A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts.<unk>  was found to be the fourth most damaging to society. Physical The physical effects of<unk>  can include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (leading to "meth mouth"), headache, irregular heartbeat (usually as accelerated heartbeat or slowed heartbeat), rapid breathing, high blood pressure, low blood pressure, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance. Long-term<unk>  users may have sores on their skin; these may be caused by scratching due to itchiness or the belief that insects are crawling under their skin, and the damage is compounded by poor diet and hygiene. Numerous deaths related to<unk>  overdoses have also been reported as well.<unk>  mouth A suspected case of<unk>  mouth<unk>  users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as<unk>  mouth. The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it. According to the American Dental Association,<unk>  mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)". As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that<unk> -associated tooth decay is more due to users' other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones. Sexually transmitted infection<unk>  use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners, an association more pronounced in HIV-positive participants. These findings suggest that<unk>  use and engagement in unprotected anal intercourse are co-occurring risk behaviors, behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men.<unk>  use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as priapism in men.<unk>  may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection. Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle. The level of needle sharing among<unk>  users is similar to that among other drug injection users. Fatal Doses of 200 mg or more of<unk>  are considered fatal. Psychological The psychological effects of<unk>  can include euphoria, dysphoria, changes in libido, alertness, apprehension and concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors. Peculiar to<unk>  and related stimulants is "punding", persistent non-goal-directed repetitive activity.<unk>  use also has a high association with anxiety, depression,<unk> etamine psychosis, suicide, and violent behaviors. Neurotoxic and neuroimmunological neuroimmune mechanisms that mediate<unk> -induced neurodegeneration in the human brain. The NF-κB-mediated neuroimmune response to<unk>  use which results in the increased permeability of the blood–brain barrier arises through its binding at and activation of sigma receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate transporters (specifically, EAAT1 and EAAT2) and glucose metabolism, and excessive Ca2+ ion influx in glial cells and dopamine neurons." Figure 7.1: Neuroimmune mechanisms of<unk> -induced CNS toxicity "<unk>  is directly neurotoxic to dopaminergic neurons in both lab animals and humans. Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity. In line with its dopaminergic neurotoxicity,<unk>  use is associated with a higher risk of Parkinson's disease. In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose<unk>  use can also be neurotoxic to serotonergic neurons. It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of<unk> . Withdrawal of<unk>  in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period. Magnetic resonance imaging studies on human<unk>  users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function. In particular,<unk>  appears to cause hyperintensity and hypertrophy of white matter, marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational<unk>  users. Moreover, evidence suggests that adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction in N-acetylaspartate and creatine levels and elevated levels of choline and myoinositol.<unk>  has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result. Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which<unk>  attenuates membrane-bound EAAT2 (SLC1A2) levels and function in these cells.<unk>  binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity. Sigma receptor activation may promote<unk> -induced neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulating apoptotic signaling cascades and the formation of reactive oxygen species. Addictive Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens. The most important transcription factors that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for most of the behavioral and neural adaptations that arise from addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine,<unk> ylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted<unk> etamines, among others. ΔJunD, a transcription factor, and G9a, a histone<unk> yltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression). Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. ΔFosB is the most significant factor involved in both<unk> etamine addiction and<unk> etamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and<unk> etamine use. These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs, such as<unk> etamine or<unk> . Epigenetic factors<unk>  addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year. About half of those with<unk>  addiction continue with use over a ten-year period, while the other half reduce use starting at about one to four years after initial use. The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. Recently a crucial role has been found for epigenetic mechanisms in driving lasting changes in gene expression in the brain. A review in 2015 summarized a number of studies involving chronic<unk>  use in rodents. Epigenetic alterations were observed in the brain reward pathways, including areas like ventral tegmental area, nucleus accumbens, and dorsal striatum, the hippocampus, and the prefrontal cortex. Chronic<unk>  use caused gene-specific histone acetylations, deacetylations and<unk> ylations. Gene-specific DNA<unk> ylations in particular regions of the brain were also observed. The various epigenetic alterations caused downregulations or upregulations of specific genes important in addiction. For instance, chronic<unk>  use caused<unk> ylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c-fos is well known to be important in addiction. The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction. In<unk>  addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors. Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs. Administration of<unk>  to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region. During repair of such DNA damages, persistent chromatin alterations may occur such as in the<unk> ylation of DNA or the acetylation or<unk> ylation
Methamphetamine
Benzphetamine
Amphetamine
Benzyl alcohol
Benzocaine
Cannabis
Cannabis 
Nicotine