Amphetamine is a potent  central nervous system  (CNS) stimulant of the  phenethylamine class  that is approved for the treatment of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy . [ 82 ]  Amphetamine is also used off-label as a  performance  and  cognitive enhancer , and recreationally as an  aphrodisiac  and  euphoriant . [ 83 ] [ 84 ] [ 85 ] [ 86 ]  Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use. [ 87 ] [ 88 ]  As a consequence, amphetamine is illegally manufactured in  clandestine labs  to be trafficked and sold to users. [ 89 ]  Based upon drug and  drug precursor  seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of  methamphetamine . [ 89 ]


The first pharmaceutical amphetamine was  Benzedrine , a brand of inhalers used to treat a variety of conditions. [ 90 ] [ 91 ]  Because the dextrorotary isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as  mixed amphetamine salts ,  dextroamphetamine , and  lisdexamfetamine . [ 90 ] [ 92 ]


Amphetamine is a  norepinephrine-dopamine releasing agent  (NDRA). It enters neurons through  dopamine  and  norepinephrine transporters  and facilitates neurotransmitter efflux by activating  TAAR1  and inhibiting  VMAT2 . [ 71 ]  At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved  cognitive control . [ 84 ] [ 85 ] [ 93 ]  Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. [ 83 ]  In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid  muscle breakdown . [ 82 ] [ 84 ] [ 94 ]  Very high doses can result in  psychosis  (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use. [ 95 ] [ 96 ]  As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects, such as dependence, which only rarely arises with therapeutic amphetamine use. [ 82 ] [ 94 ] [ 95 ]


Caffeine is a stimulant compound belonging to the  xanthine  class of chemicals naturally found in  coffee ,  tea , and (to a lesser degree)  cocoa  or  chocolate . It is included in many  soft drinks , as well as a larger amount in  energy drinks . Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In  North America , 90% of adults consume caffeine daily. [ 97 ]


A few jurisdictions restrict the sale and use of caffeine. In the United States, the FDA has banned the sale of pure and highly concentrated caffeine products for personal consumption, due to the risk of overdose and death. [ 98 ]  The Australian Government has announced a ban on the sale of pure and highly concentrated caffeine food products for personal consumption, following the death of a young man from acute caffeine toxicity. [ 99 ] [ 100 ]  In Canada, Health Canada has proposed to limit the amount of caffeine in energy drinks to 180 mg per serving, and to require warning labels and other safety measures on these products. [ 99 ]


Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, [ 101 ]  or reducing one of its side-effects (especially drowsiness). [ 102 ]  Tablets containing standardized doses of caffeine are also widely available. [ 103 ]


Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors. [ 104 ]   Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness. [ 105 ]   Caffeine has been found to increase striatal dopamine in animal models, [ 106 ]  as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors, [ 107 ]  however the implications for humans are unknown.  Unlike most stimulants, caffeine has no addictive potential.  Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, per a study on drug abuse liability published in an NIDA research monograph that described a group preferring placebo over caffeine. [ 108 ]  In large telephone surveys only 11% reported dependence symptoms.  However, when people were tested in labs, only half of those who claim dependence actually experienced it, casting doubt on caffeine's ability to produce dependence and putting societal pressures in the spotlight. [ 109 ]


Coffee consumption is associated with a lower overall risk of  cancer . [ 110 ]  This is primarily due to a decrease in the risks of  hepatocellular  and  endometrial cancer , but it may also have a modest effect on colorectal cancer. [ 111 ]  There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of  bladder cancer . [ 111 ]  A protective effect of caffeine against  Alzheimer's disease  is possible,  but the evidence is inconclusive. [ 112 ] [ 113 ] [ 114 ]  Moderate coffee consumption may decrease the risk of  cardiovascular disease , [ 115 ]  and it may somewhat reduce the risk of  type 2 diabetes . [ 116 ]  Drinking 1-3 cups of coffee per day does not affect the risk of  hypertension  compared to drinking little or no coffee. However those who drink 2–4 cups per day may be at a slightly increased risk. [ 117 ]  Caffeine increases  intraocular pressure  in those with  glaucoma  but does not appear to affect normal individuals. [ 118 ]  It may protect people from  liver cirrhosis . [ 119 ]  There is no evidence that coffee stunts a child's growth. [ 120 ]  Caffeine may increase the effectiveness of some medications including ones used to treat  headaches . [ 121 ]   Caffeine may lessen the severity of  acute mountain sickness  if taken a few hours prior to attaining a high altitude. [ 122 ]


Ephedrine is a  sympathomimetic   amine  similar in molecular structure to the well-known drugs  phenylpropanolamine  and  methamphetamine , as well as to the important  neurotransmitter   epinephrine  (adrenaline). Ephedrine is commonly used as a stimulant,  appetite suppressant , concentration aid, and  decongestant , and to treat  hypotension  associated with anesthesia. [ citation needed ]


In chemical terms, it is an  alkaloid  with a  phenethylamine  skeleton found in various plants in the genus  Ephedra  (family  Ephedraceae ). It works mainly by increasing the activity of  norepinephrine  (noradrenaline) on  adrenergic receptors . [ 123 ]  It is most usually marketed as the  hydrochloride  or  sulfate  salt.


The herb  má huáng  ( Ephedra sinica ), used in  traditional Chinese medicine  (TCM), contains ephedrine and  pseudoephedrine  as its principal active constituents. The same may be true of other herbal products containing extracts from other  Ephedra  species.


3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant,  empathogen , and stimulant of the amphetamine class. [ 124 ]  Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the  DEA  listed MDMA as a  Schedule I controlled substance , prohibiting most medical studies and applications. MDMA is known for its  entactogenic  properties. The stimulant effects of MDMA include  hypertension ,  anorexia  (appetite loss),  euphoria , social disinhibition,  insomnia  (enhanced wakefulness/inability to sleep), improved  energy , increased arousal, and increased  perspiration , among others. Relative to catecholaminergic transmission, MDMA enhances serotonergic transmission significantly more, when compared to classical stimulants like amphetamine. MDMA does not appear to be significantly addictive or dependence forming. [ 125 ]


Due to the relative safety of MDMA, some researchers such as  David Nutt  have criticized the scheduling level, writing a satirical article finding MDMA to be 28 times less dangerous than horseriding, a condition he termed "equasy" or "Equine Addiction Syndrome". [ 126 ]


Methylenedioxypyrovalerone (MDPV) is a  psychoactive drug  with stimulant properties that acts as a  norepinephrine-dopamine reuptake inhibitor  (NDRI). [ 127 ]  It was first developed in the 1960s by a team at Boehringer Ingelheim. [ 128 ]  MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a  designer drug . Products labeled as  bath salts  containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for  Spice  and  K2  as incense. [ 129 ] [ 130 ]


Incidents of psychological and physical harm have been attributed to MDPV use. [ 131 ] [ 132 ]


Mephedrone is a  synthetic  stimulant drug of the  amphetamine  and  cathinone  classes. Slang names include drone [ 133 ]  and MCAT. [ 134 ]  It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the  khat  plant of  eastern Africa . It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to  MDMA ,  amphetamines , and  cocaine .


Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the US, it is considered an  analog  of other illegal drugs and can be controlled by laws similar to the  Federal Analog Act . In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011.


Mephedrone is neurotoxic and has abuse potential, predominantly exerted on 5-hydroxytryptamine (5-HT) terminals, mimicking that of MDMA with which it shares the same subjective sensations on abusers. [ 135 ] [ 136 ] [ 137 ]


Methamphetamine (contracted from  N - meth yl - a lpha- m ethyl ph en et hyl amine ) is a potent psychostimulant of the  phenethylamine  and  amphetamine   classes  that is used to treat  attention deficit hyperactivity disorder  (ADHD) and  obesity . [ 138 ] [ 139 ] [ 140 ]  Methamphetamine exists as two  enantiomers ,  dextrorotary  and  levorotary . [ 141 ] [ 142 ]  Dextromethamphetamine is a stronger CNS stimulant than  levomethamphetamine ; [ 94 ] [ 141 ] [ 142 ]  however, both are addictive and produce the same toxicity symptoms at high doses. [ 142 ]  Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the  United States Food and Drug Administration  (USFDA) under the trade name  Desoxyn . [ 139 ]  Recreationally, methamphetamine is used to  increase sexual desire ,  lift the mood , and increase  energy , allowing some users to engage in sexual activity continuously for several days straight. [ 139 ] [ failed verification ] [ 143 ] [ unreliable source? ]


Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an  equal parts  mixture of the right- and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine). [ 143 ]  Both dextromethamphetamine and racemic methamphetamine are  schedule II  controlled substances in the United States. [ 139 ]  Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the  United Nations Convention on Psychotropic Substances  treaty. [ 144 ] [ 145 ]   In contrast,  levomethamphetamine  is an  over-the-counter drug  in the United States. [ note 1 ]


In low doses, methamphetamine can cause an  elevated mood  and increase alertness, concentration, and energy in fatigued individuals. [ 94 ] [ 139 ]  At higher doses, it can induce  psychosis ,  rhabdomyolysis , and  cerebral hemorrhage . [ 94 ] [ 139 ]  Methamphetamine is known to have a high potential for  abuse  and  addiction . [ 94 ] [ 139 ]  Recreational use of methamphetamine may result in psychosis or lead to  post-withdrawal syndrome , a withdrawal syndrome that can persist for months beyond the typical withdrawal period. [ 148 ]  Unlike  amphetamine  and  cocaine , methamphetamine is  neurotoxic  to humans, damaging both  dopamine  and  serotonin  neurons in the  central nervous system  (CNS). [ 138 ] [ 140 ]  Unlike the long-term use of amphetamine in prescription doses, which may improve certain brain regions in individuals with ADHD, there is evidence that methamphetamine causes brain damage from long-term use in humans; [ 138 ] [ 140 ]  this damage includes adverse changes in brain structure and function, such as reductions in  gray matter  volume in several brain regions and adverse changes in markers of metabolic integrity. [ 149 ] [ 150 ] [ 140 ]  However, recreational amphetamine doses may also be neurotoxic. [ 151 ]


Methylphenidate is a stimulant drug that is often used in the treatment of ADHD and narcolepsy and occasionally to treat obesity in combination with diet restraints and exercise. Its effects at therapeutic doses include increased focus, increased alertness, decreased appetite, decreased need for sleep and decreased impulsivity. Methylphenidate is not usually used recreationally, but when it is used, its effects are very similar to those of amphetamines.


Methylphenidate acts as a  norepinephrine-dopamine reuptake inhibitor  (NDRI), by blocking the  norepinephrine transporter  (NET) and the  dopamine transporter  (DAT). Methylphenidate has a higher affinity for the dopamine transporter than for the norepinephrine transporter, and so its effects are mainly due to elevated dopamine levels caused by the inhibited reuptake  of dopamine, however increased norepinephrine levels also contribute to various of the effects caused by the drug.


Methylphenidate is sold under a number of brand names including Ritalin. Other versions include the long lasting tablet Concerta and the long lasting transdermal patch Daytrana.


Cocaine is an  SNDRI . Cocaine is made from the leaves of the  coca  shrub, which grows in the mountain regions of South American countries such as  Bolivia ,  Colombia , and  Peru , regions in which it was cultivated and used for centuries mainly by the  Aymara people . In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in  ophthalmology . [ 152 ]  Most cocaine use is recreational and its abuse potential is high (higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other  tropane  derivative drugs related to cocaine are also known such as  troparil  and  lometopane  but have not been widely sold or used recreationally. [ 153 ]


Nicotine  is the active chemical constituent in  tobacco , which is available in many forms, including  cigarettes ,  cigars ,  chewing tobacco , and  smoking cessation  aids such as  nicotine patches ,  nicotine gum , and  electronic cigarettes . Nicotine is used widely throughout the world for its stimulating and relaxing effects.  Nicotine exerts its effects through the agonism of  nicotinic acetylcholine receptors , resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrain  reward system , and acetaldehyde one of the tobacco constituent decreased the expression of  monoamine oxidase  in the brain. [ 154 ]   Nicotine is addictive and dependence forming. Tobacco, the most common source of nicotine, has an overall harm to user and self score 3 percent below cocaine, and 13 percent above amphetamines, ranking 6th most harmful of the 20 drugs assessed, as determined by a multi-criteria decision analysis. [ 155 ]


Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the  stereoisomers  norephedrine and norpseudoephedrine, is a  psychoactive drug  of the  phenethylamine  and  amphetamine   chemical classes  that is used as a stimulant,  decongestant , and  anorectic  agent. [ 156 ]  It is commonly used in  prescription  and  over-the-counter   cough and cold preparations . In  veterinary medicine , it is used to control  urinary incontinence  in dogs under  trade names  Propalin and Proin.


In the United States, PPA is no longer sold without a prescription due to a possible increased risk of  stroke  in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001. [ 157 ]  In India, human use of PPA and its formulations were banned on 10 February 2011. [ 158 ]


Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating  ADHD . [ 159 ]  Its effects typically last around 14 hours. [ 160 ]  Lisdexamfetamine is inactive on its own and is metabolized into  dextroamphetamine  in the body. [ 60 ]  Consequently, it has a lower abuse potential. [ 60 ]


Pseudoephedrine is a  sympathomimetic   drug  of the  phenethylamine  and  amphetamine   chemical classes . It may be used as a  nasal/sinus decongestant , as a stimulant, [ 161 ]  or as a  wakefulness-promoting agent . [ 162 ]


The  salts  pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many  over-the-counter   preparations , either as a single ingredient or (more commonly) in combination with  antihistamines ,  guaifenesin ,  dextromethorphan , and/or  paracetamol  (acetaminophen) or another  NSAID  (such as  aspirin  or  ibuprofen ). It is also used as a precursor chemical in the illegal production of methamphetamine.


Khat is a  flowering plant  native to the  Horn of Africa  and the  Arabian Peninsula . [ 163 ] [ 164 ]


Khat contains a  monoamine   alkaloid  called  cathinone , a "keto-amphetamine". This alkaloid causes excitement,  loss of appetite , and  euphoria . In 1980, the  World Health Organization  (WHO) classified it as a  drug of abuse  that can produce mild to moderate  psychological dependence  (less than tobacco or  alcohol ), [ 165 ]  although the WHO does not consider khat to be seriously addictive. [ 164 ]  It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other countries, including  Djibouti ,  Ethiopia ,  Somalia , Kenya and  Yemen . [ 166 ]


Modafinil  is an  eugeroic  medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat  excessive daytime sleepiness  due to  narcolepsy ,  shift work sleep disorder , or  obstructive sleep apnea . While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive. [ 167 ]  Despite being a CNS stimulant, the addiction and  dependence  liabilities of modafinil are considered very low. [ 168 ] [ 169 ] [ 170 ]  Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have  mood-elevating properties . [ 169 ]  The similarities in effects with  caffeine  are not clearly established. [ 171 ] [ 172 ]  Unlike other stimulants, modafinil does not induce a subjective  feeling of pleasure or reward , which is commonly associated with  euphoria , an intense feeling of well-being. Euphoria is a potential indicator of  drug abuse , which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised. [ 173 ] [ 174 ]


Pitolisant is an  inverse agonist  (antagonist) of the  histamine 3 (H 3 ) autoreceptor . As such, pitolisant is an  antihistamine medication  that also belongs to the class of CNS stimulants. [ 175 ] [ 176 ] [ 177 ] [ 178 ]  Pitolisant is also considered a medication of  eugeroic  class, which means that it promotes wakefulness and alertness. Pitolisant is the first  wakefulness-promoting agent  that acts by blocking the  H 3  autoreceptor . [ 179 ] [ 180 ] [ 181 ]


Pitolisant has been shown to be effective and well-tolerated for the treatment of  narcolepsy  with or without cataplexy. [ 181 ] [ 180 ] [ 179 ]


Pitolisant is the only non-controlled anti-narcoleptic drug in the  US . [ 179 ]  It has shown minimal abuse risk in studies. [ 179 ] [ 182 ]


Blocking the  histamine 3 (H 3 ) autoreceptor  increases the activity of histamine  neurons  in the brain. The H 3  autoreceptors regulate  histaminergic activity  in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting  histamine  biosynthesis and release upon binding to endogenous histamine. [ 183 ]  By preventing the binding of endogenous histamine at the H 3 , as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain. [ 184 ]


Stimulants enhance the activity of the  central  and  peripheral nervous systems . Common effects may include increased  alertness ,  awareness ,  wakefulness ,  endurance ,  productivity , and  motivation ,  arousal ,  locomotion ,  heart rate , and  blood pressure , and a diminished desire for  food  and  sleep . Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a " crash ", and may provoke reuse of the stimulant.


Abuse  of  central nervous system  (CNS) stimulants is common.  Addiction  to some CNS stimulants can quickly lead to  medical ,  psychiatric , and  psychosocial  deterioration.  Drug tolerance ,  dependence , and  sensitization  as well as a  withdrawal  syndrome can occur. [ 185 ]  Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity. [ 186 ]   Research on a progressive ratio  self-administration  protocol has found amphetamine, methylphenidate, modafinil, cocaine, and nicotine to all have a higher break point than placebo that scales with dose indicating reinforcing effects. [ 187 ]  A progressive ratio self-administration protocol is a way of testing how much an animal or a human wants a drug by making them do a certain action (like pressing a lever or poking a nose device) to get the drug. The number of actions needed to get the drug increases every time, so it becomes harder and harder to get the drug. The highest number of actions that the animal or human is willing to do to get the drug is called the break point. The higher the break point, the more the animal or human wants the drug. In contrast to the classical stimulants such as amphetamine, the effects of modafinil depend on what the animals or humans have to do after getting the drug. If they have to do a performance task, like solving a puzzle or remembering something, modafinil makes them work harder for it than placebo, and the subjects wanted to self-administer modafinil. But if they had to do a relaxation task, like listening to music or watching a video, the subjects did not want to self-administer modafinil. This suggests that modafinil is more rewarding when it helps the animals or humans do something better or faster, especially considering that modafinil is not commonly abused or depended on by people, unlike other stimulants. [ 187 ]


Psychosocial treatments, such as  contingency management , have demonstrated improved effectiveness when added to treatment as usual consisting of counseling and/or case-management.  This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence. [ 188 ]


The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry. [ 189 ]


Sulfozinum  ( sulfazin ) is a pharmaceutical drug that causes a  pyrogenic reaction  (body temperature elevation) [ 1 ] [ 2 ]   and severe pain. [ 3 ]  Sulfozinum is a 0.37 – 2% sterilized solution of purified elemental  sulfur  in  peach oil  or  olive oil  for intramuscular injections. The preparation is unstable, so it was prepared only in local hospital pharmacies. In the  Soviet Union , it was used in the pyrogenic treatment of syphilitic encephalitis (mostly in the pre-antibiotics era), various psychiatric conditions, [ 4 ] [ 5 ]  and alcoholism. [ 6 ]  Sulfozin was not used in American psychiatry. [ 3 ]


The American delegation during its visit to the USSR in 1989 confirmed charges of the use of sulfozine injections. [ 7 ]  Psychiatrists in the USSR employed sulfozine treatment allegedly to increase treatment response to neuroleptic administration but were unable to present any research evidence of its efficiency for this purpose. [ 8 ]  The muscle necrosis, fever, immobility, and severe pain caused by sulfozine, as well as the pattern of its use in 10 persons, suggest that the medication was applied for  punitive  rather than therapeutic purposes. [ 8 ]


Real benefits of its use in psychiatry are disputable, but it was widely used due to its extremely painful action, lasting from several hours to 2–3 days, as a punishment for psychiatric patients and in  political abuse of psychiatry . [ 9 ]  Sulfozine symbolised Soviet punitive psychiatry. [ 10 ]


In 1989, during  Perestroika , its use was restricted only to cases when its prescription was confirmed both by consilium [ clarification needed ]  and by informed consent of the patient or his representatives. [ 11 ]  Its present use is not known.


Some psychiatrists in post-Soviet Russia call the criticism of sulfozin attacks on psychiatry and still believe that sulfozin was sometimes the only effective treatment when all other ones were ineffective in calming down violent patients. [ 12 ]  The psychiatrists say that sulfozin really brought a psychosis to remission. [ 12 ]


" Truth serum " is a colloquial name for any of a range of psychoactive drugs used in an effort to obtain information from subjects who are unable or unwilling to provide it otherwise. These include  ethanol ,  scopolamine ,  3-quinuclidinyl benzilate ,  midazolam ,  flunitrazepam ,  sodium thiopental , and  amobarbital , among others.


Although a variety of such substances have been tested, serious issues have been raised about their use scientifically, ethically and legally. There is currently no drug proven to cause consistent or predictable enhancement of truth-telling. [ 1 ]  Subjects questioned under the influence of such substances have been found to be suggestible and their memories subject to reconstruction and fabrication. When such drugs have been used in the course of investigating civil and criminal cases, they have not been accepted by Western legal systems and legal experts as genuine investigative tools. [ 2 ]  In the United States, it has been suggested that their use is a potential violation of the  Fifth Amendment  of the  U.S. Constitution  (the  right to remain silent ). [ 3 ] [ 4 ]  Concerns have also been raised through the  European Court of Human Rights  arguing that use of a truth serum could be considered a violation of a human right to be free from degrading treatment, [ 5 ]  or could be considered a form of  torture . [ 6 ]  It has been noted to be a violation of the  Inter-American Convention to Prevent and Punish Torture . [ 7 ]


"Truth serum" was previously used in the management of  psychotic  patients in the practice of  psychiatry . [ 8 ]  In a therapeutic context, the controlled administration of  intravenous   hypnotic  medications is called " narcosynthesis " or "narcoanalysis". Such application was first documented by Dr.  William Bleckwenn . Reliability and suggestibility of patients are concerns, and the practice of chemically inducing an involuntary mental state is now widely considered to be a form of torture. [ 9 ] [ 10 ]


Sedatives  or  hypnotics  that alter higher cognitive function include  ethanol ,  scopolamine ,  3-quinuclidinyl benzilate , potent short or intermediate acting hypnotic  benzodiazepines  such as  midazolam ,  flunitrazepam , and various short and ultra-short acting  barbiturates , including  sodium thiopental  (commonly known by the brand name Pentothal) and  amobarbital  (formerly known as sodium amytal). [ 11 ] [ 2 ] [ 12 ]


While there have been many clinical studies of the efficacy of narcoanalysis in interrogation or  lie detection , there is dispute whether any of them qualify as a  randomized ,  controlled study , that would meet scientific standards for determining effectiveness. [ 13 ] [ 14 ] [ 15 ] [ 16 ]


India's  Central Bureau of Investigation  has used intravenous barbiturates for interrogation, often in high-profile cases. [ 2 ]  One such case was the interrogation of  Ajmal Kasab , the only terrorist captured alive by police in the  2008 attacks  in  Mumbai, India . [ 17 ] [ 18 ]  Kasab was a  Pakistani [ 19 ] [ 20 ]  militant and a member of the  Lashkar-e-Taiba  terrorist group. [ 21 ] [ 22 ]  On 3 May 2010, Kasab was found guilty of 80 offences, including murder, waging war against India, possessing explosives, and other charges. [ 23 ]  On 6 May 2010, the same trial court sentenced him to death on four counts and to a life sentence on five counts. [ 24 ]


The Central Bureau of Investigation also conducted this test on Krishna, a key witness and suspect in the high-profile  2008 Aarushi-Hemraj Murder Case  to seek more information from Krishna and also determine his credibility as a witness with key information, yet not known to the investigating authorities. Per unverified various media sources, Krishna had purported to have deemed Hemraj (the prime suspect) as not guilty of Aarushi's murder, claiming he [Hemraj] "treated Aarushi like his own daughter".


On May 5, 2010 the Supreme Court Judge Balasubramaniam in the case "Smt. Selvi vs. State of Karnataka" held that narcoanalysis,  polygraph  and  brain mapping  tests were to be allowed with the consent of the accused. The judge stated: "We are of the considered opinion that no individual can be forced and subjected to such techniques involuntarily, and by doing so it amounts to unwarranted intrusion of personal liberty." [ 25 ]


In  Gujarat , Madhya Pradesh High Court permitted narcoanalysis in the investigation of a killing of a tiger that occurred in May 2010. The Jhurjhura Tigress at  Bandhavgarh National Park , a mother of three cubs, was found dead as a result of being hit by a vehicle. A Special Task Force requested the narcoanalysis testing of four persons, one of whom refused to consent on grounds of potential post-test complications. [ 26 ]


In 2004,  Novaya Gazeta , with reference to  KGB  General  Oleg Kalugin , published an article that said that since the end of the 1980s the  First  and Second Directorates of the KGB had used, in exceptional cases and mostly on foreign citizens, a soluble odourless, colourless and tasteless substance code-named SP-117, an improved successor to similar drugs used by the KGB prior, that was effective in making a subject lose control of oneself 15 minutes after intake. [ 27 ]  Most importantly, a person who would be given, consecutively, two parts of the drug, i.e. both the "dote" and "antidote", would have no recollection of what had occurred in between and feel afterward as though he had suddenly fallen asleep, the preferable way to administer the "dote" being in an alcoholic drink, as that would serve as a plausible explanation of the sudden onset of drowsiness. [ 27 ]


Other reports state that SP-117 was just a form of concentrated alcohol meant to be added to alcoholic drinks such as champagne. [ 28 ]


According to the Russian  Foreign Intelligence Service  (SVR) officer, Alexander Kouzminov, who quit the service in the early 1990s, the officers of SVR′s Directorate S, which runs SVR's " illegals ", primarily used the drug to verify fidelity and trustworthiness of their agents who operated overseas, such as  Vitaly Yurchenko . [ 29 ]  According to  Alexander Litvinenko ,  Russian presidential candidate   Ivan Rybkin  was drugged with the same substance by FSB agents during his kidnapping in 2004. [ 30 ]


Scopolamine  was promoted by obstetrician Robert Ernest House as an advance that would prevent false convictions, beginning in 1922. He had noted that women in childbirth who were given scopolamine could answer questions accurately even while in a state of  twilight sleep , and were oftentimes "exceedingly candid" in their remarks. House proposed that scopolamine could be used when interrogating suspected criminals. He even arranged to administer scopolamine to prisoners in the  Dallas County  jail. Both men were believed to be guilty, both denied guilt under scopolamine, and both were eventually acquitted. [ 16 ]  In 1926, the use of scopolamine was rejected in a court case, by Judge Robert Walker Franklin, who questioned both its scientific origin, and the uncertainty of its effect. [ 12 ] [ 2 ]


The United States  Office of Strategic Services  (OSS) experimented with the use of  mescaline ,  scopolamine , and  marijuana  as possible truth drugs during  World War II . They concluded that the effects were not much different from those of  alcohol : subjects became more talkative but that did not mean they were more truthful. Like  hypnosis , there were also issues of suggestibility and interviewer influence. Cases involving scopolamine resulted in a mixture of testimonies both for and against those suspected, at times directly contradicting each other. [ 2 ] [ 31 ]


LSD  was also considered as a possible truth serum, but found unreliable. [ 2 ]  During the 1950s and 1960s, the United States  Central Intelligence Agency  (CIA) carried out a number of investigations including  Project MKUltra [ 32 ]  and  Project MKDELTA [ citation needed ] , which involved illegal use of truth drugs including LSD. [ 33 ] [ 31 ] [ 34 ]  A CIA report from 1961, released in 1993, concludes:


The salient points that emerge from this discussion are the following. No such magic brew as the popular notion of truth serum exists. The barbiturates, by disrupting defensive patterns, may sometimes be helpful in interrogation, but even under the best conditions they will elicit an output contaminated by deception, fantasy, garbled speech, etc. A major vulnerability they produce in the subject is a tendency to believe he has revealed more than he has. It is possible, however, for both normal individuals and psychopaths to resist drug interrogation; it seems likely that any individual who can withstand ordinary intensive interrogation can hold out in narcosis. The best aid to a defense against narco-interrogation is foreknowledge of the process and its limitations. There is an acute need for controlled experimental studies of drug reaction, not only to depressants but also to stimulants and to combinations of depressants, stimulants, and ataraxics. [ 16 ]


In 1963, the  U.S. Supreme Court  ruled, in  Townsend v. Sain , that confessions produced as a result of ingestion of truth serum were "unconstitutionally coerced" and therefore inadmissible. [ 35 ]  The viability of forensic evidence produced from truth sera has been addressed in lower courts – judges and expert witnesses have generally agreed that they are not reliable for lie detection. [ 36 ]


In 1967, during his investigation into the  assassination of President John F. Kennedy ,  New Orleans  District Attorney  Jim Garrison  arranged for his key witness,  Perry Russo , to be administered sodium pentothal before being questioned about his knowledge regarding an alleged  conspiracy . [ 37 ]  Russo would later describe "his conditioning by the DA's office as a complete brainwashing job." [ 38 ]


In 1995, during the search for evidence that could acquit  Andres English-Howard , his defense attorney employed  methohexital .


More recently, a judge approved the use of narcoanalysis in the  2012 Aurora, Colorado shooting  trial to evaluate whether  James Eagan Holmes 's state of mind was valid for an  insanity plea . [ 39 ]  Judge William Sylvester ruled that prosecutors would be allowed to interrogate Holmes "under the influence of a medical drug designed to loosen him up and get him to talk", such as sodium amytal, if he filed an insanity plea. [ 3 ]  The hope was that a 'narcoanalytic interview' could confirm whether or not he had been legally insane on 20 July, the date of the shootings. [ 3 ]  It is not known whether such an examination was carried out. [ 2 ]


William Shepherd, chair of the criminal justice section of the  American Bar Association , stated, with respect to the Holmes case, that use of a "truth drug" as proposed, "to ascertain the veracity of a defendant's plea of insanity... would provoke intense legal argument relating to Holmes's right to remain silent under the fifth amendment of the US constitution." [ 3 ]  Discussing possible effectiveness of such an examination, psychiatrist August Piper stated that "amytal's inhibition-lowering effects in no way prompt the subject to offer up true statements or memories." [ 40 ]   Psychology Today 's  Scott Linfield noted, as per Piper, that "there's good reason to believe that truth serums merely lower the threshold for reporting virtually all information, both true and false." [ 40 ]


The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023). Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023). The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023). The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001). The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023). Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)


Methampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use.


Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011). Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010). Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007). Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)


Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)


Mycobacterium tuberculosis infection of the lung has resulted in upper lung field granulomatous and cavitary disease.Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022). Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)


The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states). Chronic alcohol abuse leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023). In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke–Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff’s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol abuse leads to permanent brain damage. (Nutt et al, 2021). Abrupt cessation of alcohol ingestion in persons who are chronic alcohol abusers predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022). Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023). Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)


Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)


Emphysema, of the centrilobular type, with numerous enlarged air spaces as a result of the loss of lung tissue from smoking is demonstrated here grossly.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)


A large squamous cell carcinoma of the lung in a smoker is shown here. The incidence of both squamous cell carcinomas and small cell anaplastic carcinomas of lung is far greater in smokers than non-smokers.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)


Small cell anaplastic (oat cell) carcinoma of the lung appears here in a smoker. Smokers who stop will diminish their risk for lung cancer, even after just a couple of years.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)


The normal gross appearance of a lung in cross section is shown here for comparison.Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017). Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)