Abusing controlled substances, including cannabis and various drugs, can result in severe intoxication and even death. Therefore, a comprehensive postmortem analysis is crucial for understanding the underlying causes of such fatalities. This narrative review discusses the characteristics of commonly abused controlled substances, the methodologies employed in postmortem analysis, lethal dosage levels, mechanisms of toxicity, side effects, and existing regulations. The focus centers on seven prevalent groups of controlled substances, namely cannabis, opioids, amphetamine-type stimulants, cocaine, new psychoactive substances, and hallucinogens. These groups have been linked to an increased risk of fatal overdose. Most substances in these groups exert neurotoxic effects by targeting the central nervous system (CNS). Consequently, strict regulation is essential to mitigate the potential harm posed by these substances. To combat abuse, prescribers must adhere to guidelines to ensure their prescribed medications comply with the outlined regulations. Through an enhanced understanding of controlled substance abuse and its consequences, more effective strategies can be developed to reduce its prevalence and associated mortality. Although there is no specific data on the toxic concentration of THC in humans, high doses of cannabis consumption are known to cause organ damage. In a case report by Nourbakhsh et al. (2018), a deceased individual had a history of nausea and vomiting two days before death. The individual had visited the emergency room, where symptomatic therapy was provided, but it was unclear whether their CHS had improved or worsened. Low plasma glucose levels (34 mg/dL) discovered by biochemical testing following cardiac arrest in the emergency room indicated food intolerance brought on by irreversible CHS. However, cannabis toxicity can be fatal because it can trigger traumatic brain injury due to loss of consciousness [ 32 ]. In addition, cannabis toxicity will be fatal if it occurs in individuals with a history of heart disease, as it can lead to heightened sympathetic activity, and reduced parasympathetic activity, resulting in tachycardia and an elevation in cardiac output even at low or moderate doses [ 33 ]. Therefore, it is necessary to consider the impact of addiction to cannabis consumption, which is fatal to causes death [ 34 ]. 4. Amphetamine-Type Stimulant Amphetamine-Type Stimulant (ATS) is a class of drugs regulated by the 1971 Convention on Psychotropic Substances. Opioids are considered the most lethal drug group and are responsible for two-thirds of deaths directly related to drugs, primarily due to overdoses [ 3 ]. There are 3 types of opioid receptors, namely µ (MOP), δ (DOP), and κ (KOP). Among these receptors, MOP receptors are the primary target for severe pain relief in opioid therapy [ 43 ]. Fentanyl is a synthetic opioid with a strong affinity for MOP, making it a strong analgesic about 50 to 100 times stronger than morphine. Fentanyl is well-known in the form of a transdermal patch which is very comfortable for patients with acute and chronic pain [ 44 ]. The cause of death was attributed to a fentanyl overdose [ 47 ]. Tramadol, or O-desmethyl-tramadol (its active metabolite), is an opioid with a high affinity for MOP. It reduces pain by preventing Despite aggressive resuscitation efforts and supportive therapies, he developed acute hepatic and renal failure, with a liver biopsy revealing steatosis and centrolobular necrosis. Clinical toxicological screening ruled out the presence of other toxic drugs, and GC-MS analysis showed only the presence of tramadol [ 49 ]. Morphine is a classic opioid class that acts primarily on MOP receptors within the CNS and the Peripheral Nervous System (PNS). Common side effects that occur when consuming morphine are CNS depression, nausea, vomiting, and urinary retention. A morphine overdose can lead to the accumulation of morphine in the brain, resulting in respiratory depression and death [ 50 ]. The physician suspected a morphine overdose based on these symptoms, and the patient eventually passed away [ 51 ]. These case reports emphasize the dangers of opioid misuse, the need for caution and proper administration, the importance of recognizing potential drug interactions, and the significance of environmental factors in opioid administration, providing valuable insights for medical professionals to enhance patient safety and guide appropriate opioid prescriptions. In light of these dangers, it becomes essential for medical professionals to be aware of the lethal doses of different agents within the opioids group, as summarized in Table 2 . Cocaine In 2020, it is estimated that approximately 21.5 million individuals, accounting for 0.4% of the world’s population between the ages of 15 and 64, used cocaine at least once in the previous year. Although the prevalence of cocaine use has slightly increased since 2010, the actual number of cocaine users has grown by 32% due to population growth [ 35 ]. Misuse of cocaine poses various potentially fatal side effects, including acute myocardial. Ventricular free-wall rupture, a highly lethal complication, occurs in up to 2% of patients facing acute myocardial infarction [ 61 , 62 ]. A recent case reported by Massimiliano Esposito et al. This statute demands: (1) Protection from legal action for those who seek assistance during an overdose (2) Control of pain clinics (3) Patient identification before administration (4) Physical examination before prescribing opioids (5) Prescription limits (6) Prohibition of obtaining a controlled substance recipe (7) Tamper-resistant recipe. This can be executed to reduce the incidence of overdose or controlled substance abuse [ 94 , 95 ]. Countries, communities, and populations have different levels of risk, protection, and substance use. In Uruguay and Portugal, the law does not criminalize drug use or possession for personal consumption.