A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Crack<unk>  and<unk>  was found to be the third and fifth overall most dangerous drugs respectively. File:US timeline. Opioid involvement in<unk>  overdose.Opioid involvement in<unk>  overdose deaths. The green line is<unk>  and any opioid (top line in 2017). The gray line is<unk>  without any opioids (bottom line in 2017). The yellow line is<unk>  and other synthetic opioids (middle line in 2017). File:Rational harm assessment of drugs radar plot.Delphic analysis regarding 20 popular recreational drugs based on expert opinion.<unk>  was ranked the 2nd in dependence and physical harm and 3rd in social harm. Acute Acute exposure to<unk>  has many effects on humans, including euphoria, increases in heart rate and blood pressure, and increases in cortisol secretion from the adrenal gland. In humans with acute exposure followed by continuous exposure to<unk>  at a constant blood concentration, the acute tolerance to the chronotropic cardiac effects of<unk>  begins after about 10 minutes, while acute tolerance to the euphoric effects of<unk>  begins after about one hour. With excessive or prolonged use, the drug can cause itching, fast heart rate, and paranoid delusions or sensations of insects crawling on the skin. Intranasal<unk>  and crack use are both associated with pharmacological violence. Aggressive behavior may be displayed by both addicts and casual users.<unk>  can induce psychosis characterized by paranoia, impaired reality testing, hallucinations, irritability, and physical aggression.<unk>  intoxication can cause hyperawareness, hypervigilance, and psychomotor agitation and delirium. Consumption of large doses of<unk>  can cause violent outbursts, especially by those with preexisting psychosis. Crack-related violence is also systemic, relating to disputes between crack dealers and users. Acute exposure may induce cardiac arrhythmias, including atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation. Acute exposure may also lead to angina, heart attack, and congestive heart failure.<unk>  overdose may cause seizures, abnormally high body temperature and a marked elevation of blood pressure, which can be life-threatening, abnormal heart rhythms, and death. Anxiety, paranoia, and restlessness can also occur, especially during the comedown. With excessive dosage, tremors, convulsions and increased body temperature are observed. Severe cardiac adverse events, particularly sudden cardiac death, become a serious risk at high doses due to<unk> 's blocking effect on cardiac sodium channels. Incidental exposure of the eye to sublimated<unk>  while smoking crack<unk>  can cause serious injury to the cornea and long-term loss of visual acuity. Chronic Side effects of chronic<unk>  useAlthough it has been commonly asserted, the available evidence does not show that chronic use of<unk>  is associated with broad cognitive deficits. Research is inconclusive on age-related loss of striatal dopamine transporter (DAT) sites, suggesting<unk>  has neuroprotective or neurodegenerative properties for dopamine neurons. Exposure to<unk>  may lead to the breakdown of the blood-brain barrier. Physical side effects from chronic smoking of<unk>  include coughing up blood, bronchospasm, itching, fever, diffuse alveolar infiltrates without effusions, pulmonary and systemic eosinophilia, chest pain, lung trauma, sore throat, asthma, hoarse voice, dyspnea (shortness of breath), and an aching, flu-like syndrome.<unk>  constricts blood vessels, dilates pupils, and increases body temperature, heart rate, and blood pressure. It can also cause headaches and gastrointestinal complications such as abdominal pain and nausea. A common but untrue belief is that the smoking of<unk>  chemically breaks down tooth enamel and causes tooth decay.<unk>  can cause involuntary tooth grinding, known as bruxism, which can deteriorate tooth enamel and lead to gingivitis. Additionally, stimulants like<unk> , methamphetamine, and even caffeine cause dehydration and dry mouth. Since saliva is an important mechanism in maintaining one's oral pH level, people who use<unk>  over a long period of time who do not hydrate sufficiently may experience demineralization of their teeth due to the pH of the tooth surface dropping too low (below 5.5).<unk>  use also promotes the formation of blood clots. This increase in blood clot formation is attributed to<unk> -associated increases in the activity of plasminogen activator inhibitor, and an increase in the number, activation, and aggregation of platelets. Chronic intranasal usage can degrade the cartilage separating the nostrils (the septum nasi), leading eventually to its complete disappearance. Due to the absorption of the<unk>  from<unk>  hydrochloride, the remaining hydrochloride forms a dilute hydrochloric acid. Illicitly-sold<unk>  may be contaminated with levamisole. Levamisole may accentuate<unk> 's effects. Levamisole-adulterated<unk>  has been associated with autoimmune disease.<unk>  use leads to an increased risk of hemorrhagic and ischemic strokes.<unk>  use also increases the risk of having a heart attack. Addiction<unk>  addiction occurs through ΔFosB overexpression in the nucleus accumbens, which results in altered transcriptional regulation in neurons within the nucleus accumbens. ΔFosB levels have been found to increase upon the use of<unk> . Each subsequent dose of<unk>  continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug. Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to<unk> . They self-administer<unk>  at lower doses than control, but have a greater likelihood of relapse when the drug is withheld. ΔFosB increases the expression of AMPA receptor subunit GluR2 and also decreases expression of dynorphin, thereby enhancing sensitivity to reward. DNA damage is increased in the brain of rodents by administration of<unk> . During DNA repair of such damages, persistent chromatin alterations may occur such as methylation of DNA or the acetylation or methylation of histones at the sites of repair. These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in<unk>  addiction. Dependence and withdrawal<unk>  dependence develops after even brief periods of regular<unk>  use and produces a withdrawal state with emotional-motivational deficits upon cessation of<unk>  use. During pregnancy<unk>  is known to have a number of deleterious effects during pregnancy. Pregnant people who use<unk>  have an elevated risk of placental abruption, a condition where the placenta detaches from the uterus and causes bleeding. Due to its vasoconstrictive and hypertensive effects, they are also at risk for hemorrhagic stroke and myocardial infarction.<unk>  is also teratogenic, meaning that it can cause birth defects and fetal malformations. In-utero exposure to<unk>  is associated with behavioral abnormalities, cognitive impairment, cardiovascular malformations, intrauterine growth restriction, preterm birth, urinary tract malformations, and cleft lip and palate. Mortality Persons with regular or problematic use of<unk>  have a significantly higher rate of death, and are specifically at higher risk of traumatic deaths and deaths attributable to infectious disease.
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