study than others users.
While Castellanos and Thornton  and Stogner  found no associations between SCs use and age, marital status, athlete status, and employment.
All the included subjects in the current study were smokers. Cohen et al.  explained that early onset of smoking cigarettes is usually associated with high incidence of substance abuse. Also, Palamar and Acosta  and Clayton et al.  reported significant association between smoking regularly and using SCs.
Among the studied SCs users, it was found that multiple time users represented 63% of them. Multiple users used SCs as a replacement or substitute for another substance because of its unavailability or its price. This comes with agreement with Baggio et al.  in the survey of Swedish military recruits which revealed that SCs use tends to be unmaintained. Frequency of use appears to be restricted to a few numbers of times. Rather than being used on a long-term basis. In the existing study, participants reported that the cause of discontinuation is that their regular substance produces more powerful and longer effect, others reported the undesired effect (fear of death and panic attack). The fact that mentioned by those users is that their own experience of natural cannabis seems to be preferred to SC in terms of both more positive effects and less negative effects, which may interpret why SC is only tried a few times then discontinued.
According to the route of administration of SCs, all cases in the current study were rolling a drug into a joint using unknown dose for smoking. This was agreed with the studies done in the USA, the UK, Australia, and Canada [3, 32]. SCs are consumed typically as cannabis products as both are not ruined by the heat generated within the cigarette. As regards the place of administering the substance, nearly two-thirds (64% of the studied group) take it in the street followed by (18%) of them taking it at home and in street, and 10%, 8% of the cases at home only and at work, respectively. However, in the study conducted by Maxwell , it was demonstrated that the exposure sites were in the patient’s home or another residence (unknown location and in a public area).
In the current study regarding the cause of abuse, curiosity was the most motivation for users to try SCs followed by friends. The same was found by Goode and Ben-Yehuda  and Loeffler et al.  who reported that curiosity was responsible for the spread of most other illicit drugs like marijuana in the 1930s, to lysergic acid diethylamide and glue-sniffing in the 1960s, phencyclidine in the 1970s, cocaine in the 1980s, and, most recently, methamphetamine, ecstasy, and other street drugs. Additionally, non-availability of the usual abuse substance and cost in addition to friends were reported as other motives for the use of SCs in the studies of Werse et al. , Barratt et al. , and Wagner et al. .
In the presenting study, concerning the age of starting addiction, the mean age of starting substance abuse was 17.5 ± 4.5 years (adolescence) and this was associated with starting to use SCs at 28 ± 8 years of age. Clayton et al.  suggested that early onset of addiction is associated with multiple drugs abusing and reported that early marijuana might be a risk factor for subsequent SCs use. Marijuana is usually described as being the gateway for other drug abuse [45, 51].
Half of multiple users of SCs in the current study experienced the need to increase the initial dose to get the same primary effect (tolerance). This was in agreement with many studies of Vandrey et al. , Panlilio et al. , and van Amsterdam et al.  reported the rapid development of tolerance with using SCs. In the existing study, regarding relapse following trials to discontinue using SCs, this was observed in only 10% of multiple users with mild withdrawal symptoms which was resolved by using cannabis or more addictive substances like opioids or heroin. Most commonly described withdrawal manifestations were headache, fatigue, insomnia, anxiety, loss of appetite, and aggressiveness. Withdrawal symptoms after cessation of SCs use were also described by [9, 46]. The presence of withdrawal syndrome associated with SCs may lead users to seek more addictive substances as what was found in the current study.
Considering past medical history, it was important to exclude the presence of a previous psychiatric history of the cases to detect the psychiatric effects of SCs. In the present study, psychiatric illness history was exhibited in 4% of the subjects, whereas 96% did not experience any psychiatric illness. However, admission of the cases to psychiatric hospitals was to manage addiction and not to treat psychiatric disorders.
In the context of family history of addiction, it was positive in 28% of the cases mostly for cannabis and was negative in the remaining 62%. Family history became an important factor to evaluate in substance misuse as it was found that it influences the outcome of the cases as patients with positive family history are associated with more incidence of comorbid psychiatric disorders, co-morbid substance dependencies, severe antisocial behavior, and greater medical problems than those with no family history .
Concerning the symptoms experienced in the included cases following SCs abuse, most SCs are extraordinarily potent and effective, as a result of the full agonism of the cannabinoid receptors (CB1 and CB2) . However, SCs may bind with non-cannabinoid receptor directly, such as the vanilloid type1 receptor (TRPV1) , or by forming heterodimers between CB1 receptors and D2 dopamine, μ-opioid, or orexin-1 receptors [26, 34]. The clinical effects of SCs might be quite unpredictable, even among subjects who have smoked the same batch of SCs . The neuropsychiatric manifestations may be explained mostly as being a result of an imbalance of a number of neurotransmitter pathways and receptors. Being a highly lipophilic compound and crossing the blood-brain-barrier easily .
Results obtained in this study revealed that the neuropsychiatric effects experienced after SCs smoking, alteration in perception was reported by 66% of abusers. This included dissociation from reality, auditory, visual hallucinations, hyperactive thoughts, and irritability. This agreed with Bonaccorso et al. ,who stated the psychoactive effects produced by high doses of SCs. In the study done by Castellanos et al. , it showed that hallucinations are five times more common to develop after consuming SCs as compared to cannabis. Additionally, dizziness or drowsiness were among the most reported CNS symptoms among users (68%). Passing out and losing consciousness were also observed. Others suffered convulsion and fell on the floor prior to blackouts (8%). Users stated having panic attacks related to the use of SCs then eventually passed out (26%). This comes in agreement with the finding of Schifano et al.  who reported panic attacks; thought disorganization, and agitated/excited delirium. Headache as well was described by some users after being waken up the next day of using the SCs (22%). Acute severe psychosis with delusion of grandiosity, which developed after a multiple use of SCs (third dose) utilization was found in one patient, lasted for several days, and needed hospital admission.
The major cardiovascular adverse effects experienced by abusers were palpitations (76%) and chest pain (12%). Gastrointestinal adverse effects experienced by abusers included general gastrointestinal irritations, with nausea, and vomiting (24%). This is different from the supposed action of cannabinoids as anti-emetic drugs. Opposite to the presenting finding, the most reported side effect was cardiovascular in the form of tachycardia and this is also observed in the study of Maxwell . Controversies to these results Abass et al.  showed that the most reported effect with the use of voodoo (other commonly used synthetic cannabinoid) was the neuropsychiatric in the form of hallucination and gastrointestinal in the form of nausea and vomiting.
Withdrawal symptoms experienced by users in the presenting results after discontinuing SCs included anxiety, myalgia, insomnia, nausea, diarrhea, and irritability (20%). This was agreed with Macfarlane and Christie  who described these withdrawal symptoms and assisted the need for detoxification of the SCs users with similar symptoms as present in the current study with the addition of tachycardia and tremors.
The different symptoms observed after synthetic cannabinoids consumption are related to the distribution of CB1 receptors in the central and peripheral neurological system. Thus, CB1 receptors are abundant in areas associated with affective regulation (e.g., amygdala, ventral tegmental area, nucleus accumbens), and cognitive and memory functions (e.g., hippocampus, neocortex). CB1 receptors are also found in the brain stem, and their activation may be the cause of synthetic cannabis’ cardiovascular, respiratory, and emetic effects [24, 52].
As regarding first dose and effect duration, the participant cases reported duration of effect range from 7 to 90 min in their first use and this was subjective estimation, as well this was positively correlated to the dose received by them quantified by number of breaths or cigarettes (they could not assess the grams used). The reported range of effect in the study of Assi et al.  after smoking SCs was from 2 to 270 min. They also reported their need to increase the dose to obtain the same effect with the repeated use with the maximum of 4 ± 2.7 cigarettes/day although the first dose mean was only 2.46 ± 0.86 breaths with difficulty to even finish one cigarette described by all included users.
In the context of injuries and violence, fourteen cases out of the 50 cases were involved in injurious events, half of them were victims, and the other half were assailants under the SCs influence. On exploring the injury types, they were mostly cut wounds representing 65% of the total injuries. Also, (32% of studied cases) got involved in domestic violence. There was also a legal involvement in 15 cases out of 50 as follows: 40% were accused of abusing, 20% of them were involved in drug dealing and became suppliers themselves, 27% were legally considered as assailants, and 13% were involved legally in both; assault and drug dealing. The higher prevalence of psychotic symptoms, such as agitation and aggression among SC users, is an important factor. Moreover, hallucinations that were described by many SCs users also added to the violence acts observed in these cases. So, synthetic cannabinoids are thought to be linked to concerns such as aggression, self-harm, suicide, and mental illness (). The marked risk of psychopathological problems and accompanying violence occurrence that is usually associated with drug abuse is generally attributed to the imbalance of some neurotransmitter pathways and receptors .
This coincides with the study of Clayton et al. , who showed that sexual violence, harming someone with a weapon, physical fighting, and carrying a weapon were all more common among SCs users. Also, Ralphs et al.  correlated the sharp increase in serious violence, self-harm, and suicide in England and Wiles’ prisons to the increased consumption of SCs.
SCs users included in the present study tended mostly to be poly-drug users. This is in agreement with Stogner  results who found that mostly all synthetic cannabinoid users have as well used tobacco, alcohol, and cannabis. Also, they used a broad variety of substances including opioids, heroin, tramadol, and benzodiazepines. Assi et al.  mentioned combinations to SCs ranged from two to five substances to enhance the psychedelic effects, extend the duration of effects, or resist the impulse to re-dose. Users of SCs, compared with subjects had never used SCs, had a significantly higher prevalence of using heroin, prescription opioids/sedatives, amphetamines or ecstasy, natural cannabis, hallucinogens, inhalants, and tobacco .
Users of SCs typically have a history of cannabis use in the study of Hu et al.  or actually most studies do find high rates of overlap between the two substances [5, 12, 59]. That is confirming the possibility that marijuana usage may have been a risk factor for later synthetic cannabinoid use within the study population. Indeed, researchers usually have described marijuana usage as a risk factor for later use of other illicit drugs [33, 45]. Thus, preventing marijuana usage, especially among young teenagers, may have an impact on the reduction of synthetic cannabinoids usage. The exact doses and effects of such combinations makes interpretation of the pharmacological and toxicological effects of these substances very difficult. Additionally, the incidence of seeking emergency treatment after SCs use increased in cases who took other substances with SCs, especially alcohol .
Laboratory routine investigations done at time of presentation revealed that abnormal routine laboratory findings were found in included cases in the form of 12% of studied cases anemia, 10% of studied cases leucocytosis, and 6% of studied cases leucopenia. Anemia is a frequent nutritional problem seen in substance use as they are not usually concerned about their nutrition and diet. Guzel et al.  illustrated the effect of SCs on iron metabolism resulting in subclinical anemia in SCs users. While leucopenia may be explained by immune system activation through the stimulation of CB2 receptors which are known to be activated more by SCs than cannabis. However, it is worth noting that there are many forms of synthetic cannabinoids and each may have different effects on CB receptors that may potentially interfere with hematological results .
Also, liver and kidney functions were elevated in 8% and 4% of the cases, respectively. Elevated liver enzymes may correspond with the presence of 22% of cases with positive serology for hepatitis C or being affected by SCs. Finally, 4% of participants were positive for HIV. Müller et al.  demonstrated elevation of hepatic and renal function in association with SCs use. However, the study of Abass et al.  found that there was not statistically significant difference in liver and kidney function tests between the SCs users. Positive serology is more associated with the injection of substances, so the incidence concluded in the presenting study related with the co-use of other injecting substances. This coincides with Dagli ’s screening of hepatitis and HIV viruses among users in an alcohol and drug addiction treatment center, as they noticed that infected patients were significantly higher in the persons who used opiates than other substance included SCs. He also reported zero cases of infection with the patient used SCs as the first drug.