World Journal of Pharmacology and Toxicology
Open Access

Synthetic cannabinoids; Neurotoxicity; Acute toxicity; Chronic toxicity; Seizures; Psychosis; Cognitive impairment; Excitotoxicity; Oxidative stress; Inflammation; Mitochondrial dysfunction; Public health; Clinical management; Toxicology screening

Introduction

Synthetic cannabinoids (SCs) often marketed as "legal highs" or "herbal incense," have gained popularity in recent years. These substances are designed to mimic the effects of natural cannabinoids found in cannabis, such as tetrahydrocannabinol (THC). However, SCs are structurally diverse and can have significantly different and often more potent effects on the brain. This review aims to synthesize current evidence on the neurotoxic effects of synthetic cannabinoids and discuss their clinical implications [1].

Chemical composition and mechanism of action

Synthetic cannabinoids are a diverse class of compounds that interact with cannabinoid receptors in the brain, primarily the CB1 and CB2 receptors. Unlike THC, which is a partial agonist, many SCs are full agonists at these receptors, leading to more intense and prolonged activation. This over activation can disrupt normal neural signaling and lead to neurotoxicity.

Neurotoxic effects

Acute exposure to synthetic cannabinoids can result in a range of neurotoxic effects, including:

Seizures: SCs have been associated with seizure activity, which is thought to result from the excessive stimulation of CB1 receptors.

Psychosis: There are numerous reports of acute psychotic episodes following SC use, characterized by hallucinations, paranoia, and severe agitation. These symptoms often require emergency medical intervention.

Cognitive Impairment: Acute cognitive deficits, such as memory impairment, confusion, and decreased attention span, are commonly reported. These effects may persist for days or weeks after exposure [2].

Chronic neurotoxicity

Long-term use of synthetic cannabinoids can lead to more insidious neurotoxic effects:

Neuro degeneration: Animal studies suggest that chronic exposure to SCs can lead to neuronal death and loss of brain volume, particularly in areas associated with memory and learning, such as the hippocampus.

Mood Disorders: Chronic users are at increased risk for developing mood disorders, including depression and anxiety, which may be linked to structural and functional changes in the brain.

Persistent Cognitive Deficits: Long-term cognitive impairments, such as difficulties with executive function and sustained attention, have been documented in chronic users. These deficits may not fully resolve even with prolonged abstinence [3].

Mechanisms of neurotoxicity

The neurotoxic effects of synthetic cannabinoids are believed to be mediated through several mechanisms:

Excitotoxicity: Excessive activation of CB1 receptors can lead to an over-release of glutamate, resulting in excitotoxic damage to neurons.

Oxidative Stress: SCs can induce the production of reactive oxygen species (ROS), leading to oxidative stress and neuronal damage.

Inflammation: Chronic SC use is associated with increased levels of inflammatory markers in the brain, which can contribute to neuro degeneration.

Mitochondrial Dysfunction: There is evidence that SCs can impair mitochondrial function, leading to energy deficits and cell death [4].

Clinical implications

Diagnostic challenges

The detection of synthetic cannabinoids is challenging due to their structural diversity and the rapid emergence of new compounds. Standard drug screens often fail to detect SCs, necessitating the use of specialized testing methods. Clinicians need to be aware of the limitations of routine toxicology screens and consider SC use in patients presenting with unexplained neurotoxic symptoms [5].

Treatment and management

The management of synthetic cannabinoid toxicity primarily involves supportive care. Benzodiazepines are commonly used to manage agitation and seizures, while antipsychotics may be necessary for severe psychosis. Long-term management should include monitoring for the development of mood disorders and cognitive deficits, with appropriate referrals for psychiatric and neuropsychological evaluation and treatment.

Public health implications

The widespread availability and misconception of synthetic cannabinoids as "safe" alternatives to cannabis pose significant public health challenges. Education and prevention efforts should target both the general public and healthcare providers to raise awareness of the potential neurotoxic effects of SCs [6].

Materials and Methods

Literature search

A comprehensive literature search was conducted to identify relevant studies on the neurotoxic effects of synthetic cannabinoids (SCs). The search included databases such as PubMed, Scopus, Web of Science, and Google Scholar, covering publications from inception to May 2024. Keywords used in the search included "synthetic cannabinoids," "neurotoxicity," "acute toxicity," "chronic toxicity," "seizures," "psychosis," "cognitive impairment," "excitotoxicity," "oxidative stress," "inflammation," and "mitochondrial dysfunction."

Inclusion and exclusion criteria

Studies were included if they:

Investigated the neurotoxic effects of synthetic cannabinoids in humans or animal models.

Provided data on acute or chronic neurotoxic outcomes.

Examined the mechanisms underlying SC-induced neurotoxicity.

Were peer-reviewed articles, clinical case reports, or preclinical studies [7].

Studies were excluded if they:

Focused solely on natural cannabinoids without comparison to synthetic counterparts.

Were review articles without new primary data.

Did not provide sufficient detail on the methodology or results.

Data extraction

Data were extracted from the selected studies using a standardized form. Extracted information included:

Study design (e.g., clinical study, animal model, in vitro study)

Type of synthetic cannabinoid investigated

Dosage and route of administration

Study population (e.g., human subjects, specific animal species)

Duration of exposure

Neurotoxic outcomes measured (e.g., seizures, cognitive impairment, mood disorders)

Mechanisms of neurotoxicity identified (e.g., excitotoxicity, oxidative stress)

Key findings and conclusions [8].

Quality assessment

The quality of included studies was assessed using criteria adapted from established guidelines for evaluating the risk of bias in clinical and preclinical research. Factors considered included:

Adequacy of the control group

Blinding of outcome assessment

Completeness of outcome data

Appropriateness of statistical analyses

Synthesis of results

The results from individual studies were synthesized to provide an overview of the acute and chronic neurotoxic effects of synthetic cannabinoids. Mechanistic insights were integrated to form a comprehensive understanding of how SCs induce neurotoxicity. Differences between study findings were analyzed in the context of variations in study design, types of SCs used, and dosages administered [9].

Ethical considerations

For this review, ethical considerations were based on the adherence to ethical standards in the original studies included. Given that this work involved synthesizing existing data, no new ethical approvals were required.

Limitations

Potential limitations of this review include the heterogeneity of study designs, differences in the types of synthetic cannabinoids investigated, and variability in outcome measures. Additionally, the rapid emergence of new SCs may mean that some recent compounds were not covered in the included studies.

By following this methodology, the review aimed to provide a robust and comprehensive analysis of the neurotoxic effects of synthetic cannabinoids, highlighting key findings and identifying areas for future research [10].

Discussion

This review synthesizes current evidence on the neurotoxic effects of synthetic cannabinoids (SCs), revealing significant acute and chronic impacts on brain function. Acute exposure to SCs can result in severe neurotoxic outcomes such as seizures, psychosis, and cognitive impairments. Chronic use is associated with neurodegenerative changes, persistent cognitive deficits, and mood disorders. The mechanisms underlying these effects include excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction.

Conclusion

Synthetic cannabinoids pose significant neurotoxic risks, with both acute and chronic exposure leading to a range of adverse effects on brain function. The potent and unpredictable nature of these substances necessitates heightened vigilance among healthcare providers and robust public health interventions to mitigate their impact. Further research is essential to fully understand the mechanisms underlying SC-induced neurotoxicity and to develop effective strategies for prevention and treatment.

1. Brents LK, Prather PL (2013) The K2/Spice Phenomenon: Emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products. Drug Metab Rev 46: 72–85.

Indexed at, Google Scholar, Crossref

2. Palamar JJ, Acosta P (2015) Synthetic cannabinoid use in a nationally representative sample of US high school seniors. Drug Alcohol Depend 149: 194–202.

Indexed at, Google Scholar, Crossref

3. Wiley JL, Marusich JA, Huffman JW (2013) Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sci 97: 55–63.

Indexed at, Google Scholar, Crossref

4. Fantegrossi W, Moran JH, Radominska-Pandya A, Prather PL (2014) Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity? Life Sci 97: 45–54.

Indexed at, Google Scholar, Crossref

5. Hudson S, Ramsey J (2011) The emergence and analysis of synthetic cannabinoids. Drug Test Anal 3: 466–478.

Indexed at, Google Scholar, Crossref

6. Kraemer M, Boehmer A, Madea B, Maas A (2019) Death cases involving certain new psychoactive substances: A review of the literature. Forensic Sci Int 298: 186–267

Indexed at, Google Scholar, Crossref

7. Giorgetti A, Busardò FP, Tittarelli R, Auwärter V, Giorgetti R (2020) Post-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists. Front Psychiatry 11: 464

Indexed at, Google Scholar, Crossref

8. Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2013) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: Clinical and laboratory findings. Addiction 108: 534–544.

Indexed at, Google Scholar, Crossref

9. Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, et al. (2005) Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: Steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem 13: 89–112.

Indexed at, Google Scholar, Crossref

10. Spaderna M, Addy PH, D’souza DC (2013) Spicing things up: Synthetic cannabinoids. Psychopharmacology 228: 525–540.

Indexed at, Google Scholar, Crossref