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Drug Abuse: Recognizing Its Neurological Impact

Drug abuse is a significant public health burden. Globally, it has been estimated that 3.5 to 5.7% of the population age 15 to 64 years, or approximately 250 million persons consumed an illicit drug once in the past year.  An estimated 16 to 38 million persons are believed to be regular or frequent users due to the resultant psychic and physical drug dependence or addiction, with 11 to 21 million injecting illicit drugs. The misuse and abuse of drugs in the United States has reached epidemic proportion, and extends to both adolescents and adults. Although individuals with a drug addiction may favor one or another class of illicit drugs, most use more than one substance, a trend that was discerned in an analysis of accidental overdose deaths in New York City between 1990 and 1998 due to heroin, cocaine and alcohol; poly-substance use accounted for 57% of deaths attributed to accidental overdoses. Among accidental drug overdose deaths attributed to one drug alone, those positive for cocaine were the commonest representing 1.93 per 100,000 person-years.  In developing countries, public health concern surrounding substance abuse is complicated by illicit use, non-pharmacy sales, counterfeit drugs, and self-treatment.  

The earliest reports of misuse of amphetamine sulfate occured in the late 1930s when it was used by students to avoid sleep during examination periods. This was followed by reports of death by those who ingested the drug repeatedly as a stimulant. During the Second World War, amphetamine and methamphetamine were used clinically and illicitly but its abuse soared in San Francisco after 1962 wherein it was illegally produced and distributed.  By 2010, an estimated 16 to 51 million persons between the age of 15 and 64 years consumed amphetamine drugs, exceeding the combined consumption of all other drugs of abuse except cannabis. Amphetamines are consumed in powder, capsule, tablet, and injectable fluid forms. They are ingested, snorted and taken intra-nasally; and smoked or injected with highly variable purity and dosage equivalence. Their potent effects, which include elevation of blood pressure, pulse rate, and increased level of alertness, sometimes in association with insomnia, excitability, panic attacks, and aggressive behavior, can also be associated with seizures and stroke. Their effect are distributed throughout the brain, where they alter serotonin concentrations, and postsynaptic 5-HT2 receptors that play a role in the regulation of brain microvessels. 

Cocaine is derived from the leaves of the Erythroxylum coca plant found in the eastern mountains of Peru, Ecuador, and Bolivia. It is abused as a hydrochloride, water-soluble white salt in crystal, granular, and white powder that can be sniffed and “snorted” or injected by vein.  The “free base” alkaloid form is known as “crack”, derives its name from the cracking sound that occurs after dissolution of the hydrochloride salt in water, heated, and mixed with ammonia without or without baking soda.  This chemical reaction converts cocaine hydrochloride to a volatile form of the drug, almost pure cocaine.  Street cocaine or the non-crack form is highly variable in purity, and often cut with various agents.  The alkaloid free-based form is inhaled or smoked and is accompanied by higher blood concentrations and more pronounced euphoria.  When smoked as free-base, it is absorbed into the pulmonary circulation and transmitted to the brain in <10 seconds.  After appearance in the bloodstream, cocaine is rapidly hydrolyzed where it can be accurately tested in the urine. However levels may persist for up to 27 to 36 hours depending upon the route of administration and host cholinesterase activity. In recent years, with increasing availability and purity, and a drop in the price of cocaine from the early 1970 of $85 per gram, new cohorts from all socioeconomic backgrounds and age groups have been attracted to this highly addictive drug, and use has continued to expand on a year-by-year basis. 

The opioid drugs comprise a large number of agonists, antagonists and mixed agonist-antagonists.  Opioid overdose accounts for at least 16,000 deaths annually in the United States,   and occurs across sex, ethnic, age and geographic strata, and involves both medical and nonmedical opioid uses. Also known as diacetylmorphine, heroin was first synthesized by the Bayer Company in 1889 as a less addictive morphine sulfate substitute, however it has since become cheaper and more readily available.  Opioids or narcotic drugs have pharmacologic properties similar to those of morphine that include the derivatives morphine, hydrocodone, oxycodone, hydromorphone, codeine, fentanyl, meperidine, methadone, and opium.  Whereas the source of opioids is the exudate of seed from the poppy plant, heroin is derived from acetylation of morphine. It is administered intravenously, nasally and subcutaneously. A higher bioavailability of heroin is present after heating on foil for inhalation compared to smoking after heating.  Agonist actions at kappa receptors lead to separate analgesia. Circulating serum morphine is transformed into morphine-3-glucuronide or morphine-6-glucuronide by the liver and the kidney. The investigation of single nucleotide polymorphisms (SNP) that encode amino acid substitutions in opioid receptors and ligands implicated in drug addiction, particularly mu and kappa receptors, have contributed understanding to the variability in drug addiction among susceptible individuals. Opiates bind to endogenous mu1 receptors which are responsible for most of the analgesic effects. Agonist actions at mu2 receptors are responsible for respiratory depression, delayed gastrointestinal motility, miosis, and physical dependence. Opiate overdose produces the triad of coma, respiratory depression and miosis.

To understand the impact of illicit substances on the brain requires a basic knowledge of the blood-brain barrier (BBB) where the drug must first cross before exerting its effects in the brain. The BBB is composed of brain capillary endothelial cells, pericytes, astrocytes, and neuronal processes, which together ensure a well-controlled internal environment, provided by cellular exchange mechanisms in the interface between blood, cerebrospinal fluid and the brain.  Together with local neuronal circuits, the BBB plays a vital role in maintaining integrity of the brain environment from external insults including drugs. Disruption of BBB tight and adherens junctions and enzymatic degradation of brain capillary basement membranes by toxic insults, including illicit drug metabolites that impact the BBB, can lead to an alteration in the expression and function of membrane transporters or enzymes with a range of local alterations including passage of inflammatory cells across the BBB, astrocyte dysfunction, accumulation of toxic substances in brain interstitial fluid, heightened oxidative stress, and impaired ion and water homeostasis.   
Amphetamines block the reuptake of dopamine (DA) and stimulation of the release of DA and norepinephrine (NE), as well as, involvement upon the serotonergic and endogenous opiate system. There can be DA receptor desensitization with marked reduction of DA transporters and drug levels, as well as other dopaminergic axonal markers.  The neurotoxic effects of amphetamine are mediated by the generation of free radicals, nitric oxide, excite-toxicity, mitochondrial dysfunction, apoptosis, and the induction of immediate early inflammatory genes and transcription factors.  All forms of amphetamine administration increase the risk of stroke 4-fold, surpassing the rate of hemorrhagic stroke caused by cocaine use compared to non-abusers.  They are the second commonest cause of all strokes, occurring largely in persons younger than 45 years.  
Cocaine rapidly crosses the BBB due to its highly lipophilic properties and is widely distributed through the brain with its major metabolites binding at receptors with varying affinities at presynaptic sites, stimulating the release of DA from synaptic vesicles and blocking DA reuptake resulting in enhanced dopaminergic neurotransmission, in addition to its local anesthetic action. 
Injection of an opioid drug leads to extreme euphoria that peaks at 10 minutes followed by profound sedation and analgesia that lasts for up to one hour.  According to the Centers for Disease Control and Prevention (CDC), since 2003, opioid analgesic abuse overdose deaths involving opioid analgesics exceeded those due to cocaine. For every unintentional overdose death related to an opioid analgesic, nine persons were admitted for substance abuse treatment, 161 reported drug abuse or dependency, and 461 reported nonmedical uses of opioid analgesic drugs. Heroin abuse and overdose is associated with an average  mortality rate of 2% in regularly injecting persons, half of which is attributable to overdose, equivalent to 20 times the mortality rate of non-drug using peers.  

In a cross-sectional nationally representative United Kingdom sample of more than 10,000 adolescents aged 13 to 18 years, those with prior lifetime mental disorders had a 15% rates of illicit drug abuse, with or without dependence. Drug abuse was highest among adolescents with prior anxiety disorder and behavior disorders however any prior disorder significantly increases the risk of transition from nonuse to first use, and from problematic to illicit drug use. Treatment of primary mental disorders is likely to be an important target for the prevention of substance abuse in later adult years. A similar finding was noted among a cohort of 90 adolescents mean age 15 years, with crack cocaine dependence admitted to a psychiatric inpatient unit, all of whom met criteria for cocaine dependence. All patients had experimented with at least one other addictive substance before crack cocaine including tobacco, alcohol, and cannabis. The most common psychiatric comorbidity in drug abuse was conduct disorder followed by oppositional defiant disorder and attention-deficit/hyperactivity disorder, all of which were more prevalent in the patient population.  The heightened concurrence of a neuropsychiatric disturbances supports the necessity of treatment by multidisciplinary health care team members to successfully abate addiction. For each year of delay in the age at first drug use, the chance of crack cocaine initiation can be reduced by 18%, supporting the premise that prevention programs should be aimed at delaying experimentation with addictive substances, especially the gateway drugs, to reduce progression to drug dependence I adolescents and young adults. The impact of intervention programs to direct adult drug-misusing offenders out of crime and into treatment programs has been examined employing quality-adjusted life year estimates and cost-utility assessments. Such programs are both effective and cost-effective, as they reduce crime, improve quality-of-life and reduce subsequent drug use.