Antipsychotics have been associated with decreases in brain volume over time, which may indicate a neurotoxic effect. However, untreated psychosis has also been associated with decreases in brain volume and treatments have been shown improve cognitive functioning. [ 32 ] [ 33 ] [ 34 ] [ 35 ]


This is an alphabetical  list of  psychiatric medications  used by  psychiatrists  and other  physicians  to treat  mental illness  or distress.


Acamprosate ,  Alprazolam ,  Alpidem ,  Amisulpride ,  Amitriptyline ,  Amoxapine ,  Amphetamine ,  Mixed Amphetamine Salts ,  Aripiprazole ,  Atomoxetine


Benperidol ,  Bromazepam ,  Bupropion ,  Buspirone


Calcium carbimide ,  Carbamazepine ,  Chloralhydrate ,  Chlordiazepoxide ,  Clorgiline ,  Chlorpromazine ,  Citalopram ,  Clomipramine ,  Clonazepam ,  Clonidine , Clorazepate ,  Clozapine


Desvenlafaxine ,  Dextroamphetamine ,  Diazepam ,  Disulfiram ,  Divaplon ,  Duloxetine


Escitalopram ,  Eszopiclone


Fasiplon ,  Fluoxetine ,  Fluphenazine ,  Flurazepam ,  Fluvoxamine


Gabapentin ,  Guanfacine


Haloperidol


Imipramine ,  Indalpine , Indiplon ,   Itopride


Lamotrigine ,  Lemborexant ,  Levoamphetamine ,  Levomepromazine ,  Lisdexamfetamine ,  Lithium ,  Lorazepam ,  Lorediplon ,  Loxapine ,  Lumateperone ,  Lurasidone


Maprotiline ,  Melperone ,  Meprobamate ,  Mesoridazine ,  Methamphetamine ,  Methaqualone ,  Methylphenidate ,  Mianserin ,  Mirtazapine ,  Mixed Amphetamine Salts ,  Moclobemide ,  Modafinil


Naltrexone ,  Necopidem ,  Nitrazepam ,  Nortriptyline


Ocinaplon ,  Olanzapine ,  Oxazepam ,  Oxcarbazepine


Pagoclone ,  Paliperidone ,  Panadiplon ,  Pargyline ,  Paroxetine ,  Pazinaclone ,  Perphenazine ,  Phenelzine ,  Phenytoin ,  Pipamperone ,  Pimavanserin ,  Pimozide ,  Pipotiazine ,  Pramipexole ,  Pregabalin ,  Primidone ,  Prochlorperazine ,  Promethazine ,  Prothipendyl ,  Protriptyline


Quetiapine


Reboxetine ,  Risperidone ,  Rozerem ,  Rubidium chloride


Saripidem ,  Scopolamine ,  Selegiline ,  Sertraline ,  Sodium Thiopental ,  Sulfonmethane ,  Sulpiride ,  Suriclone


Taniplon ,  Temazepam ,  Thioridazine ,  Thiothixene ,  Topiramate ,  Tranylcypromine ,  Trazodone ,  Triazolam ,  Trifluoperazine ,  Trimipramine


Valbenazine ,  Valproate ,  Venlafaxine


Zaleplon ,  Zimelidine ,  Ziprasidone ,  Zolpidem ,  Zopiclone ,  Zotepine ,  Zuclopenthixol


Psychopharmacology  (from  Greek   ψῡχή ,  psȳkhē , 'breath, life, soul';  φάρμακον ,  pharmakon , 'drug'; and  -λογία ,  -logia ) is the scientific study of the effects  drugs  have on  mood ,  sensation ,  thinking ,  behavior ,  judgment  and  evaluation , and  memory . It is distinguished from  neuropsychopharmacology , which emphasizes the correlation between drug-induced changes in the functioning of  cells  in the  nervous system  and changes in  consciousness  and behavior. [ 1 ]


The field of psychopharmacology studies a wide range of substances with various types of  psychoactive  properties, focusing primarily on the chemical interactions with the brain. The term "psychopharmacology" was likely first coined by  David Macht  in 1920. Psychoactive drugs interact with particular target sites or receptors found in the  nervous system  to induce widespread changes in physiological or psychological functions. The specific interaction between drugs and their receptors is referred to as " drug action ", and the widespread changes in physiological or psychological function is referred to as " drug effect ". [ 2 ]  These drugs may originate from natural sources such as plants and animals, or from artificial sources such as  chemical synthesis  in the laboratory.


Not often mentioned or included in the field of psychopharmacology today are  psychoactive  substances not identified as useful in modern  mental health  settings or references. These substances are naturally occurring, but nonetheless psychoactive, and are compounds identified through the work of  ethnobotanists  and  ethnomycologists  (and others who study the native use of naturally occurring psychoactive drugs). However, although these substances have been used throughout history by various cultures, and have a profound effect on mentality and brain function, they have not always attained the degree of scrutinous evaluation that lab-made compounds have. Nevertheless, some, such as  psilocybin  and  mescaline , have provided a basis of study for the compounds that are used and examined in the field today.  Hunter-gatherer  societies tended to favor  hallucinogens , and today their use can still be observed in many surviving  tribal  cultures. The exact drug used depends on what the particular  ecosystem  a given tribe lives in can support, and are typically found growing wild. Such drugs include various  psychoactive mushrooms  containing psilocybin or  muscimol  and  cacti  containing mescaline and other chemicals, along with myriad other  plants containing psychoactive chemicals . These societies generally attach spiritual significance to such drug use, and often incorporate it into their religious practices.
With the dawn of the  Neolithic  and the proliferation of agriculture, new psychoactives came into use as a natural by-product of farming. Among them were  opium ,  cannabis , and  alcohol  derived from the fermentation of cereals and fruits. Most societies began developing  herblores , lists of herbs which were good for treating various physical and mental ailments. For example,  St. John's wort  was traditionally prescribed in parts of Europe for depression (in addition to use as a general-purpose tea), and  Chinese medicine  developed elaborate lists of  herbs  and preparations. These and various other substances that have an effect on the brain are still used as remedies in many cultures. [ 3 ]


The dawn of contemporary psychopharmacology marked the beginning of the use of psychiatric drugs to treat psychological illnesses. It brought with it the use of opiates and barbiturates for the management of acute behavioral issues in patients. In the early stages, psychopharmacology was primarily used for sedation. With the 1950s came the establishment of  lithium  for  mania ,  chlorpromazine  for  psychoses , and then in rapid succession, the development of tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines, among other antipsychotics and antidepressants. A defining feature of this era includes an evolution of research methods, with the establishment of  placebo-controlled ,  double-blind  studies, and the development of methods for analyzing blood levels with respect to clinical outcome and increased sophistication in clinical trials. The early 1960s revealed a revolutionary model by  Julius Axelrod  describing nerve signals and  synaptic transmission , which was followed by a drastic increase of biochemical brain research into the effects of psychotropic agents on brain chemistry. [ 4 ]  After the 1960s, the field of psychiatry shifted to incorporate the indications for and efficacy of pharmacological treatments, and began to focus on the use and toxicities of these medications. [ 5 ] [ 6 ]  The 1970s and 1980s were further marked by a better understanding of the synaptic aspects of the action mechanisms of drugs. However, the model has its critics, too – notably  Joanna Moncrieff  and the  Critical Psychiatry Network . [ citation needed ]


Psychoactive drugs exert their sensory and behavioral effects almost entirely by acting on  neurotransmitters  and by modifying one or more aspects of synaptic transmission. Neurotransmitters can be viewed as chemicals through which  neurons  primarily communicate; psychoactive drugs affect the mind by altering this communication. Drugs may act by 1) serving as a  precursor  to a neurotransmitter; 2) inhibiting neurotransmitter synthesis; 3) preventing storage of neurotransmitters in the pre synaptic vesicle ; 4) stimulating or inhibiting neurotransmitter release; 5) stimulating or blocking post-synaptic receptors; 6) stimulating  autoreceptors , inhibiting neurotransmitter release; 7) blocking autoreceptors, increasing neurotransmitter release; 8) inhibiting neurotransmission breakdown; or 9) blocking neurotransmitter  reuptake  by the presynaptic neuron. [ 1 ]


The other central method through which drugs act is by affecting communications between cells through  hormones . Neurotransmitters can usually only travel a microscopic distance before reaching their target at the other side of the  synaptic cleft , while hormones can travel long distances before reaching target cells anywhere in the body. Thus, the  endocrine system  is a critical focus of psychopharmacology because 1) drugs can alter the secretion of many hormones; 2) hormones may alter the behavioral responses to drugs; 3) hormones themselves sometimes have psychoactive properties; and 4) the secretion of some hormones, especially those dependent on the  pituitary gland , is controlled by neurotransmitter systems in the brain. [ 1 ]


Alcohol  is a  depressant , the effects of which may vary according to dosage amount, frequency, and chronicity. As a member of the sedative-hypnotic class, at the lowest doses, the individual feels relaxed and less anxious. In quiet settings, the user may feel drowsy, but in settings with increased sensory stimulation, individuals may feel uninhibited and more confident. High doses of alcohol rapidly consumed may produce  amnesia  for the events that occur during intoxication. Other effects include reduced coordination, which leads to slurred speech, impaired fine-motor skills, and delayed reaction time. The effects of alcohol on the body's neurochemistry are more difficult to examine than some other drugs. This is because the chemical nature of the substance makes it easy to penetrate into the brain, and it also influences the  phospholipid bilayer  of neurons. This allows alcohol to have a widespread impact on many normal cell functions and modifies the actions of several neurotransmitter systems. Alcohol inhibits  glutamate  (a major excitatory neurotransmitter in the nervous system) neurotransmission by reducing the effectiveness at the  NMDA  receptor, which is related to memory loss associated with intoxication. It also modulates the function of  GABA , a major inhibitory amino acid neurotransmitter. Abuse of alcohol has also been correlated with thiamine deficiencies within the brain, leading to lasting neurological conditions that affect primarily the ability of the brain to effectively store memories. [ 7 ]  One such neurological condition is called  Korsakoff's syndrome , for which very few effective treatment modalities have been found. [ 7 ] [ 8 ]  The reinforcing qualities of alcohol leading to repeated use – and thus also the mechanisms of withdrawal from chronic alcohol use – are partially due to the substance's action on the  dopamine  system. This is also due to alcohol's effect on the  opioid  systems, or  endorphins , that have opiate-like effects, such as modulating pain, mood, feeding, reinforcement, and response to stress. [ 1 ]


Antidepressants  reduce symptoms of mood disorders primarily through the regulation of  norepinephrine  and  serotonin  (particularly the  5-HT receptors ). After chronic use, neurons adapt to the change in biochemistry, resulting in a change in pre- and postsynaptic receptor density and second messenger function. [ 1 ]  The Monoamine Theory of Depression and Anxiety, which states that the disruption of the activity of nitrogen containing neurotransmitters (i.e. serotonin, norepinephrine, and dopamine) is strongly correlated with the presence of depressive symptoms. [ 9 ]  Despite its longstanding prominence in pharmaceutical advertising, the myth that low serotonin levels cause depression is not supported by scientific evidence. [ 10 ] [ 11 ] [ 12 ]


Monoamine oxidase inhibitors  (MAOIs) are the oldest class of antidepressants. They inhibit  monoamine oxidase , the enzyme that metabolizes the monoamine neurotransmitters in the presynaptic terminals that are not contained in protective synaptic vesicles. The inhibition of the enzyme increases the amount of neurotransmitter available for release. It increases norepinephrine, dopamine, and 5-HT, thus increasing the action of the transmitters at their receptors. MAOIs have been somewhat disfavored because of their reputation for more serious side effects. [ 1 ]


Tricyclic antidepressants  (TCAs) work through binding to the presynaptic transporter proteins and blocking the reuptake of norepinephrine or 5-HT into the presynaptic terminal, prolonging the duration of transmitter action at the synapse.


Selective serotonin reuptake inhibitors  (SSRIs) selectively block the reuptake of serotonin (5-HT) through their inhibiting effects on the sodium/potassium  ATP -dependent serotonin transporter in presynaptic neurons. This increases the availability of 5-HT in the synaptic cleft. [ 13 ]  The main parameters to consider in choosing an antidepressant are side effects and safety. Most SSRIs are available generically and are relatively inexpensive. Older antidepressants such as TCAs and MAOIs usually require more visits and monitoring, which may offset the low expense of the drugs. SSRIs are relatively safe in overdoses and better tolerated than TCAs and MAOIs for most patients. [ 13 ]


All proven antipsychotics are postsynaptic dopamine receptor blockers (dopamine  antagonists ). For an antipsychotic to be effective, it generally requires a dopamine antagonism of 60%–80% of dopamine D 2  receptors. [ 13 ]


First generation (typical) antipsychotics : Traditional  neuroleptics  modify several neurotransmitter systems, but their clinical effectiveness is most likely due to their ability to antagonize dopamine transmission by competitively blocking the receptors or by inhibiting dopamine release. The most serious and troublesome side effects of these classical antipsychotics are movement disorders that resemble the symptoms of  Parkinson's disease , because the neuroleptics antagonize dopamine receptors broadly, also reducing the normal dopamine-mediated inhibition of  cholinergic  cells in the  striatum . [ 1 ]


Second-generation (atypical) antipsychotics : The concept of "atypicality" is from the finding that second generation antipsychotics (SGAs) have a greater serotonin/dopamine ratio than earlier drugs, and might be associated with improved efficacy (particularly for the  negative symptoms  of psychosis) and reduced  extrapyramidal side effects . Some of the efficacy of atypical antipsychotics may be due to 5-HT 2  antagonism or the blockade of other dopamine receptors. Agents that purely block 5-HT 2  or dopamine receptors other than D 2  have often failed as effective antipsychotics. [ 13 ]


Benzodiazepines  are often used to reduce anxiety symptoms, muscle tension, seizure disorders, insomnia, symptoms of alcohol withdrawal, and panic attack symptoms. Their action is primarily on specific benzodiazepine sites on the GABA A  receptor. This receptor complex is thought to mediate the  anxiolytic , sedative, and  anticonvulsant  actions of the benzodiazepines. [ 13 ]  Use of benzodiazepines carries the risk of tolerance (necessitating increased dosage), dependence, and abuse. Taking these drugs for a long period of time can lead to  severe withdrawal symptoms  upon abrupt discontinuation. [ 14 ]


Psychedelics  cause perceptual and cognitive distortions without delirium. The state of intoxication is often called a "trip". Onset is the first stage after an individual ingests ( LSD ,  psilocybin ,  ayahuasca , and  mescaline ) or smokes ( dimethyltryptamine ) the substance. This stage may consist of visual effects, with an intensification of colors and the appearance of geometric patterns that can be seen with one's eyes closed. This is followed by a plateau phase, where the subjective sense of time begins to slow and the visual effects increase in intensity. The user may experience  synesthesia , a crossing-over of sensations (for example, one may "see" sounds and "hear" colors). These outward sensory effects have been referred to as the "mystical experience", and current research suggests that this state could be beneficial to the treatment of some mental illnesses, such as depression and possibly addiction. [ 15 ]  In instances where some patients have seen a lack of improvement from the use of antidepressants, serotonergic hallucinogens have been observed to be rather effective in treatment. [ 16 ]  In addition to the sensory-perceptual effects, hallucinogenic substances may induce feelings of depersonalization, emotional shifts to a euphoric or anxious/fearful state, and a disruption of logical thought. Hallucinogens are classified chemically as either  indolamines  (specifically  tryptamines ), sharing a common structure with serotonin, or as  phenethylamines , which share a common structure with norepinephrine. Both classes of these drugs are  agonists  at the 5-HT 2  receptors; this is thought to be the central component of their hallucinogenic properties. Activation of 5-HT 2A  may be particularly important for hallucinogenic activity. However, repeated exposure to hallucinogens leads to rapid tolerance, likely through down-regulation of these receptors in specific target cells. [ 1 ]  Research suggests that hallucinogens affect many of these receptor sites around the brain and that through these interactions, hallucinogenic substances may be capable of inducing positive introspective experiences. [ 16 ]  The current research implies that many of the effects that can be observed occur in the occipital lobe and the frontomedial cortex; however, they also present many secondary global effects in the brain that have not yet been connected to the substance's biochemical mechanism of action. [ 16 ]


Another class of hallucinogens, known as  dissociatives , includes drugs such as  ketamine ,  phencyclidine  (PCP), and  Salvia divinorum . Drugs such as these are thought to interact predominantly with glutamate receptors within the brain. Specifically, ketamine is thought to block NMDA receptors that are responsible for signalling in the glutamate pathways. [ 17 ]  Ketamine's more tranquilizing effects can be seen in the central nervous system through interactions with parts of the thalamus by inhibition of certain functions. [ 17 ]  Ketamine has become a major drug of research for the treatment of depression. [ 18 ]  These antidepressant effects are thought to be related to the drug's action on the glutamate receptor system and the relative spike in glutamate levels, as well as its interaction with mTOR, which is an enzymatic protein involved in catabolic processes in the human body. [ 19 ] [ 18 ]  Phencyclidine's biochemical properties are still mostly unknown; however, its use has been associated with dissociation, hallucinations, and in some cases seizures and death. [ 20 ]   Salvia divinorum , a plant native to Mexico, has strong dissociative and hallucinogenic properties when the dry leaves are smoked or chewed. [ 21 ]  The qualitative value of these effects, whether negative or positive, has been observed to vary between individuals with many other factors to consider. [ 21 ]


Hypnotics  are often used to treat the symptoms of insomnia or other sleep disorders. Benzodiazepines are still among the most widely prescribed sedative-hypnotics in the United States today. Certain non-benzodiazepine drugs are used as hypnotics as well. Although they lack the chemical structure of the benzodiazepines, their sedative effect is similarly through action on the GABA A  receptor. They also have a reputation of being less addictive than benzodiazepines.  Melatonin , a naturally-occurring hormone, is often used over the counter (OTC) to treat insomnia and jet lag. This hormone appears to be excreted by the pineal gland early during the sleep cycle and may contribute to human  circadian rhythms . Because OTC melatonin supplements are not subject to careful and consistent manufacturing, more specific melatonin agonists are sometimes preferred. They are used for their action on melatonin receptors in the  suprachiasmatic nucleus , responsible for sleep-wake cycles. Many barbiturates have or had an FDA-approved indication for use as sedative-hypnotics, but have become less widely used because of their limited safety margin in overdose, their potential for dependence, and the degree of  central nervous system depression  they induce. The amino-acid  L-tryptophan  is also available OTC, and seems to be free of dependence or abuse liability. However, it is not as powerful as the traditional hypnotics. Because of the possible role of serotonin in sleep patterns, a new generation of 5-HT 2  antagonists are in current development as hypnotics. [ 13 ]


Cannabis  consumption produces a dose-dependent state of intoxication in humans. There is commonly increased blood flow to the skin, which leads to an increased heart rate and sensations of warmth or flushing. It also frequently induces increased hunger. [ 1 ]  Iversen (2000) categorized the subjective and behavioral effects often associated with cannabis into three stages. The first is the "buzz", a brief period of initial responding where the main effects are lightheadedness or slight dizziness, in addition to possible tingling sensations in the extremities or other parts of the body. The "high" is characterized by feelings of euphoria and exhilaration characterized by mild psychedelia as well as a sense of disinhibition. If the individual has taken a sufficiently large dose of cannabis, the level of intoxication progresses to the stage of being "stoned", and the user may feel calm, relaxed, and possibly in a dreamlike state. Sensory reactions may include the feeling of floating, enhanced visual and auditory perception, visual illusions, or the perception of the slowing of time passage, which are somewhat psychedelic in nature. [ 22 ]


There exist two primary CNS cannabinoid receptors, on which marijuana and the cannabinoids act. Both the  CB 1  and  CB 2  receptor  are found in the brain. The CB 2  receptor is also found in the immune system. CB 1  is expressed at high densities in the  basal ganglia ,  cerebellum ,  hippocampus , and  cerebral cortex . Receptor activation can inhibit  cAMP  formation, inhibit voltage-sensitive calcium ion channels, and activate potassium ion channels. Many CB 1  receptors are located on axon terminals, where they act to inhibit the release of various neurotransmitters. In combination, these chemical actions work to alter various functions of the central nervous system, including the motor system, memory, and various cognitive processes. [ 1 ]


The  opioid  category of drugs – including drugs such as  heroin ,  morphine , and  oxycodone  – belong to the class of  narcotic   analgesics , which reduce pain without producing unconsciousness but do produce a sense of relaxation and sleep, and at high doses may result in coma and death. The ability of opioids (both  endogenous  and  exogenous ) to relieve pain depends on a complex set of neuronal pathways at the spinal cord level, as well as various locations above the spinal cord. Small  endorphin  neurons in the spinal cord act on receptors to decrease the conduction of pain signals from the spinal cord to higher brain centers. Descending neurons originating in the  periaqueductal gray  give rise to two pathways that further block pain signals in the spinal cord. The pathways begin in the locus coeruleus (noradrenaline) and the nucleus of raphe (serotonin). Similar to other abused substances, opioid drugs increase dopamine release in the  nucleus accumbens . [ 1 ]  Opioids are more likely to produce  physical dependence  worse than that of other classes of psychoactive drugs, and can lead to painful withdrawal symptoms if discontinued abruptly after regular use.


Cocaine  is one of the more common stimulants and is a complex drug that interacts with various neurotransmitter systems. It commonly causes heightened alertness, increased confidence, feelings of exhilaration, reduced fatigue, and a generalized sense of well-being. The effects of cocaine are similar to those of amphetamines, though cocaine tends to have a shorter duration of effect. In high doses or with prolonged use, cocaine can result in a number of negative effects, including irritability, anxiety, exhaustion, total insomnia, and even psychotic symptomatology. Most of the behavioral and physiological actions of cocaine can be explained by its ability to block the reuptake of the two  catecholamines , dopamine and norepinephrine, as well as serotonin. Cocaine binds to transporters that normally clear these transmitters from the synaptic cleft, inhibiting their function. This leads to increased levels of neurotransmitter in the cleft and transmission at the synapses. [ 1 ]  Based on in-vitro studies using rat brain tissue, cocaine binds most strongly to the serotonin transporter, followed by the dopamine transporter, and then the norepinephrine transporter. [ 23 ]


Amphetamines  tend to cause the same behavioral and subjective effects of cocaine. Various forms of amphetamine are commonly used to treat the symptoms of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy , or are used recreationally. Amphetamine and  methamphetamine  are indirect agonists of the catecholaminergic systems. They block catecholamine reuptake, in addition to releasing catecholamines from nerve terminals. There is evidence that dopamine receptors play a central role in the behavioral responses of animals to cocaine, amphetamines, and other psychostimulant drugs. One action causes the dopamine molecules to be released from inside the vesicles into the cytoplasm of the nerve terminal, which are then transported outside by the  mesolimbic  dopamine pathway to the nucleus accumbens. This plays a key role in the rewarding and reinforcing effects of cocaine and amphetamine in animals, and is the primary mechanism for amphetamine dependence. [ citation needed ]


In psychopharmacology, researchers are interested in any substance that crosses the  blood–brain barrier  and thus has an effect on behavior, mood, or cognition. Drugs are researched for their physiochemical properties, physical  side effects , and psychological side effects. Researchers in psychopharmacology study a variety of different psychoactive substances, including alcohol, cannabinoids,  club drugs , psychedelics, opiates,  nicotine ,  caffeine ,  psychomotor stimulants ,  inhalants , and  anabolic–androgenic steroids . They also study drugs used in the treatment of affective and anxiety disorders, as well as  schizophrenia .


Clinical studies are often very specific, typically beginning with animal testing and ending with human testing. In the human testing phase, there is often a group of subjects: one group is given a placebo, and the other is administered a carefully measured  therapeutic dose  of the drug in question. After all of the testing is completed, the drug is proposed to the concerned regulatory authority (e.g. the U.S.  FDA ), and is either commercially introduced to the public via  prescription , or deemed safe enough for  over-the-counter  sale.


Though particular drugs are prescribed for specific symptoms or syndromes, they are usually not specific to the treatment of any single mental disorder.


A somewhat controversial application of psychopharmacology is "cosmetic psychiatry": persons who do not meet criteria for any psychiatric disorder are nevertheless prescribed psychotropic medication. The antidepressant  bupropion  is then prescribed to increase perceived energy levels and assertiveness while diminishing the need for sleep. The antihypertensive compound  propranolol  is sometimes chosen to eliminate the discomfort of day-to-day anxiety.  Fluoxetine  in nondepressed people can produce a feeling of generalized well-being.  Pramipexole , a treatment for restless leg syndrome, can dramatically increase libido in women. These and other off-label lifestyle applications of medications are not uncommon. Although occasionally reported in the medical literature, no guidelines for such usage have been developed. [ 24 ]  There is also a potential for the misuse of prescription psychoactive drugs by elderly persons, who may have multiple drug prescriptions. [ 25 ] [ 26 ]


Psychoplastogens  are a group of  small molecule drugs  that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. [ 1 ] [ 2 ]  Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including  ketamine ,  MDMA ,  scopolamine , and the  serotonergic psychedelics , including  LSD ,  psilocin  (the active metabolite of  psilocybin ),  DMT , and  5-MeO-DMT . Compounds of this sort are being explored as therapeutics for a variety of  brain disorders  including  depression ,  addiction , and  PTSD . The ability to rapidly promote neuronal changes via mechanisms of  neuroplasticity  was recently discovered as the common therapeutic activity and mechanism of action. [ 3 ]


The term psychoplastogen comes from the Greek roots  psych - (mind), - plast  (molded), and - gen  (producing) and covers a variety of chemotypes and receptor targets. It was coined by  David E. Olson  in collaboration with Valentina Popescu, both at the University of California, Davis. [ 3 ]


The term neuroplastogen is sometimes used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic.


Psychoplastogens come in a variety of  chemotypes  and chemical families, but, by definition, are small-molecule drugs. [ 1 ]  Ketamine has been described as, "the prototypical psychoplastogen". [ 3 ]


Psychoplastogens exert their effects by promoting structural and functional  neural plasticity  through diverse targets including, but not limited to,  5-HT2A ,  NMDA , and  muscarinic receptors . Some are  biased agonists . While each compound may have a different receptor binding profile, signaling appears to converge at the  tyrosine kinase B  (TrkB) and  mammalian target of rapamycin  (mTOR) pathways. [ 3 ] [ 4 ]  Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset. [ 5 ]


Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently. In addition to the  neuroplasticity  effects, these compounds can have other epiphenomena including sedation, dissociation, and hallucinations. [ 6 ]


Psychedelics  show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances. [ 7 ]  Single doses of  DMT ,  5-MeO-DMT ,  psilocybin , and  DOI  have been found to produce robust and long-lasting increases in neuroplasticity in animals. [ 7 ]  Likewise, repeated doses of  LSD  for 7   days increased neuroplasticity. [ 7 ]  However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation. [ 7 ]  In addition, DOI has been found to decrease  brain-derived neurotrophic factor  (BDNF) levels in the  hippocampus . [ 7 ]  The effects of psychedelics on neuroplasticity appear to be dependent on  serotonin   5-HT 2A  receptor  activation, as they are abolished in 5-HT 2A  receptor  knockout mice . [ 7 ]  Non-hallucinogenic serotonin 5-HT 2A  receptor agonists, like  tabernanthalog  and  lisuride , have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics. [ 7 ]


In terms of  neurogenesis , DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and  25I-NBOMe  decreased hippocampal neurogenesis. [ 7 ]  5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by  sigma   σ 1  receptor   antagonists . [ 7 ]


Several psychoplastogens have either been approved or are in development for the treatment of a variety of brain disorders associated with neuronal atrophy where neuroplasticity can elicit beneficial effects. [ 6 ]


Esketamine , sold under the brand name Spravato and produced by  Janssen Pharmaceuticals , was approved by the  FDA  in March 2019 for the treatment of  Treatment-Resistant Depression  (TRD) and  suicidal ideation . [ 8 ]  As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder. [ 6 ]  Esketamine is the S(+)  enantiomer  of ketamine and functions as an  NMDA receptor  antagonist. [ 9 ]


Other psychoplastogens that are being investigated in the clinic include:


Miodrag (Misha) Radulovacki  ( Serbian Cyrillic : Миодраг Радуловачки;  Serbian Latin : Miodrag Radulovački), was a  Serbian American  scientist and inventor.  He was Professor of  Pharmacology  in the  College of Medicine at the University of Illinois at Chicago  (UIC), [ 1 ]  Radulovacki's research accomplishments include: (1) the  Adenosine  Sleep Theory, [ 2 ]  and (2) pioneering pharmacological studies for the treatment of  sleep apnea , [ 3 ]  together with research collaborator, David W. Carley, [ 4 ]  (Professor of Medicine at the UIC). Radulovacki and Carley invented several  drug therapies  for the treatment of sleep apnea which have been patented by the UIC. The UIC recognized them as the 2010 "Inventors of the Year." [ 5 ] [ 6 ]  Radulovacki published more than 170 scientific papers. [ 7 ]  Radulovacki was also a Foreign Member of the  Serbian Academy of Sciences and Arts . [ 8 ]


Miodrag Radulovacki was born on April 28, 1933, in  Parage , a village in northwestern  Serbia . Both of his parents were  elementary school   teachers . At the beginning of  World War II , Radulovacki's father was drafted into the  Yugoslav Army  and was later taken prisoner by the invading  Germans . [ citation needed ]


In 1943, Radulovacki moved to  Sremski Karlovci  after his mother accepted a teaching position in the town.  Sremski Karlovci (also known as Karlovci), a  baroque  Serbian town on the banks of the  Danube River , had been home to the Radulovacki family for over 200 years. [ citation needed ]  Radulovacki attended  Karlovci High School  or "Gymnasium," which is the oldest high school in Serbia. [ 9 ] [ 10 ]  Radulovacki called Karlovci Gymnasium the "Serbian  Cambridge  and  Oxford ". [ 9 ] [ 10 ]  Radulovacki graduated as  valedictorian  of the Karlovci High School Class of 1951. [ 9 ] [ 10 ]  Radulovacki gained admission to the  University of Belgrade   School of Medicine . [ 9 ] [ 10 ]


Radulovacki graduated from the University of Belgrade School of Medicine in 1959. [ 11 ] [ 12 ] [ 13 ]  He went on to obtain a  PhD  in  Neurophysiology . [ 12 ] [ 13 ]  The topic of his PhD thesis was: "Sleep in Split-Brain Cats," partly done at the Brain Research Institute at UCLA. [ citation needed ]


Radulovacki spent 18 months at the  University of California, Los Angeles  (UCLA) Brain Research Institute [ 14 ] [ failed verification ]  where his mentor was Ross Adey. [ 15 ]  One of the findings of his research at UCLA was that the  electroencephalographic  (EEG) pattern of sleep in cats with split brain to the  pons  is synchronous in both  brain hemispheres , indicating the importance of the  brainstem  in sleep regulation. [ 11 ] [ 16 ]


In 1966, Radulovacki accepted a teaching position with the  Physiology  Department in the College of Medicine at the  University of Khartoum ,  Sudan . [ 11 ]  There he invented an approach for obtaining  cerebrospinal fluid  using a  cannula  to the  cisterna magna  in the brain of cats. The cannulation method enabled researchers to obtain cerebrospinal fluid during sleep and wakefulness for the analysis of  monoamine   metabolites . [ 17 ]  This approach was of interest since  Michel Jouvet 's  Monoamine  Theory of Sleep, [ 18 ]  with  serotonin  as the sleep inducing agent, was dominant at the time. From 1970 to 1984, at the University of Illinois, Radulovacki published a series of papers dealing with the role of monoamines in sleep. [ 7 ]


In 1970, Radulovacki was recruited by Klaus Unna [ 19 ]   to join the Department of Pharmacology in the College of Medicine at the University of Illinois at Chicago as an Assistant Professor. [ 11 ]  Radulovacki published more than 170 scientific papers during his career at the UIC. [ 7 ]


In 1984, Radulovacki postulated the Adenosine Sleep Theory, (JPET, 228: 268-274, 1984). [ 20 ]  The idea for adenosine's role in sleep occurred to him after reading a paper by  Sol Snyder 's group (Proc. Natl. Acad. Sci, 78: 3260-64, 1981) [ 21 ]  about the importance of adenosine receptors in the behavioral actions of  methylxanthines . In the article, the authors correlated the behavioral excitation produced by  theophylline  in  micromolar  concentrations with the blockade of adenosine  receptors .


Radulovacki reasoned that if the blocking of adenosine receptors produces excitation, then perhaps stimulation of the same receptors could induce sleep. [ 22 ]  He knew that experiments by John Phillis and his group (Can. J. Physiol. Pharmacol. 57:1289-1312, 1979), [ 23 ]  which utilized an  iontophoretic  application of adenosine in the brain, had demonstrated adenosine's  depressant  effect on the responses of  neurons  in several brain regions and that the general  neurophysiological  effects of adenosine were shown to be inhibitory. In addition, the preliminary experiments in dogs by Haulica  et al.  (J. Neurochem. 21:,1019–20, 1973) [ 24 ]  and the administration of adenosine into the brains of rats, cats and fowl suggested that adenosine was able to produce  behavioral   sleep . The explanation of adenosine's  hypnotic  effect was through its interaction with  serotonin , widely believed to be a sleep inducing agent. However, since there was no suggestion how this adenosine-serotonin link was achieved, experiments highlighting the potential role of adenosine in sleep had largely been forgotten.


In 1993, Radulovacki started a collaboration with David W. Carley, a Professor of  Medicine ,  Bioengineering  and Pharmacology at the UIC. Their research efforts focused on developing pharmacological approaches for the treatment of  sleep apnea . [ 25 ]  Since there were no medicines to alleviate this condition, Radulovacki and Carley set out to develop a  drug treatment . [ 26 ]  Their initial work focussed on an  experimental   model  of sleep apnea in rats, initially testing the effects of adenosine compounds. [ 27 ]  Eventually, they obtained positive results using serotonin and other compounds. As a result, the UIC  patented  their discoveries, obtaining numerous US and international patents. [ 28 ]


Patents for sleep and sleep-related disorders include:


Radulovacki was named the 2010 Inventor of the Year at the University of Illinois, alongside Carley. [ 5 ]  Radulovacki and Carley were honored by the University of Illinois for producing a dozen potential treatments for sleep apnea, many of which are now under consideration for commercial development. [ 38 ]  Their results have culminated in an IllinoisVentures-supported start-up company, Pier Pharmaceuticals, that focuses on the treatment of obstructive sleep apnea. [ 39 ]


In October 2003, the Serbian Academy of Sciences and Arts in Belgrade elected Radulovacki as one of its Foreign Members for his significant scientific research contributions in the fields of Neuropharmacology, sleep disorders and sleep-related breathing disorders. [ 8 ]


In 1990, Radulovacki initiated the Yugoslav Student Summer Program at the  University of Illinois  at Chicago (UIC) and the University of Illinois at  Champaign-Urbana  (UIUC) after the creation of International Linkage Agreements between the UIC and the Universities of Belgrade and  Novi Sad  in Yugoslavia. [ 40 ]  The Yugoslav Student Summer Program lasted for 12 years and had 304 participants. [ 41 ]


In 2005, Radulovacki established the Miodrag Radulovacki Family Prize for Excellence in Basic Sciences at the University of Illinois College of Medicine at Chicago. [ 11 ]  The purpose of the prize, given annually, is to honor a fourth year Medical student who displays a high degree of intellectual integrity and who has demonstrated strong academic achievement. The prize consists of a plaque and a check for $1,000.


Radulovacki made numerous contributions to his home town of  Sremski Karlovci .


Radulovacki lived in  Chicago . He was a  cross-country skier . [ 12 ]  He participated in several Birkebeiner-Kortelopet cross-country ski marathons in Cable-Hayward,  Wisconsin . [ citation needed ]  Radulovacki died on May 27, 2014, in Belgrade, Serbia, while on two-week trip to promote his philanthropic projects.  He is survived by two sons (Brad Radulovacki and Branko Radulovacki) and four grandchildren (Grant, Katie, Reid and Ryan). [ 46 ] [ 47 ]


Reward dependence  ( RD ) is characterized as a tendency to respond markedly to signals of  reward , particularly to verbal signals of social approval, social support, and sentiment. [ 1 ]  When reward dependence levels deviate from normal we see the rise of several personality and addictive disorders.


In  psychology , reward dependence is considered a moderately heritable  personality trait  which is stable throughout our lives. It is an inherited neurophysiological mechanism that drives our perception of our society and the environment. Even though we are born with these personality traits, their expression during our life span can be modulated throughout our development.


Reward dependence is one of the  temperament  dimensions from the  "tridimensional personality theory" , which was proposed by  C. Robert Cloninger  as part of his "unified bio-social theory of personality". [ 2 ]  His personality theory suggested the hypothesis that specific  neurochemical transmitters  in our brain determine how we respond to a specific stimulus we may experience.


These innate personality traits can play a significant role not only in an individual's predisposition to certain disorders, but also in their maintenance of those disorders.


By understanding the specific temperamental traits that are common among individuals with specific disorders, clinicians can form a more targeted, informed approach to treatment and look to newer psychotherapies for guidance. The relationship between temperament and individual clusters of  DSM  personality disorders is often investigated. According to the DSM-IV, [ 3 ]  the tridimensional structure allows up to nine major  personality disorders  to be identified, the theory thereby making a great contribution to the understanding of psychiatric disorders.


Cloninger's tridimensional personality theory offers three independent "temperament" dimensions which aid in measuring how different individuals feel or behave. Reward Dependence (RD) is one of the three temperament dimensions, the other two being  "Harm Avoidance (HA)"  and  "Novelty Seeking (NS)" . A temperament, according to Cloninger, is the automatic emotional response to experience. [ 4 ]


Cloninger suggested that RD is influenced by a single  monoamine neurotransmitter  system: the  noradrenergic  system  [ 2 ]  and RD is correlated with low basal noradrenergic activity. This suggestion has led to several research experiments that have investigated and supported his hypothesis, that RD traits are indeed in part determined by norepinephrine. [ 5 ] [ 6 ] [ 7 ]


Measure of the RD dimension, as suggested by Cloninger, is used to assess the Altruistic-warm  versus  detached-tough mindedness components of our personalities.


According to Cloninger's theory, [ 8 ]  individuals  high  in reward dependence and  low  in norepinephrine levels are ambitious, warm, sentimental, pleasant, sociable, sensitive, sympathetic and socially dependent. Individuals with high RD personalities have a disposition to recognize salient social cues which in turn facilitates effective communication, warm social relations, and their genuine care for others, but these individuals are then disadvantaged in being excessively socially dependent. High reward dependent individuals also exhibit persistent behaviors and are easily influenced by emotional appeals.


Individuals  low  in reward dependence and  high  in norepinephrine levels are then hypothesized to be typically independent, non-conformist, practical, tough-minded, cynical, unwilling to share their intimate feelings with others, socially detached, irresolute, insensitive to social cues and pressures, and content to be alone. They are also minimally motivated to please others and act for immediate gratification. So being low in reward dependence is related to social withdrawal, with aggressive anti-social behavior, [ 9 ] [ 10 ]  detachment, and coldness in social attitudes. [ 11 ]


The RD temperament interacts with other temperaments and  characters  inherent in us enabling us to adapt to life experiences and influence susceptibility to emotional and behavioral disorders [ 11 ]


Two questionnaires were devised by Cloninger to measure the temperaments and characters of individuals. RD can be measured using both the  Tridimensional Personality Questionnaire  (TPQ) personality test and by the newer and refined version of the personality test called  Temperament and Character Inventory  (TCI) and its revised version (TCI-R). Owing to the limitations encountered in the TPQ, in that the three dimensions' clinical utility was not readily apparent to many clinicians, [ 12 ]  Cloninger revamped the questionnaire and produced the TCI scale, which incorporates four dimensions of "temperament" and three dimensions of "character".


The so-called subscales of RD in TCI-R are


A study comparing the TCI to the  five factor model  of personality found that reward dependence was substantially positively associated with  extraversion  and to a lesser extent  openness to experience . [ 13 ]


Cloninger describes reward dependence as being a prime component of the  Behavior   maintenance  System (BMS). [ 6 ]   Norepinephrine  (NE), apart from producing alertness and arousal, is seen as influencing the brain reward system [ 14 ]  by aiding in the learning of new paired  associations . [ 15 ]


According to Cloninger, the norepinephrine neurotransmitter has its major ascending pathways arising in the locus coeruleus in the  pons , projecting onward to the  hypothalamic  and  limbic structures , and then branching upwards to the  neocortex . [ 16 ]


Cloninger's theory suggests that over  expression  of the RD temperament could cause psychiatric illnesses, such as  addictive behaviors ,  sociopathies , and  personality disorders . [ 22 ]


Low levels of norepinephrine cause an increase in reward dependence. When produced in normal levels, norepinephrine creates a sense of well-being, but low levels of norepinephrine cause symptoms of  depression , lack of  arousal  and lack of  motivation . In humans, this leads to then a  negative feedback  mechanism whereby we seek out pleasurable activities to remove the negative  affect  caused by the low levels of norepinephrine, therefore increasing our reward dependence.


An increase in the RD temperament leads us to seek out those behaviors or substances that will allow us to remain in a pleasant physical and/or mental state, attributing to the fact that we humans are  hedonistic  individuals, seeking to avoid pain and embracing pleasurable stimuli. [ 23 ]  Our pleasure and reward systems in the brain are hyper-activated, which makes us display continuous approach behaviors to the reward in question. Our neuro-circuitry is as such that when we stop having access to such pleasurable objects of desire, we then experience negative consequences ( withdrawal  symptoms). Addictive behaviors then arise to alleviate such negative consequences and the cycle continues. [ 24 ]


People who have high reward dependent personalities but find themselves in situations where they are unable to find rewards and approval through family support or other types, will seek reward through other means e.g.  substance abuse  or over-eating. It is then suggested that individuals with such predispositions should adopt preventive strategies or avoid such situations, where they seek such rewards that could potentially have adverse consequences. [ 20 ]  Reward dependence drives behavior maintenance systems, and in addictive behaviors, maintenance of behaviors occurs despite adverse consequences.


According to researchers the reward circuit is continuously involved in initiating behaviors that are essential for the sustenance of the individual (such as eating) or of the preservation of the species (such as sexual reproduction). Food intake or sexual stimuli then lead to endorphin regulated release of dopamine in core substrates of the reward processing system, which subsequently activate  craving  sensations. The development of addictions is then directly related to the acquired or genetic abuse of the reward circuit. This finding then suggests that individuals with increased reward dependence have a relative deficit of endorphins and are possibly at higher risk for developing addictive behaviors. [ 19 ]


Adolescents  low in reward dependence may find conventional sources of reward unfulfilling (e.g., academic achievement or activities involving social affiliation), and eventually turn to unconventional reward sources (e.g.,  smoking  and other forms of substance misuse) to derive satisfaction and pleasure. [ 25 ]  A study conducted using adolescents with Excessive Internet video Game Play (EIGP) showed that such addictive behaviors were correlated with higher RD scores on the TCI, [ 26 ]  whereas both low and high scores of RD were implicated in specific alcoholic and drug addictions.


Social reward dependence is hypothesized to be related to behaviors that represent the RD personality dimension sub-scales of  social sensitivity  and attachment. It is suggested that the brain substrates that are involved in the response to simple primary rewards stimuli are also implicated in the response to complex social rewards stimuli. The RD sub-scale from the TCI inventory measures how sensitive individuals are to social rewards. High RD scores on the test correlate to increased attachment and an increased need for social relationships. Low RD scores show a movement towards social detachment and insensitivity. [ 21 ]


At the 2010 Annual meeting of the  American Psychological Association  (APA), a study looking at treatment methods of personality disorders was presented in which it was found, that panic disorder patients with higher RD scores were more resistant to  Escitalopram  treatment. Since long-term  pharmacotherapy  is needed for treatment of panic disorder, the present results suggest that development of therapeutic strategy for panic patients with high reward dependence is needed. [ 40 ]


In response to  a lack of social reward , individuals with high reward dependence are more likely to have increased noradrenergic activity. These individuals experience feelings of depression,  agitation  and extreme discontent, leading them to indulge in habits that reinforce reward-seeking, such as increased sexual activity or overeating. [ 2 ]


Individuals with higher reward dependence also look for more social approval, and are more inclined to succumb to peer-pressure. They often become overly concerned with their  body image  and maybe prone to eating disorders, such as  Bulimia nervosa . [ 41 ]  Whereas restricting  anorexia , in particular, tends to reflect low reward dependence. [ 42 ]


Reward dependence is not consistently associated with diagnosis but can also significantly affect treatment issues, such as  Therapeutic alliance . Persistence in completing  weight-loss programs  were related to high RD scores during pre-treatment. This demonstrates that, having higher reward dependence enhances an individual's disposition to being more dedicated and sociable, making them increasingly respond to societal pressures, thereby reducing their risk of dropping out from weight-loss programs. [ medical citation needed ]


A study of norepinephrine levels in gamblers found high  cerebrospinal fluid  (CSF) levels of the norepinephrine (NE) metabolite 3-methoq-4-hydroxyphenylglycol (MI-IPG). [ 43 ]  This could suggest a relationship between the noradrenergic system and gambling, and gambling could be seen as a reward-dependent behavior, but according to Cloninger's theory these gamblers should exhibit low levels of NE, not high. Cloninger suggests that had these gamblers been retested after they had refrained from gambling for a determined period, their CSF MHPG levels might have been low. [ 12 ]  A study of norepinephrine levels in alcoholics with high reward dependence also showed a significant decrease of MHPG in their CSF. [ 44 ]  This finding demonstrates a significant relationship between reward dependence and norepinephrine.


Several genes have also been found to express the RD temperament dimension. Specifically, the gene  MAOA-uVNTR  has been highly implicated in evoking the RD personality trait. [ 45 ]


The Ritalin class-action lawsuits  were a series of federal lawsuits in 2000, filed in five separate US states. [ 1 ]  All five lawsuits were dismissed by the end of 2002. The lawsuits alleged that the makers of  methylphenidate  (brand name Ritalin) and the  American Psychiatric Association  had conspired to invent and promote the disorder  ADHD  to create a highly profitable market for the drug. The lawsuit also alleged that  CHADD  (children and adults with attention deficit/hyperactivity disorder) deliberately attempted to increase the supply of Ritalin and ease restrictions on the supply of Ritalin to help increase profits for  Novartis .


Beginning in the 1980s, a series of lawsuits were filed based on the perceived harmful side effects of Ritalin.  John Coale , who had participated in one of these lawsuits, joined what became an ever larger contingent of lawyers involved in what was then a growing series of Ritalin class action lawsuits. In the late 1990s, there was a significant increase in production of Ritalin. A minority but vocal group of critics perceived that a crisis was on hand. [ 2 ]  Coale also expressed alarm, "They were giving this stuff away like candy". The  Church of Scientology  advocacy organization,  Citizens Commission on Human Rights , and  anti-psychiatry  critics believed Ritalin to be highly dangerous and completely unnecessary. Coale seemed to share these beliefs as he stated the purpose of the lawsuit to be; "...to put [Ritalin] off the market." [ 3 ]  The  St. Petersburg Times  wrote at that time that Coale, like his wife  Greta Van Susteren , was a practicing Scientologist. [ 4 ]   Richard Scruggs , like John Coale, and a few other lawyers who participated in the Ritalin class action lawsuits, had previously helped win a landmark settlement from the asbestos and tobacco industries, Ritalin was to be the next major battleground. Scruggs would lead and also become a spokesman for the plaintiffs. He asserted the Ritalin defendants, "manufactured a disease"...and "it has been grossly over-prescribed. It is a huge risk." [ 5 ]   Peter Breggin  who is a noted psychiatrist and industry critic, was hired as a medical consultant by the firm and was also involved as a consultant in the other lawsuits. [ 6 ]


The first class action was filed in Texas by the law firm Waters & Kraus in 2000. They created a webpage called Ritalinfraud.com which had an online form to seek additional participants in class action lawsuits. According to Breggin, plaintiff Andy Waters had previously read his book  Talking back to Ritalin  before filing his lawsuit.  The firm believed that the improper conduct of Novartis rivaled the improper conduct of the tobacco and asbestos industries and that the drug company could be liable for billions of dollars. The firm claimed that Novartis specifically took the following steps to dramatically increase the sale of Ritalin. [ citation needed ]


A spokesperson for Novartis responded to the Texas suit, "Ritalin has been used safely and effectively in the treatment of millions of ADHD patients for over 40 years, and is the most studied drug prescribed for the disorder." [ 7 ]


The American Psychiatric Association stated, "the allegation that it had conspired with Novartis to create the ADHD diagnosis was "ludicrous and totally false," and said there existed "a mountain of scientific evidence to refute these meritless allegations." [ 7 ]


The first suit to be dismissed occurred in California in 2001. U.S. District Judge Rudi Brewster dismissed the suit under California's anti- SLAPP  statute. A SLAPP (strategic lawsuit against public participation) is a form of litigation filed to intimidate and silence a less powerful critic by so severely burdening them with the cost of a legal defense that they abandon their criticism. The Anti-SLAPP statute is designed to eliminate potential lawsuits that are in reality political actions by stopping them early in court procedures. Judge Brewster dismissed the suit stating that the defendants' speech is "protected under both the United States and California Constitutions" and that plaintiffs "failed to state a cause of action." In addition to dismissing the suit, the court also ordered that the plaintiffs pay the legal fees for Novartis, APA and CHADD.


In the conclusion to one of the other lawsuits, Judge Tagla stated "that the allegations were fully without merit. Plaintiffs failed to provide any concrete statements to document their claims." [ 8 ]


By 2002 all five class action lawsuits had been dismissed or had been withdrawn. A Novartis spokesperson stated;"...the fact that all five of the class action lawsuits have been dismissed, sends a strong message that the decision of how to treat ADHD is between the parent, patient and physician, and has no place in the courts."


Arsenic biochemistry  is the set of  biochemical  processes that can use  arsenic  or its compounds, such as  arsenate . Arsenic is a  moderately abundant element in Earth's crust , and although many arsenic compounds are often considered  highly toxic  to most life, a wide variety of  organoarsenic compounds  are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous  organisms . This pattern is general for other related elements, including  selenium , which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some  aquifers , [ 1 ]  potentially affecting many millions of people via biochemical processes. [ 2 ]


The evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed has been reviewed. [ 3 ]  Some organoarsenic compounds found in nature are  arsenobetaine  and arsenocholine, [ 4 ]  both being found in many marine organisms. [ 2 ]   Some As-containing  nucleosides  (sugar derivatives) are also known. [ 5 ]   Several of these organoarsenic compounds arise via  methylation  processes.  For example, the mold  Scopulariopsis brevicaulis  produces significant amounts of  trimethylarsine  if inorganic arsenic is present. [ 6 ]  The organic compound  arsenobetaine  is found in some marine foods such as fish and algae, and also in mushrooms in larger concentrations. In clean environments, the edible mushroom species  Cyanoboletus pulverulentus  hyperaccumulates arsenic in concentrations reaching even 1,300 mg/kg in dry weight;  cacodylic acid  is the major As compound. [ 7 ]  A very unusual composition of organoarsenic compounds was found in deer truffles ( Elaphomyces  spp.). [ 8 ]  The average person's intake is about 10–50 μg/day. Values about 1000 μg are not unusual following consumption of fish or mushrooms; however, there is little danger in eating fish since this arsenic compound is nearly non-toxic. [ 9 ]


A topical source of arsenic are the green pigments once popular in wallpapers, e.g.  Paris green . A variety of illness have been blamed on this compound, although its toxicity has been exaggerated. [ 10 ]


Trimethylarsine , once known as Gosio's gas, is an intensely malodorous organoarsenic compound that is commonly produced by microbial action on inorganic arsenic substrates. [ 11 ]


Arsenic (V) compounds are easily reduced to arsenic (III) and could have served as an electron acceptor on primordial Earth. [ 12 ]  Lakes that contain a substantial amount of dissolved inorganic arsenic, harbor arsenic-tolerant  biota .


Although phosphate and arsenate are structurally similar, there is no evidence that arsenic replaces phosphorus in  DNA  or  RNA . [ 13 ]   A 2010 experiment involving the bacteria  GFAJ-1  that made this claim was refuted by 2012. [ 14 ] [ 15 ]


Anthropogenic (man-made) sources of arsenic, like the natural sources, are mainly arsenic oxides and the associated anions. Man-made sources of arsenic, include wastes from mineral processing, swine and poultry farms. [ 16 ]  For example, many ores, especially  sulfide minerals , are contaminated with arsenic, which is released in  roasting  (burning in air). In such processing,  arsenide  is converted to  arsenic trioxide , which is volatile at high temperatures and is released into the atmosphere. Poultry and swine farms make heavy use of the organoarsenic compound  roxarsone  as an  antibiotic  in feed. [ 17 ] [ 18 ]  Some wood is treated with copper arsenates as a preservative. The mechanisms by which these sources affect "downstream" living organisms remains uncertain but are probably diverse. One commonly cited pathway involves  methylation . [ 19 ]


The monomethylated acid, methanearsonic acid (CH 3 AsO(OH) 2 ), is a precursor to fungicides (tradename Neoasozin) in the cultivation of rice and cotton.  Derivatives of  phenylarsonic acid  (C 6 H 5 AsO(OH) 2 ) are used as feed additives for livestock, including  4-hydroxy-3-nitrobenzenearsonic acid  (3-NHPAA or Roxarsone), ureidophenylarsonic acid, and   p -arsanilic acid .  These applications are controversial as they introduce soluble forms of arsenic into the environment.


Despite, or possibly because of, its long-known toxicity, arsenic-containing potions and drugs have a history in  medicine  and  quackery  that continues into the 21st century. [ 20 ] [ 21 ]   Starting in the early 19th century and continuing into the 20th century,  Fowler's solution , a toxic concoction of  sodium arsenite , was sold. The organoarsenic compound  Salvarsan  was the first  synthetic   chemotherapeutic agent , discovered by  Paul Ehrlich . [ 21 ]  The treatment, however, led to many problems causing long lasting health complications. [ 22 ]   Around 1943 it was finally superseded by  penicillin .
The related drug  Melarsoprol  is still in use against late-state  African trypanosomiasis  (sleeping sickness), despite its high toxicity and possibly fatal side effects.


Arsenic trioxide  (As 2 O 3 ) inhibits cell growth and induces  apoptosis  (programmed cell death) in certain types of cancer cells, [ 23 ]  which are normally immortal and can multiply without limit. In combination with  all-trans retinoic acid , it is FDA-approved as first-line treatment for  promyelocytic leukemia .


Inorganic arsenic and its compounds, upon entering the  food chain , are progressively metabolised (detoxified) through a process of  methylation . [ 19 ]  The methylation occurs through alternating reductive and oxidative methylation reactions, that is, reduction of pentavalent to trivalent arsenic followed by addition of a  methyl group  (CH 3 ). [ 24 ]


In mammals, methylation occurs in the liver by  methyltransferases , the products being the (CH 3 ) 2 AsOH ( dimethylarsinous acid ) and (CH 3 ) 2 As(O)OH ( dimethylarsinic acid ), which have the oxidation states As(III) and As(V), respectively. [ 2 ]   Although the mechanism of methylation of arsenic in humans has not been elucidated, the source of  methyl  is  methionine , which suggests a role of  S-adenosyl methionine . [ 25 ]   Exposure to toxic doses begin when the liver's methylation capacity is exceeded or inhibited.


There are two major forms of arsenic that can enter the body, arsenic (III) and arsenic (V). [ 26 ]  Arsenic (III) enters the cells though  aquaporins  7 and 9, which is a type of aquaglyceroporin. [ 26 ]  Arsenic (V) compounds use phosphate transporters to enter cells. [ 26 ]  The arsenic (V) can be converted to arsenic (III) by the enzyme  purine nucleoside phosphorylase . [ 26 ]  This is classified as a bioactivation step, as although arsenic (III) is more toxic, it is more readily methylated. [ 27 ]


There are two routes by which inorganic arsenic compounds are methylated. [ 28 ]  The first route uses Cyt19 arsenic methyltransferase to methylate arsenic (III) to a mono-methylated arsenic (V) compound. [ 26 ]  This compound is then converted to a mono-methylated arsenic (III) compound using Glutathione S-Transferase Omega-1 ( GSTO1 ). [ 26 ]  The mono-methylated arsenic (V) compound can then be methylated again by Cyt19 arsenic methyltransferase, which forms a dimethyl arsenic (V) compound, which can be converted to a dimethyl arsenic (III) compound by Glutathione S-Transferase Omega-1 (GTSO1). [ 26 ]  The other route uses  glutathione  (GSH) to conjugate with arsenic (III) to form an arsenic (GS)  3  complex. [ 26 ]  This complex can form a monomethylated arsenic (III) GS complex, using Cyt19 arsenic methyltransferase, and this monomethylated GS complex is in equilibrium with the monomethylated arsenic (III). [ 26 ]  Cyt19 arsenic methyltransferase can methylate the complex one more time, and this forms a dimethylated arsenic GS complex, which is in equilibrium with a dimethyl arsenic (III) complex. [ 26 ]  Both of the mono-methylated and di-methylated arsenic compounds can readily be excreted in urine. [ 27 ]  However, the monomethylated compound was shown to  be more reactive and more toxic than the inorganic arsenic compounds to human  hepatocytes  (liver), keratinocytes in the skin, and bronchial epithelial cells (lungs). [ 29 ]


Studies in experimental animals and humans show that both inorganic arsenic and methylated metabolites cross the  placenta  to the  fetus , however, there is evidence that methylation is increased during pregnancy and that it could be highly protective for the developing organism. [ 30 ]


Enzymatic methylation of arsenic is a detoxification process; it can be methylated to methylarsenite, dimethylarsenite or trimethylarsenite, all of which are trivalent. The methylation is catalyzed by arsenic  methyltransferase  (AS3MT) in mammals, which transfers a methyl group on the  cofactor  S-adenomethionine (SAM) to arsenic (III). An orthologue of AS3MT is found in bacteria and is called CmArsM. This enzyme was tested in three states (ligand free, arsenic (III) bound and SAM bound). Arsenic (III) binding sites usually use thiol groups of cysteine residues. The catalysis involves thiolates of Cys72, Cys174, and Cys224. In an SN2 reaction, the positive charge on the SAM sulfur atom pulls the bonding electron from the carbon of the methyl group, which interacts with the arsenic lone pair to form an As−C bond, leaving SAH. [ 31 ]


In humans, the major route of excretion of most arsenic compounds is via the  urine . The biological  half-life  of inorganic arsenic is about 4 days, but is slightly shorter following exposure to arsenate than to arsenite.  The main metabolites excreted in the urine of humans exposed to inorganic arsenic are mono- and dimethylated  arsenic acids , together with some unmetabolized inorganic arsenic. [ 25 ]


The biotransformation of arsenic for excretion is primarily done through the nuclear factor erythroid 2 related factor 2 ( Nrf2 ) pathway. [ 32 ]  Under normal conditions the Nrf2 is bound to Kelch-like ECH associated protein 1 ( Keap1 ) in its inactive form. [ 33 ]  With the uptake of arsenic within cells and the subsequent reactions that result in the production of  reactive oxygen species  (ROS), the Nrf2 unbinds and becomes active. Keap1 has reactive thiol moieties that bind ROS or electrophilic arsenic species such as monomethylted arsenic (III) and induces the release of Nrf2 which then travels through the  cytoplasm  to the  nucleus . [ 34 ]  The Nrf2 then activates antioxidant responsive element (ARE) as well as electrophilic responsive element (EpRE) both of which contribute in the increase of antioxidant proteins. [ 35 ]  Of particular note in these antioxidant proteins is heme oxygenase 1 ([HO-1]), NAD(P)H-quinone oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthase (γGCS) which work in conjunction to reduce the oxidative species such as  hydrogen peroxide  to decrease the oxidative stress upon the cell. The increase in γGCS causes an increased production of arsenite triglutathionine (As(SG) 3 ) an important adduct that is taken up by either multidrug associated protein 1 or 2 ( MRP1  or  MRP2 ) which removes the arsenic out of the cell and into  bile  for excretion. [ 34 ]  This adduct can also decompose back into inorganic arsenic.


Of particular note in the excretion of arsenic is the multiple  methylation  steps that take place which may increase the toxicity of arsenic [ 36 ]  due to MMeAsIII being a potent inhibitor of glutathione peroxidase, [ 37 ]  glutathione reductase, pyruvate dehydrogenase, [ 38 ]  and thioredoxin reductase. [ 39 ]


Arsenic is a cause of mortality throughout the world; associated problems include heart, respiratory, gastrointestinal, liver, nervous and kidney diseases. [ 2 ] [ 25 ]


Arsenic interferes with cellular longevity by  allosteric inhibition  of an essential metabolic enzyme  pyruvate dehydrogenase  (PDH) complex, which catalyzes the oxidation of  pyruvate  to  acetyl-CoA  by  NAD + . With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular  apoptosis  episode. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling  thiamine deficiency . Poisoning with arsenic can raise lactate levels and lead to  lactic acidosis .


Genotoxicity  involves inhibition of DNA repair and DNA methylation.  The  carcinogenic  effect of arsenic arises from the  oxidative stress  induced by arsenic.  Arsenic's high toxicity naturally led to the development of a variety of arsenic compounds as  chemical weapons , e.g. dimethylarsenic chloride. Some were employed as  chemical warfare agents , especially in  World War I .  This threat led to many studies on  antidotes  and an expanded knowledge of the interaction of arsenic compounds with living organisms.  One result was the development of antidotes such as  British anti-Lewisite .  Many such antidotes exploit the affinity of As(III) for  thiolate   ligands , which convert highly toxic organoarsenicals to less toxic derivatives. It is generally assumed that arsenates bind to  cysteine  residues in proteins.


By contrast, arsenic oxide is an approved and effective chemotherapeutic drug for the treatment of  acute promyelocytic leukemia  (APL). [ 3 ]


Due to its similar structure and properties, pentavalent arsenic metabolites are capable of replacing the phosphate group of many metabolic pathways. [ 40 ]  The replacement of phosphate by arsenate is initiated when arsenate reacts with glucose and gluconate in vitro. [ 40 ]  This reaction generates glucose-6-arsenate and 6-arsenogluconate, which act as analogs for glucose-6-phosphate and 6-phosphogluconate. [ 40 ]  At the substrate level, during  glycolysis , glucose-6-arsenate binds as a substrate to glucose-6-phosphate dehydrogenase, and also inhibits hexokinase through negative feedback. [ 40 ]  Unlike the importance of phosphate in glycolysis, the presence of arsenate restricts the generation of  ATP  by forming an unstable anhydride product, through the reaction with D-glyceraldehyde-3-phosphate. [ 40 ]  The anhydride 1-arsenato-3-phospho-D-glycerate generated readily hydrolyzes due to the longer bond length of As-O compared to P-O. [ 40 ]  At the mitochondrial level, arsenate uncouples the synthesis of ATP by binding to ADP in the presence of  succinate , thus forming an unstable compound that ultimately results in a decrease of ATP net gain. [ 40 ]  Arsenite (III) metabolites, on the other hand, have limited effect on ATP production in red blood cells. [ 40 ]


Enzymes and receptors that contain thiol or  sulfhydryl  functional groups are actively targeted by arsenite (III) metabolites. [ 40 ]  These sulfur-containing compounds are normally glutathione and the  amino acid  cysteine. [ 40 ]  Arsenite derivatives generally have higher binding affinity compared to the arsenate metabolites. [ 40 ]  These bindings restrict activity of certain metabolic pathways. [ 40 ]  For example, pyruvate dehydrogenase (PDH) is inhibited when monomethylarsonous acid (MMA III ) targets the thiol group of the lipoic acid cofactor. [ 40 ]  PDH is a precursor of  acetyl-CoA , thus the inhibition of PDH eventually limits the production of ATP in  electron transport chain , as well as the production of  gluconeogenesis  intermediates. [ 40 ]


Arsenic can cause oxidative stress through the formation of  reactive oxygen species  (ROS), and  reactive nitrogen species  (RNS). [ 28 ]  Reactive oxygen species are produced by the enzyme  NADPH oxidase , which transfers electrons from  NADPH  to oxygen, synthesizing a  superoxide , which is a reactive free radical. This superoxide can react to form  hydrogen peroxide  and a reactive oxygen species. The enzyme  NADPH oxidase  is able to generate more reactive oxygen species in the presence of arsenic, due to the subunit p22phox, which is responsible for the electron transfer, being upregulated by arsenic. [ 28 ]  The reactive oxygen species are capable of stressing the  endoplasmic reticulum , which increases the amount of the unfolded protein response signals. [ 28 ]  This leads to inflammation, cell proliferation, and eventually to cell death. [ 28 ]  Another mechanism in which reactive oxygen species cause cell death would be through the  cytoskeleton  rearrangement, which affects the contractile proteins. [ 28 ]


The reactive nitrogen species arise once the reactive oxygen species destroy the  mitochondria . [ 28 ]  This leads to the formation of the reactive nitrogen species, which are responsible for damaging  DNA  in arsenic poisoning. [ 28 ]  Mitochondrial damage is known to cause the release of reactive nitrogen species, due to the reaction between superoxides and  nitric oxide  (NO). [ 28 ]  Nitric oxide (NO) is a part of cell regulation, including cellular  metabolism , growth, division and death. [ 28 ]  Nitric oxide (NO) reacts with reactive oxygen species to form  peroxynitrite . [ 28 ]  In cases of chronic arsenic exposure, the nitric oxide levels are depleted, due to the superoxide reactions. [ 28 ]  The enzyme NO synthase (NOS) uses L-arginine to form nitric oxide, but this enzyme is inhibited by monomethylated arsenic (III) compounds. [ 28 ]


Arsenic is reported to cause  DNA  modifications such as  aneuploidy ,  micronuclei  formation,  chromosome abnormality ,  deletion mutations ,  sister chromatid exchange  and  crosslinking of DNA  with proteins. [ 41 ]  It has been demonstrated that arsenic does not directly interact with DNA and it is considered a poor  mutagen , but instead, it helps mutagenicity of other  carcinogens . [ 42 ]  For instance, a synergistic increase in the mutagenic activity of arsenic with  UV light  has been observed in human and other mammalian cells after exposing the UV-treated cells to arsenic. [ 43 ] [ 44 ]  A series of experimental observations suggest that the arsenic  genotoxicity  is primarily linked to the generation of  reactive oxygen species  (ROS) during its biotransformation. [ 45 ] [ 46 ] [ 47 ]  The ROS production is able to generate  DNA adducts , DNA strand breaks, crosslinks and chromosomal aberrations. [ 48 ] [ 49 ] [ 50 ]  The oxidative damage is caused by modification of DNA  nucleobases , in particular  8-oxoguanine  (8-OHdG) which leads to G:C to T:A  mutations. [ 51 ]  Inorganic arsenic can also cause DNA strand break even at low concentrations. [ 52 ]


Inhibition of  DNA repair  processes is considered one of main mechanism of inorganic arsenic genotoxicity.  Nucleotide excision repair  (NER) and  base excision repair  (BER) are the processes implicated in the repair of DNA base damage induced by ROS after arsenic exposure. In particular, the NER mechanism is the major pathway for repairing bulky distortions in DNA double helix, while the BER mechanism is mainly implicated in the repair of single strand breaks induced by ROS, [ 53 ] [ 54 ] [ 55 ] [ 56 ]  but inorganic arsenic could also repress the BER mechanism. [ 57 ] [ 58 ] [ 59 ]


Exposure of isolated  lymphocytes  to arsenic causes decreased expression of the  DNA repair  protein  ERCC1 . [ 60 ]   Consistent with an inhibitory effect on DNA repair, lymphocytes from arsenic exposed individuals have higher levels of  DNA damage . [ 60 ]   Arsenic can act as a co-carcinogen by inhibiting repair of DNA damage through its interaction with sensitive  zinc finger  DNA repair proteins. [ 61 ] [ 62 ]


Arsenic is highly detrimental to the innate and the adaptive  immune system  of the body. [ 63 ]   When the amount of unfolded and misfolded proteins in  endoplasmic reticulum  stress is excessive, the  unfolded protein response  (UPR) is activated to increase the activity of several receptors that are responsible the restoration of homeostasis. [ 63 ]  The inositol-requiring enzyme-1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) are two receptors that restrict the rate of translation. [ 63 ]  On the other hand, the unfolded proteins are corrected by the production of  chaperones , which are induced by the activating transcription factor 6 (ATF6). [ 63 ]  If the number of erroneous proteins elevates, further mechanism is active which triggers  apoptosis . [ 63 ]  Arsenic has evidentially shown to increase the activity of these protein sensors. [ 63 ]


Arsenic exposure in small children distorts the ratio of  T helper cells  ( CD4 ) to  cytotoxic T cells  ( CD8 ), which are responsible for immunodepression. [ 64 ]  In addition, arsenic also increases the number of  inflammatory  molecules being secreted through  macrophages . [ 64 ]  The excess amount of  granulocytes  and  monocytes  lead to a chronic state of inflammation, which might result in  cancer  development. [ 64 ]


There are three molecules that serve as  chelator  agents that bond to arsenic. These three are  British Anti-Lewisite  (BAL, Dimercaprol), succimer ( DMSA ) and Unithiol ( DMPS ). [ 65 ]


When these agents  chelate  inorganic arsenic, it is converted into an organic form of arsenic because it is bound to the organic chelating agent. The  sulfur  atoms of the  thiol  groups are the site of interaction with arsenic. This is because the thiol groups are  nucleophilic  while the arsenic atoms are  electrophilic . Once bound to the chelating agent the molecules can be excreted, and therefore free inorganic arsenic atoms are removed from the body.


Other chelating agents can be used, but may cause more side effects than British Anti-Lewisite (BAL, Dimercaprol), succimer ( DMSA ) and ( DMPS ). DMPS and DMSA also have a higher  therapeutic index  than BAL. [ 65 ]


These drugs are efficient for acute poisoning of arsenic, which refers to the instantaneous effects caused by arsenic poisoning. For example, headaches, vomiting or sweating are some of the common examples of an instantaneous effect. In comparison, chronic poisonous effects arise later on, and unexpectedly such as organ damage. Usually it is too late to prevent them once they appear. Therefore, action should be taken as soon as acute poisonous effects arise. [ 66 ]


Arsenic poisoning  (or  arsenicosis ) is a medical condition that occurs due to elevated levels of  arsenic  in the body. [ 4 ]  If arsenic poisoning occurs over a brief period of time, symptoms may include  vomiting ,  abdominal pain ,  encephalopathy , and watery  diarrhea  that contains  blood . [ 1 ]  Long-term exposure can result in thickening of the skin,  darker skin , abdominal pain, diarrhea,  heart disease ,  numbness , and  cancer . [ 1 ]


The most common reason for long-term exposure is contaminated  drinking water . [ 3 ]   Groundwater  most often becomes contaminated naturally; however, contamination may also occur from  mining  or agriculture. [ 1 ]  It may also be found in the soil and air. [ 5 ]  Recommended levels in water are less than 10–50 μg/L (10–50  parts per billion ). [ 1 ]  Other routes of exposure include  toxic waste sites  and  pseudo-medicine . [ 1 ] [ 3 ]  Most cases of poisoning are accidental. [ 1 ]  Arsenic acts by changing the functioning of around 200  enzymes . [ 1 ]  Diagnosis is by testing the urine, blood, or hair. [ 1 ]


Prevention is by using water that does not contain high levels of arsenic. [ 1 ]  This may be achieved by the use of special filters or using  rainwater . [ 1 ]  There is not good evidence to support specific treatments for long-term poisoning. [ 1 ]  For acute poisonings treating  dehydration  is important. [ 4 ]   Dimercaptosuccinic acid  or  dimercaptopropane sulfonate  may be used while  dimercaprol  (BAL) is not recommended. [ 2 ]   Hemodialysis  may also be used. [ 4 ]


Through drinking water, more than 200 million people globally are exposed to higher-than-safe levels of arsenic. [ 3 ]  The areas most affected are  Bangladesh  and  West Bengal . [ 3 ]  Exposure is also more common in people of low income and minorities. [ 6 ]  Acute poisoning is uncommon. [ 3 ]  The toxicity of arsenic has been described as far back as 1500 BC in the  Ebers papyrus . [ 7 ]


Ingesting large amounts of arsenic can cause symptoms similar to  food poisoning , with  abdominal pain ,  nausea ,  vomiting , and  diarrhea  starting within hours. [ 8 ]  Bloody diarrhea can cause severe fluid loss, resulting in  hypovolemic shock . [ 8 ]  The heart and nervous system can also be affected, causing disruption to heart rhythms ( QT interval prolongation  or  tachycardia ), heart failure,  confusion ,  seizures , brain swelling,  coma , and death. [ 8 ] [ 9 ]  Inhaling  arsine  gas – the most toxic form of arsenic – causes a multisystem disease starting 2 to 24 hours after inhalation. Symptoms include gastrointestinal distress, headache, weakness, difficulty breathing, kidney and liver dysfunction, and the destruction of red blood cells. [ 8 ]


Chronic ingestion of lower levels of arsenic causes visible changes in the skin, typically  hyperpigmentation  (dark areas), but sometimes  hypopigmentation  (light areas) or an alternating areas of each. [ 10 ]  Some experience general  thickening of the skin  on the palms and soles of the feet, or  small thickened areas . [ 10 ]  Around 5% of those affected develop light-colored bands across the fingernail, called  Mees' lines . [ 8 ]  Chronic exposure eventually causes disease across multiple body systems, including  peripheral neuropathy  (numbness and tingling), enlargement of the  liver  and  spleen ,  diabetes ,  heart disease ,  cognitive impairment , and damage to the  portal vein  ( non-cirrhotic portal fibrosis  and  portal hypertension ). [ 8 ] [ 11 ]


Repeated arsenic exposure also increases the risk for developing several cancers, particularly of the  skin ,  lung ,  liver ,  bladder ,  prostate , and  blood vessels . [ 8 ] [ 11 ]  The most common arsenic-induced skin cancer is  squamous cell carcinoma in situ  which typically occurs 2 to 20 years after arsenic exposure. [ 12 ]


Arsenic poisoning is caused by incidental ingestion or inhalation of arsenic, typically from drinking contaminated  well  water, eating food cooked in contaminated water, or being exposed to arsenic-containing pesticides, folk medicines, or industrial chemicals. [ 8 ]  The  World Health Organization  considers arsenic levels above 10  parts per billion  (10  micrograms  per  liter ) to be unsafe. [ 10 ]


Arsenic is a ubiquitous naturally occurring  chemical element , and the 20th most common element on Earth. [ 13 ]  Arsenic levels in the groundwater vary from around 0.5 parts per billion to 5000 parts per billion, depending on an area's geologic features, and possible presence on industrial waste. [ 13 ] [ 11 ]  The highest groundwater arsenic levels have been recorded in Brazil, Cambodia, Afghanistan, Australia, and  Bangladesh . [ 11 ]


Arsenic is a ubiquitous element present in American drinking water. [ 14 ]   In the US, the  U.S. Geological Survey  estimates that the median groundwater concentration is 1 μg/L or less, although some groundwater  aquifers , particularly in the western United States, can contain much higher levels. For example, median levels in Nevada were about 8 μg/L [ 15 ]  but levels of naturally occurring arsenic as high as 1000 μg/L have been measured in the United States in drinking water. [ 16 ]  Groundwater associated with volcanics in California contain As at concentrations ranging up to 48,000 μg/L, with As-bearing sulfide minerals as the main source. [ 17 ]  Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of As >50 μg/L. [ 18 ]  In Wisconsin, As concentrations of water in sandstone and dolomite aquifers were as high as 100 μg/L. Oxidation of pyrite hosted by these formations was the likely source of the As. [ 19 ]  In the Piedmont of Pennsylvania and New Jersey, groundwater in  Mesozoic  age aquifers contains elevated levels of As—domestic well waters from Pennsylvania contained up to 65 μg/L, [ 20 ]  whereas in New Jersey the highest concentration measured recently was 215 μg/L. [ 21 ]


Organic arsenic is less harmful than inorganic arsenic. Seafood is a common source of the less toxic organic arsenic in the form of  arsenobetaine . [ 22 ]  Because of its high toxicity, arsenic is seldom used in the Western world, although in Asia it is still a popular pesticide. Arsenic is mainly encountered occupationally in the smelting of zinc and copper ores.


In the United States, Schoof et al. estimated an average adult intake of 3.2 μg/day, with a range of 1–20 μg/day. [ 23 ]  Estimates for children were similar. [ 24 ]  Food also contains many organic arsenic compounds. The key organic arsenic compounds that can be routinely found in food (depending on food type) include monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), arsenobetaine, arsenocholine, arsenosugars, and arsenolipids. DMAsV or MMAsV can be found in various types of fin fish, crabs, and mollusks, but often at very low levels. [ 25 ]


Arsenobetaine is the major form of arsenic in marine animals, and is considered nontoxic. Arsenocholine, which is mainly found in shrimp, is chemically similar to arsenobetaine, and is considered to be "essentially nontoxic". [ 26 ]  Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic. [ 27 ]  Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks. [ 28 ]  Studies addressing arsenosugar toxicity, however, have largely been limited to in vitro studies, which show that arsenosugars are significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites. [ 29 ]


It has been found that rice is particularly susceptible to accumulation of arsenic from soil. [ 30 ]   Rice grown in the United States has an average 260  ppb  of arsenic, according to a study; but U.S. arsenic intake remains far below  World Health Organization -recommended limits. [ 31 ]   China has set a standard for arsenic limits in food (150 ppb), [ 32 ]  as levels in rice exceed those in water. [ 33 ]


The European Commission (2000) reports that levels of arsenic in air range 0–1 ng/m 3  in remote areas, 0.2–1.5 ng/m 3  in rural areas, 0.5–3 ng/m 3  in urban areas, and up to about 50 ng/m 3  in the vicinity of industrial sites. Based on these data, the European Commission (2000) estimated that in relation to food, cigarette smoking, water, and soil, air contributes less than 1% of total arsenic exposure. [ better source needed ]


The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, because of the pesticide's environmental persistence, it is estimated that millions of acres of land are still contaminated with lead arsenate residues. This presents a potentially significant public health concern in some areas of the United States (e.g., New Jersey, Washington, and Wisconsin), where large areas of land used historically as orchards have been converted into residential developments. [ 34 ]


Some modern uses of arsenic-based pesticides still exist. Chromated copper arsenate has been registered for use in the United States since the 1940s as a wood preservative, protecting wood from insects and microbial agents. In 2003, manufacturers of chromated copper arsenate instituted a voluntary recall of residential uses of wood treated with the chemical. The Environmental Protection Agency Act 2008 final report stated that chromated copper arsenate is still approved for use in nonresidential applications, such as in marine facilities (pilings and structures), utility poles, and sand highway structures.


Exposure studies in the copper  smelting  industry are much more extensive and have established definitive links between arsenic, a by-product of copper smelting, and lung cancer via inhalation. [ 35 ]  Dermal and neurological effects were also increased in some of these studies. [ 36 ]  Although as time went on, occupational controls became more stringent and workers were exposed to reduced arsenic concentrations, the arsenic exposures measured from these studies ranged from about 0.05 to 0.3 mg/m 3  and are significantly higher than airborne environmental exposures to arsenic (which range from 0 to 0.000003 mg/m 3 ). [ 37 ]


Arsenic interferes with cellular longevity by  allosteric inhibition  of an essential metabolic enzyme  pyruvate dehydrogenase  complex, which catalyzes the oxidation of  pyruvate  to  acetyl-CoA  by  NAD + . With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular  apoptosis . Biochemically, arsenic prevents use of  thiamine  resulting in a clinical picture resembling  thiamine deficiency . Poisoning with arsenic can raise lactate levels and lead to  lactic acidosis . Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. [ citation needed ]
Arsenic in cells clearly stimulates the production of  hydrogen peroxide  (H 2 O 2 ). When the H 2 O 2  reacts with certain metals such as  iron  or  manganese  it produces a highly reactive  hydroxyl radical . Inorganic  arsenic trioxide  found in ground water particularly affects  voltage-gated potassium channels , [ 38 ]
disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval,  neutropenia ,  high blood pressure , [ 39 ]
central nervous system dysfunction,  anemia , and death.


Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing  fibrinolysis . Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-α, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis.


Arsenic has also been shown to induce  cardiac hypertrophy  by activating certain  transcription factors  involved in pathologically remodeling the heart. [ 41 ]  Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt  ATP  production through several mechanisms. At the level of the  citric acid cycle , arsenic inhibits  pyruvate dehydrogenase  and by competing with phosphate it uncouples  oxidative phosphorylation , thus inhibiting energy-linked reduction of  NAD+ , mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system  organ failure , probably from  necrotic  cell death, not  apoptosis . A  post mortem  reveals brick red colored  mucosa , due to severe  hemorrhage .  Although arsenic causes toxicity, it can also play a protective role. [ 42 ]


Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. [ 43 ]  (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the  glyceraldehyde 3-phosphate dehydrogenase  reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis.) As shown by Gresser (1981), submitochondrial particles synthesize adenosine-5'-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. [ 44 ]  This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.


Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses. [ 45 ]  The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide.
It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects. [ 46 ]


Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. [ 47 ]  Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial  type II  cells. [ 48 ] [ 49 ]


MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. [ 50 ]  Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, [ 51 ]  micronuclei [ 52 ] [ 53 ]  and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion. [ 54 ]


DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical. [ 55 ]
Both DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of reactive oxygen species can be promoted. [ 56 ]
Moreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially the ones containing thiol groups. The accumulation of reactive oxygen species like that cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death.
In a rat animal model, urine levels of 8-hydroxy-2'-deoxyguanosine (as a biomarker of DNA damage byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased. [ 57 ]  This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood. [ 58 ]


Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. [ 59 ]  A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure. [ 60 ]  Considering that a high partial pressure of oxygen is present in lungs and DMA(III) is excreted in gaseous state via the lungs, this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and later on stored in the bladder accounts for the other tumor localizations.


Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation; others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation. [ 61 ]  An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed polymerase chain reactions. [ 62 ]  It turned out that six of the fragments were hyper- and two of them were hypomethylated. [ 62 ]  Higher levels of DNA methyltransferase mRNA and enzyme activity were found. [ 62 ]