Psychoactive drug

An assortment of psychoactive drugs—street drugs and medications:
1. cocaine
2. crack cocaine
3. methylphenidate (Ritalin)
4. ephedrine
5. MDMA (Ecstasy)
6. mescaline (cactus)
7. LSD blotter
8. psilocybin mushroom (Psilocybe cubensis)
9. Salvia divinorum
10. diphenhydramine (Benadryl)
11. Amanita muscaria mushroom
12. Tylenol 3 (contains codeine)
13. codeine with muscle relaxant
14. pipe tobacco
15. bupropion (Zyban)
16. cannabis
17. hashish

A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that changes brain function and results in alterations in perception, mood, or consciousness.[1] These substances may be used recreationally, to purposefully alter one's consciousness, or as entheogens, for ritual, spiritual, or shamanic purposes, as a tool for studying or augmenting the mind. Some categories of psychoactive drugs, which are prescription medicines, have medical therapeutic utility, such as anesthetics, analgesics, hormonal preparations, anticonvulsant and antiparkinsonian drugs or for the treatment of neuro-psychiatric disorders, as hypnotic drugs, anxiolytic and some stimulant medications used in ADHD and some sleep disorders. There are also some psychoactive substances used in the detoxification and rehabilitation programs for psychoactive drug users.

Psychoactive substances often bring about subjective (although these may be objectively observed) changes in consciousness and mood that the user may find rewarding and pleasant (e.g. euphoria) or advantageous (e.g. increased alertness) and are thus reinforcing. Substances which are both rewarding and positively reinforcing have the potential to induce a state of addiction – compulsive drug use despite negative consequences – when used consistently in excess. In addition, sustained use of some substances may produce a physical dependence or psychological dependence syndrome associated with somatic or psychological-emotional withdrawal states respectively. Drug rehabilitation aims to break this cycle of dependency, through a combination of psychotherapy, support groups, maintenance and even other psychoactive substances. However, the reverse is also true in some cases, that certain experiences on drugs may be so unfriendly and uncomforting that the user may never want to try the substance again. This is especially true of certain deliriants (e.g. Jimson weed) and powerful dissociatives (e.g. Salvia divinorum).

In part because of this potential for substance misuse, addiction, or dependence, the ethics of drug use is debated. Restrictions on drug production and sales in an attempt to decrease drug abuse is very common among national and sub-national governments worldwide. Ethical concerns have also been raised about over-use of these drugs clinically, and about their marketing by manufacturers.

History

Alcohol is a widely used and abused psychoactive drug. The global alcoholic drinks market was expected to exceed $1 trillion in 2013.[2] Beer is the third-most popular drink overall, after water and tea.[3]

Psychoactive drug use can be traced to prehistory. There is archaeological evidence of the use of psychoactive substances (mostly plants) dating back at least 10,000 years, and historical evidence of cultural use over the past 5,000 years.[4] The chewing of coca leaves, for example, dates back over 8,000 years ago in Peruvian society.[5][6]

Medicinal use is one important facet of psychoactive drug usage. However, some have postulated that the urge to alter one's consciousness is as primary as the drive to satiate thirst, hunger or sexual desire.[7] Supporters of this belief contend that the history of drug use and even children's desire for spinning, swinging, or sliding indicate that the drive to alter one's state of mind is universal.[8]

One of the first people to articulate this point of view, set aside from a medicinal context, was American author Fitz Hugh Ludlow (1836–1870) in his book The Hasheesh Eater (1857):

[D]rugs are able to bring humans into the neighborhood of divine experience and can thus carry us up from our personal fate and the everyday circumstances of our life into a higher form of reality. It is, however, necessary to understand precisely what is meant by the use of drugs. We do not mean the purely physical craving...That of which we speak is something much higher, namely the knowledge of the possibility of the soul to enter into a lighter being, and to catch a glimpse of deeper insights and more magnificent visions of the beauty, truth, and the divine than we are normally able to spy through the cracks in our prison cell. But there are not many drugs which have the power of stilling such craving. The entire catalog, at least to the extent that research has thus far written it, may include only opium, hashish, and in rarer cases alcohol, which has enlightening effects only upon very particular characters.[9]

This relationship is not limited to humans. A number of animals consume different psychoactive plants, animals, berries and even fermented fruit, becoming intoxicated, such as cats after consuming catnip. Traditional legends of sacred plants often contain references to animals that introduced humankind to their use.[10] Animals and psychoactive plants appear to have co-evolved, possibly explaining why these chemicals and their receptors exist within the nervous system.[11]

During the 20th century, many governments across the world initially responded to the use of recreational drugs by banning them and making their use, supply, or trade a criminal offense. A notable example of this was Prohibition in the United States, where alcohol was made illegal for 13 years. However, many governments, government officials and persons in law enforcement have concluded that illicit drug use cannot be sufficiently stopped through criminalization. Organizations such as Law Enforcement Against Prohibition (LEAP) have come to such a conclusion, believing:

[T]he existing drug policies have failed in their intended goals of addressing the problems of crime, drug abuse, addiction, juvenile drug use, stopping the flow of illegal drugs into this country and the internal sale and use of illegal drugs. By fighting a war on drugs the government has increased the problems of society and made them far worse. A system of regulation rather than prohibition is a less harmful, more ethical and a more effective public policy.[12]

In some countries, there has been a move toward harm reduction by health services, where the use of illicit drugs is neither condoned nor promoted, but services and support are provided to ensure users have adequate factual information readily available, and that the negative effects of their use be minimized. Such is the case of Portuguese drug policy of decriminalization, which achieved its primary goal of reducing the adverse health effects of drug abuse.[13]

Purposes

Psychoactive substances are used by humans for a number of different purposes to achieve a specific end. These uses vary widely between cultures. Some substances may have controlled or illegal uses while others may have shamanic purposes, and still others are used medicinally. Other examples would be social drinking, nootropic, or sleep aids. Caffeine is the world's most widely consumed psychoactive substance, but unlike many others, it is legal and unregulated in nearly all jurisdictions. In North America, 90% of adults consume caffeine daily.[14]

Psychoactive drugs are divided into different groups according to their pharmacological effects. Commonly used psychoactive drugs and groups:

Example: Benzodiazepine
Example: MDMA (Ecstasy), MDA, 6-APB, Indopan
Examples: amphetamine, caffeine, cocaine, nicotine
Examples: ethanol (alcoholic beverages), opioids, barbiturates, benzodiazepines.
Examples: psilocybin, LSD, Salvia divinorum and nitrous oxide.

Uses

Anesthesia

Main article: Anesthesia

General anesthetics are a class of psychoactive drug used on people to block physical pain and other sensations. Most anesthetics induce unconsciousness, allowing the person to undergo medical procedures like surgery without the feelings of physical pain or emotional trauma.[16] To induce unconsciousness, anesthetics affect the GABA and NMDA systems. For example, halothane is a GABA agonist,[17] and ketamine is an NMDA receptor antagonist.[18]

Pain management

Main article: Analgesics

Psychoactive drugs are often prescribed to manage pain. The subjective experience of pain is primarily regulated by endogenous opioid peptides. Thus, pain can often be managed using psychoactives that operate on this neurotransmitter system, also known as opioid receptor agonists. This class of drugs can be highly addictive, and includes opiate narcotics, like morphine and codeine.[19] NSAIDs, such as aspirin and ibuprofen, are also analgesics. These agents also reduce eicosanoid-mediated inflammation by inhibiting the enzyme cyclooxygenase.

Mental disorders

Zoloft (sertraline) is an SSRI antidepressant.

Psychiatric medications are psychoactive drugs prescribed for the management of mental and emotional disorders, or to aid in overcoming challenging behavior.[20] There are six major classes of psychiatric medications:

In addition, several psychoactive substances are currently employed to treat various addictions. These include acamprosate or naltrexone in the treatment of alcoholism, or methadone or buprenorphine maintenance therapy in the case of opioid addiction.

Exposure to psychoactive drugs can cause changes to the brain that counteract or augment some of their effects; these changes may be beneficial or harmful. However, there is a significant amount of evidence that relapse rate of mental disorders negatively corresponds with length of properly followed treatment regimens (that is, relapse rate substantially declines over time), and to a much greater degree than placebo.[22]

Recreation

Main article: Recreational drug use

Many psychoactive substances are used for their mood and perception altering effects, including those with accepted uses in medicine and psychiatry. Examples of psychoactive substances include caffeine, alcohol, cocaine, LSD, and cannabis.[23] Classes of drugs frequently used recreationally include:

In some modern and ancient cultures, drug usage is seen as a status symbol. Recreational drugs are seen as status symbols in settings such as at nightclubs and parties.[24] For example, in ancient Egypt, gods were commonly pictured holding hallucinogenic plants.[25]

Because there is controversy about regulation of recreational drugs, there is an ongoing debate about drug prohibition. Critics of prohibition believe that regulation of recreational drug use is a violation of personal autonomy and freedom.[26] In the United States, critics have noted that prohibition or regulation of recreational and spiritual drug use might be unconstitutional, and causing more harm than is prevented.[27]

Ritual and spiritual

Timothy Leary was a leading proponent of spiritual hallucinogen use.
Main article: Entheogens

Certain psychoactives, particularly hallucinogens, have been used for religious purposes since prehistoric times. Native Americans have used peyote cacti containing mescaline for religious ceremonies for as long as 5700 years.[28] The muscimol-containing Amanita muscaria mushroom was used for ritual purposes throughout prehistoric Europe.[29] Various other hallucinogens, including jimsonweed, psilocybin mushrooms, and cannabis, have been used in religious ceremonies for millennia.[30]

The use of entheogens for religious purposes resurfaced in the West during the counterculture movements of the 1960s and 70s. Under the leadership of Timothy Leary, new spiritual and intention-based movements began to use LSD and other hallucinogens as tools to access deeper inner exploration. In the United States, the use of peyote for ritual purposes is protected only for members of the Native American Church, which is allowed to cultivate and distribute peyote. However, the genuine religious use of peyote, regardless of one's personal ancestry, is protected in Colorado, Arizona, New Mexico, Nevada, and Oregon.[31]

Military

Psychoactive drugs have been used in military applications as non-lethal weapons. In World War II, between 1939 and 1945, 60 million amphetamine pills were made for use by soldiers. Brown-brown, a form of cocaine adulterated with gunpowder, has been used in the Sierra Leone Civil War by child soldiers.

Both military and civilian American intelligence officials are known to have used psychoactive drugs while interrogating captives apprehended in its War on Terror. In July 2012, Jason Leopold and Jeffrey Kaye, psychologists and human rights workers, had a Freedom of Information Act request fulfilled that confirmed that the use of psychoactive drugs during interrogation was a long-standing practice.[32][33] Captives and former captives had been reporting medical staff collaborating with interrogators to drug captives with powerful psychoactive drugs prior to interrogation since the very first captives' release.[34][35] In May 2003, recently released Pakistani captive Sha Mohammed Alikhel described the routine use of psychoactive drugs. He said that Jihan Wali, a captive kept in a nearby cell, was rendered catatonic through the use of these drugs.

Route of administration

Psychoactive drugs are administered via oral ingestion as a tablet, capsule, powder, liquid, and beverage; via inhalation; via injection by subcutaneous, intramuscular, and intravenous route; via rectum by suppository and enema; and via inhalation by smoking, vaporization and insufflation ("snorting"). The efficiency of each method of administration varies from drug to drug.[36]

The psychiatric drugs fluoxetine, quetiapine, and lorazepam are ingested orally in tablet or capsule form. Alcohol and caffeine are ingested in beverage form; nicotine and cannabis are smoked or vaped; peyote and psilocybin mushrooms are ingested in botanical form or dried; and crystalline drugs such as cocaine and methamphetamines are usually insufflated (inhaled or "snorted").

Determinants of effects

The theory of dosage, set, and setting is a useful model in dealing with the effects of psychoactive substances, especially in a controlled therapeutic setting as well as in recreational use. Dr. Timothy Leary, based on his own experiences and systematic observations on psychedelics, developed this theory along with his colleagues Ralph Metzner, and Richard Alpert (Ram Dass) in the 1960s.[37]

Dosage

The first factor, dosage, has been a truism since ancient times, or at least since Paracelsus who said, "Dose makes the poison." Some compounds are beneficial or pleasurable when consumed in small amounts, but harmful, deadly, or evoke discomfort in higher doses.

Set

The set is the internal attitudes and constitution of the person, including their expectations, wishes, fears, and sensitivity to the drug. This factor is especially important for the hallucinogens, which have the ability to make conscious experiences out of the unconscious. In traditional cultures, set is shaped primarily by the worldview, health and genetic characteristics that all the members of the culture share.

Setting

The third aspect is setting, which pertains to the surroundings, the place, and the time in which the experiences transpire.

This theory clearly states that the effects are equally the result of chemical, pharmacological, psychological, and physical influences. The model that Timothy Leary proposed applied to the psychedelics, although it also applies to other psychoactives.[38]

Effects

Illustration of the major elements of neurotransmission. Depending on its method of action, a psychoactive substance may block the receptors on the post-synaptic neuron (dendrite), or block reuptake or affect neurotransmitter synthesis in the pre-synaptic neuron (axon).

Psychoactive drugs operate by temporarily affecting a person's neurochemistry, which in turn causes changes in a person's mood, cognition, perception and behavior. There are many ways in which psychoactive drugs can affect the brain. Each drug has a specific action on one or more neurotransmitter or neuroreceptor in the brain.

Drugs that increase activity in particular neurotransmitter systems are called agonists. They act by increasing the synthesis of one or more neurotransmitters, by reducing its reuptake from the synapses, or by mimicking the action by binding directly to the postsynaptic receptor. Drugs that reduce neurotransmitter activity are called antagonists, and operate by interfering with synthesis or blocking postsynaptic receptors so that neurotransmitters cannot bind to them.[39]

Exposure to a psychoactive substance can cause changes in the structure and functioning of neurons, as the nervous system tries to re-establish the homeostasis disrupted by the presence of the drug (see also, Neuroplasticity). Exposure to antagonists for a particular neurotransmitter can increase the number of receptors for that neurotransmitter or the receptors themselves may become more responsive to neurotransmitters; this is called sensitization. Conversely, overstimulation of receptors for a particular neurotransmitter may cause a decrease in both number and sensitivity of these receptors, a process called desensitization or tolerance. Sensitization and desensitization are more likely to occur with long-term exposure, although they may occur after only a single exposure. These processes are thought to play a role in drug dependence and addiction.[40] Physical dependence on antidepressants or anxiolytics may result in worse depression or anxiety, respectively, as withdrawal symptoms. Unfortunately, because clinical depression (also called major depressive disorder) is often referred to simply as depression, antidepressants are often requested by and prescribed for patients who are depressed, but not clinically depressed.

Affected neurotransmitter systems

The following is a brief table of notable drugs and their primary neurotransmitter, receptor or method of action. It should be noted that many drugs act on more than one transmitter or receptor in the brain.[41]

Neurotransmitter/receptor Classification Examples

Acetylcholine
 Cholinergics (acetylcholine receptor agonists) arecoline, nicotine, piracetam
Muscarinic antagonists (acetylcholine receptor antagonists) scopolamine, benzatropine, dimenhydrinate, diphenhydramine, atropine, quetiapine, olanzapine, most tricyclics
Nicotinic antagonists (acetylcholine receptor antagonists) memantine, bupropion
Adenosine
 Adenosine receptor antagonists[42] caffeine, theobromine, theophylline

Dopamine
 Dopamine reuptake inhibitors (DRIs) cocaine, bupropion, methylphenidate, and certain TAAR1 agonists like amphetamine, phenethylamine, and methamphetamine
Dopamine releasers agomelatine and certain TAAR1 agonists like amphetamine, phenethylamine, and methamphetamine
Dopamine receptor agonists pramipexole, Ropinirole, L-DOPA (prodrug), memantine (also see NMDA, below)
Dopamine receptor antagonists haloperidol, droperidol, many antipsychotics (e.g., risperidone, olanzapine, quetiapine)
Dopamine receptor partial agonists LSD, aripiprazole


gamma-Aminobutyric acid (GABA)
 GABA reuptake inhibitors tiagabine, vigabatrin
GABA receptor agonists ethanol, barbiturates, diazepam, clonazepam, lorazepam, temazepam, alprazolam and other benzodiazepines, zolpidem, eszopiclone, zaleplon and other nonbenzodiazepines, muscimol
GABA receptor antagonists thujone, bicuculline

Norepinephrine
 Norepinephrine reuptake inhibitors most non-SSRI antidepressants such as amoxapine, atomoxetine, bupropion, venlafaxine, quetiapine, the tricyclics, methylphenidate, SNRIs such as duloxetine, venlafaxine, and certain TAAR1 agonists like amphetamine, phenethylamine, methamphetamine.
Norepinephrine releasers ephedrine, mianserin, mirtazapine, PPA, pseudoephedrine, amphetamine, phenethylamine, methamphetamine
Norepinephrine receptor agonists clonidine, guanfacine, phenylephrine
Norepinephrine receptor antagonists carvedilol, metoprolol, mianserin, prazosin, propranolol, trazodone, yohimbine, olanzapine
Serotonin
 Selective serotonin receptor agonists methylphenidate, LSD, psilocybin, mescaline, DMT
Serotonin reuptake inhibitors most antidepressants including tricyclics such as imipramine, SSRIs such as fluoxetine, sertraline and citalopram, and SNRIs such as duloxetine and venlafaxine, cocaine, and certain TAAR1 agonists like amphetamine, tryptamine, and methamphetamine
Serotonin releasers fenfluramine, MDMA (ecstasy), mephedrone, mirtazapine, tramadol, tryptamine
Serotonin receptor antagonists ritanserin, mirtazapine, mianserin, trazodone, cyproheptadine, memantine, atypical antipsychotics (e.g., risperidone, olanzapine, quetiapine)
AMPA receptor
 AMPA receptor positive allosteric modulators aniracetam, CX717, piracetam
AMPA receptor antagonists kynurenic acid, NBQX, topiramate
Cannabinoid receptor
 Cannabinoid receptor agonists JWH-018
Cannabinoid receptor partial agonists Anandamide, THC, cannabidiol, cannabinol
Cannabinoid receptor inverse agonists Rimonabant
Anandamide reuptake inhibitors [43] LY 2183240, VDM 11, AM 404
FAAH enzyme inhibitors MAFP, URB597, N-Arachidonylglycine
Melanocortin receptor
 Melanocortin receptor agonists bremelanotide
NMDA receptor
 NMDA receptor antagonists ethanol, ketamine, PCP, DXM, Nitrous Oxide, glutamate, memantine (used for moderate to severe Alzheimers)
GHB receptor
 GHB receptor agonists GHB, Amisulpride, T-HCA
Sigma receptor
 Sigma-1 receptor agonists cocaine, DMT, DXM, fluvoxamine, ibogaine, opipramol, PCP, methamphetamine
Sigma-2 receptor agonists methamphetamine
Opioid receptor
 μ-opioid receptor agonists morphine, heroin, oxycodone, codeine
μ-opioid receptor partial agonists buprenorphine
μ-opioid receptor inverse agonists naloxone
μ-opioid receptor antagonists naltrexone
κ-opioid receptor agonists salvinorin A, butorphanol, nalbuphine, pentazocine, ibogaine[44]
κ-opioid receptor antagonists buprenorphine
Histamine receptor
 H1 histamine receptor antagonists diphenhydramine, doxylamine, mirtazapine, mianserin, quetiapine, olanzapine, meclozine, dimenhydrinate, most tricyclics
Monoamine oxidase
 Monoamine oxidase inhibitors (MAOIs) phenelzine, iproniazid, tranylcypromine
Melatonin receptor
 Melatonin receptor agonists ramelteon
Imidazoline receptor
 Imidazoline receptor agonists apraclonidine, clonidine, moxonidine, rilmenidine
Orexin receptor
 Orexin receptor agonists modafinil
Orexin receptor antagonists SB-334,867, SB-408,124, TCS-OX2-29

Addiction and dependence

Addiction and dependence glossary[45][46][47]
• addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
• addictive behavior – a behavior that is both rewarding and reinforcing
• addictive drug – a drug that is both rewarding and reinforcing
• dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
• drug withdrawal – symptoms that occur upon cessation of repeated drug use
• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
• reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
• rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
• sensitization – an amplified response to a stimulus resulting from repeated exposure to it
• tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
Main articles: addiction and ΔFosB
Comparison of the perceived harm for various psychoactive drugs from a poll among medical psychiatrists specialized in addiction treatment (David Nutt et al. 2007).[48]

Psychoactive drugs are often associated with addiction or drug dependence. Dependence can be divided into two types: psychological dependence, by which a user experiences negative psychological or emotional withdrawal symptoms (e.g., depression) and physical dependence, by which a user must use a drug to avoid physically uncomfortable or even medically harmful physical withdrawal symptoms.[49] Drugs that are both rewarding and reinforcing are addictive; these properties of a drug are mediated through activation of the mesolimbic dopamine pathway, particularly the nucleus accumbens. Not all addictive drugs are associated with physical dependence, e.g., amphetamine, and not all drugs that produce physical dependence are addictive drugs, e.g., caffeine.

Many professionals, self-help groups, and businesses specialize in drug rehabilitation, with varying degrees of success, and many parents attempt to influence the actions and choices of their children regarding psychoactives.[50]

Common forms of rehabilitation include psychotherapy, support groups and pharmacotherapy, which uses psychoactive substances to reduce cravings and physiological withdrawal symptoms while a user is going through detox. Methadone, itself an opioid and a psychoactive substance, is a common treatment for heroin addiction, as is another opioid, buprenorphine. Recent research on addiction has shown some promise in using psychedelics such as ibogaine to treat and even cure drug addictions, although this has yet to become a widely accepted practice.[51][52]

Legality

Historical image of legal heroin bottle
Main article: Prohibition of drugs

The legality of psychoactive drugs has been controversial through most of recent history; the Second Opium War and Prohibition are two historical examples of legal controversy surrounding psychoactive drugs. However, in recent years, the most influential document regarding the legality of psychoactive drugs is the Single Convention on Narcotic Drugs, an international treaty signed in 1961 as an Act of the United Nations. Signed by 73 nations including the United States, the USSR, India, and the United Kingdom, the Single Convention on Narcotic Drugs established Schedules for the legality of each drug and laid out an international agreement to fight addiction to recreational drugs by combatting the sale, trafficking, and use of scheduled drugs.[53] All countries that signed the treaty passed laws to implement these rules within their borders. However, some countries that signed the Single Convention on Narcotic Drugs, such as the Netherlands, are more lenient with their enforcement of these laws.[54]

In the United States, the Food and Drug Administration (FDA) has authority over all drugs, including psychoactive drugs. The FDA regulates which psychoactive drugs are over the counter and which are only available with a prescription.[55] However, certain psychoactive drugs, like alcohol, tobacco, and drugs listed in the Single Convention on Narcotic Drugs are subject to criminal laws. The Controlled Substances Act of 1970 regulates the recreational drugs outlined in the Single Convention on Narcotic Drugs.[56] Alcohol is regulated by state governments, but the federal National Minimum Drinking Age Act penalizes states for not following a national drinking age.[57] Tobacco is also regulated by all fifty state governments.[58] Most people accept such restrictions and prohibitions of certain drugs, especially the "hard" drugs, which are illegal in most countries.[59][60][61]

In the medical context, psychoactive drugs as a treatment for illness is widespread and generally accepted. Little controversy exists concerning over the counter psychoactive medications in antiemetics and antitussives. Psychoactive drugs are commonly prescribed to patients with psychiatric disorders. However, certain critics believe that certain prescription psychoactives, such as antidepressants and stimulants, are overprescribed and threaten patients' judgement and autonomy.[62][63]

See also

References

Notes
  1. ↑ "CHAPTER 1 Alcohol and Other Drugs". ISBN 0-7245-3361-3 http://www.nt.gov.au/health/healthdev/health_promotion/bushbook/volume2/chap1/sect1.htm. Missing or empty |title= (help)
  2. ↑ "Will Your Retirement Home Have A Liquor License?". Forbes. 26 December 2013.
  3. ↑ Nelson, Max (2005). The Barbarian's Beverage: A History of Beer in Ancient Europe. Abingdon, Oxon: Routledge. p. 1. ISBN 0-415-31121-7. Retrieved 21 September 2010.
  4. ↑ Merlin, M.D (2003). "Archaeological Evidence for the Tradition of Psychoactive Plant Use in the Old World". Economic Botany 57 (3): 295–323. doi:10.1663/0013-0001(2003)057[0295:AEFTTO]2.0.CO;2.
  5. ↑ Early Holocene coca chewing in northern Peru Volume: 84 Number: 326 Page: 939–953
  6. ↑ "Coca leaves first chewed 8,000 years ago, says research". BBC News. December 2, 2010.
  7. ↑ Siegel, Ronald K (2005). Intoxication: The Universal Drive for Mind-Altering Substances. Park Street Press, Rochester, Vermont. ISBN 1-59477-069-7.
  8. ↑ Weil, Andrew (2004). The Natural Mind: A Revolutionary Approach to the Drug Problem (Revised edition). Houghton Mifflin. p. 15. ISBN 0-618-46513-8.
  9. ↑ The Hashish Eater (1857) pg. 181
  10. ↑ Samorini, Giorgio (2002). Animals And Psychedelics: The Natural World & The Instinct To Alter Consciousness. Park Street Press. ISBN 0-89281-986-3.
  11. ↑ Albert, David Bruce, Jr. (1993). "Event Horizons of the Psyche". Retrieved February 2, 2006.
  12. ↑ http://www.leap.cc/cms/index.php?name=Content&pid=5. Retrieved 2013-05-30. Missing or empty |title= (help)
  13. ↑ "5 Years After: Portugal's Drug Decriminalization Policy Shows Positive Results". Scientific American. Retrieved 2013-05-30.
  14. ↑ Lovett, Richard (24 September 2005). "Coffee: The demon drink?" (fee required). New Scientist (2518). Retrieved 2007-11-19.
  15. ↑ Bersani FS, Corazza O, Simonato P, Mylokosta A, Levari E, Lovaste R, Schifano F; Corazza; Simonato; Mylokosta; Levari; Lovaste; Schifano (2013). "Drops of madness? Recreational misuse of tropicamide collyrium; early warning alerts from Russia and Italy". General Hospital Psychiatry 35 (5): 571–3. doi:10.1016/j.genhosppsych.2013.04.013. PMID 23706777.
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  17. ↑ Li X, Pearce RA; Pearce (2000). "Effects of halothane on GABA(A) receptor kinetics: evidence for slowed agonist unbinding". The Journal of Neuroscience 20 (3): 899–907. PMID 10648694.
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  20. ↑ Matson, Johnny L.; Neal, Daniene (2009). "Psychotropic medication use for challenging behaviors in persons with intellectual disabilities: An overview". Research in Developmental Disabilities 30 (3): 572. doi:10.1016/j.ridd.2008.08.007. PMID 18845418.
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  22. ↑ Hirschfeld, Robert (2001). "Clinical importance of long-term antidepressant treatment". The British Journal of Psychiatry 179 (s42): s4–s8. doi:10.1192/bjp.179.42.s4.
  23. ↑ Neuroscience of Psychoactive Substance Use and Dependence by the World Health Organization. Retrieved 5 July 2007.
  24. ↑ Anderson TL (1998). "Drug identity change processes, race, and gender. III. Macrolevel opportunity concepts". Substance Use & Misuse 33 (14): 2721–35. doi:10.3109/10826089809059347. PMID 9869440.
  25. ↑ Bertol E, Fineschi V, Karch SB, Mari F, Riezzo I; Fineschi; Karch; Mari; Riezzo (2004). "Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology". Journal of the Royal Society of Medicine 97 (2): 84–5. doi:10.1258/jrsm.97.2.84. PMC: 1079300. PMID 14749409.
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  27. ↑ Barnett, Randy E. "The Presumption of Liberty and the Public Interest: Medical Marijuana and Fundamental Rights". Retrieved 4 July 2007.
  28. ↑ El-Seedi HR, De Smet PA, Beck O, Possnert G, Bruhn JG; De Smet; Beck; Possnert; Bruhn (2005). "Prehistoric peyote use: alkaloid analysis and radiocarbon dating of archaeological specimens of Lophophora from Texas". Journal of Ethnopharmacology 101 (1–3): 238–42. doi:10.1016/j.jep.2005.04.022. PMID 15990261.
  29. ↑ Vetulani J (2001). "Drug addiction. Part I. Psychoactive substances in the past and presence". Polish Journal of Pharmacology 53 (3): 201–14. PMID 11785921.
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