Marijuana is used for its psychotropic effects including enhanced relaxation and perceptual alterations. The primary psychoactive ingredient found in marijuana is Δ-9 tetrahydrocannabinol (THC), which binds to endogenous cannabinoid receptors (CB1, CB2)^[1]. Specifically, cannabis products including synthetic marijuana (SM) exert all its known psychotropic effects through the CB1 cannabinoid receptors. Such important classes of neurons that express high levels of CB1 receptors are GABAergic neurons in the hippocampus, amygdala, and the cerebral cortex. Additionally, these neurons contain the neuropeptides cholecystokinin. In turn, when these cannabis products activate the CB1 receptors, the inhibition of the release of amino acids and monoamine neurotransmitters occur. Further speaking, lipid derivatives, such as anandamide and 2-arachidonylglycerol, act as endogenous ligands for CB1 receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization with possible induced suppression of inhibition or excitation in the hippocampus and cerebellum^[2]. However, some SM products, such as JWH-015 and JWH-133, show affinity not only for the CB1 receptors, but also for the CB 2 receptors. These CB-2 receptors appear to be much present on the marginal zone of the spleen, tonsils, and immune cells, especially on macrophages, B cells, natural killer cells, monocytes, T-lymphocytes, polymorphonuclear neutrophils and astrocytes^[2].

  According to^[3] many of the SM induced psychiatric effects consist of psychotic behavior and anxiety. Evidence suggests that it may trigger / and physical adverse effects, which are strikingly similar to those of marijuana^[3]. The use of SM leads to more frequent and drastic side effects than the typical use of regular marijuana, owing to the fact that SM has a shorter duration and an earlier peak of action^[4]. SM use can lead to various adverse side effects including delusions, paranoia, hallucinations, anxiety, panic attacks, agitation, seizures, dizziness, and short term cognitive deficits^[5]. In addition to the expected CNS effects, such as confusion, psychosis, agitation, loss of consciousness, and seizures, some of these SM based compounds have been associated with tachycardia, kidney damage, rhabdomyolysis, and even death.

  Despite all the potential adverse health effects associated with SM use, current health policies on SM are very limited^[6]. It is believed that the popularity of SM has increased, due to its easy accessibility in the US and lack of detection in typical urine drug screens for THC.

  Therefore, it is imperative to evaluate the impact of SM on mental health and more importantly the social and legal implications surrounding its use. Accordingly, this case illustrates how easy accessibility and limited regulation on SM adversely impacts mental health thus posing a challenging problem for psychiatrists nationwide. The present case report leads to consideration of the critical need for regulations and effective toxicology screens for SM.

Case Report

  An 18 year old Hispanic male was brought to our emergency department by his parents after five days of acute onset auditory hallucinations, paranoid delusions, and, per the mother, symptoms of panic attacks, including palpations, shortness of breath, diaphoresis, chest tightness, and hand numbness. The patient presented with impulsivity, agitation, and stated he had suicidal thoughts. Additionally, the patient reported a history of cannabis abuse, and more recently, synthetic marijuana/cannabis (SM) use (3 - 4 days prior to presentation), which were purchased from internet blog sites and convenience stores^[7].

  It was apparent that the onset of psychosis coincided with the patient’s most recent SM use. Of note, the patient did not have any previous psychiatric history, nor a psychotic episode, prior to his synthetic marijuana use. Nevertheless, an antipsychotic regimen was provided to the patient during his hospitalization which was beneficial in controlling his transient acute psychosis. Moreover, a urine drug screen in the ED was negative for THC, which fortified the patient’s history of not using regular marijuana since a month prior to hospitalization.

  Thereafter, a three month follow up phone call made to the patient, revealed that his mental health had been progressively improving after discharge and, at that moment, he was doing very well. The patient mentioned that the symptoms subsided several weeks (2 - 3 weeks) after his discharge from the hospital. During that time, the patient refrained from any illicit drug use, including SM use. The patient remained under the care of a licensed- psychiatrist throughout the period after inpatient treatment. According to the patient, compliance was maintained regarding attendance of sessions with his outpatient psychiatrist.

Discussion

  It is of outmost importance to note that there may be some differences between a psychotic episode secondary to synthetic cannabis/marijuana use, and an exacerbation of a psychotic episode due to a defined psychiatric illness. For instance, synthetic cannabis/marijuana products can induce a brief acute psychotic state that can subside within several days to weeks, after cessation of the drug, in individuals with no previous diagnosis of a psychiatric disorder. Still, synthetic cannabis/ marijuana products can trigger psychosis in individuals who have a current diagnosis of psychosis. In fact, further use of these products can worsen psychotic symptoms in those individuals with a current diagnosis of psychosis or specific type of a psychotic disorder. It is therefore very ideal to obtain a thorough psychiatric history, a complete mental status assessment, and an appropriate follow up, regarding a patient before determining the etiology of an acute psychotic episode. This would help define if an acute psychotic episode may be secondary to a substance (in this case SM) or secondary to a chronic psychiatric illness (e.g. Schizophrenia, Bipolar Disorder, and Depression). That being said, certain lab findings alone, more specifically a negative urine drug screen for THC, will not make the determination on whether the psychosis is secondary to SM or if it’s secondary to a chronic mental illness^[2].

  Ultimately, in a transient acute psychotic episode caused by SM use, the cessation of use will bring on resolution of the psychosis. The short-term use of an anti-psychotic or a benzodiazepine regimen may be warranted depending on the level of distress. Additionally, it has been shown that psychoeduation and Cognitive Behavioral Therapy (CBT) has been successful in reducing SM use in patients experiencing their first episode of psychosis^[8]. Moreover, further research has specifically shown Clozapine rather than Risperidone as being more effective in managing acute psychotic like symptoms secondary to SM use^[2].

  Users of SM products appear to have a variety of physical effects ranging from nausea to more serious sympathomimetic- like symptoms, such as psychomotor agitations, abnormal vital signs, including hypertension and tachycardia, diaphoresis and palpitations. Also, even though infrequently associated with smoking SM , clinical case reports have described generalized convulsions secondary to the usage of 4 different synthetic cannabis derivatives , JWH-018, JWH-081, JWH-250, and AM-2201^[1].

Further Conclusions
  Synthetic marijuana use is insidiously becoming a mental illness concern given its appreciable contributions to acute onset of, and exacerbation of existing psychiatric conditions. While there has been a recent increment in the level of awareness for marijuana use for medical purposes in the United States and internationally, there is necessity for strict regulations and control measures in defining limits for recreational use due to potential psychiatric conditions^[9,10]. More importantly, there is further need for production regulations, including standardization and monitoring designed structural compounds of SM, in order to create the pathway to the formulation of effective toxicology screening techniques.

Declarations
Ethical Standards and Informed Consent: All procedures and interviews conducted were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all individuals for whom identifying information is included in this manuscript.

Consent for Publication: Consent and acknowledgement was received from the individual(s) in this case-study in order for this manuscript to be published accordingly.

Availability of data and materials: The dataset(s) supporting the conclusion of this article is included within the article and its additional file(s) are located in the Microsoft Word File entitled “Journal of Addiction and Dependence, Synth. Marijuana Case Study (Table 1) JSamaan.”

Table 1: Clinical Pearls & Key Points: Synthetic Marijuana Abuse and Its Similarities and Differences to Cannabis.

Conflict of Interest /Declaration of Interest:
  The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of this case-study paper.

Funding:
  There were no sources of funding used in collection, analysis, and interpretation of data and in writing the manuscript.

Authors’ Contributions:
The authors of this case report have contributed to this manuscript / case study in the following ways:
 [1] Patricia Jonquiere (Attending Psychiatrist at Jackson Memorial Hospital, Miami, FL, USA) , Juan Oms MD (Program Director of Larkin Community Hospital’s Psychiatry Residency Program, South Miami, FL, USA), and Gerardo F. Ferrer MD (Chief Resident/Attending Psychiatrist at Larkin Community Hospital’s Psychiatry Residency Program, South Miami, FL, USA ) had provided substantial contributions to the conception and analysis of the data provided in the manuscript , primarily in regards to their expertise and knowledge on the effects of synthetic marijuana overdose and use.
 [2] Boye Akinyemi MD ( PGY-1 ( First Year Psychiatry Resident at Larkin Community Hospital’s Psychiatry Residency Program, South Miami, FL, USA ) had been involved in drafting the manuscript . Dr. Akinyemi was also responsible for revising the manuscript critically for important intellectual content, as well as being responsible for composing the “Further Conclusions” section of this manuscript.
 [3] Rhaisa Dumengio MD (Director of In-Patient Services at Larkin Community Hospital’s Psychiatry Residency Program, South Miami, FL, USA) had given final approval of this version to be published after reviewing the manuscript numerous times.

Acknowledgement:
  The authors of this manuscript would like to acknowledge and thank Dr. Marcos-Gonzalez Sanchez MD PhD, Director of Clinical and Translational Research at Larkin Community Hospital, for his assistance in revision of this manuscript, along with his additional suggestions and advice.

Abbreviation: SM: Synthetic Marijuana/Cannabis; CB1 and CB2 receptors: Cannabinoid Receptor 1 and Cannabinoid Receptor 2; CNS: Central Nervous System; HC: Tetrahydrocannabinol derivatives; ED: Emergency Department

References