What is the Convention on Psychotropic Substances?

Introduction

The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February 1971.

The Single Convention on Narcotic Drugs of 1961 did not ban the many newly discovered psychotropics, since its scope was limited to drugs with cannabis, coca, and opium-like effects.

During the 1960s such drugs became widely available, and government authorities opposed this for numerous reasons, arguing that along with negative health effects, drug use led to lowered moral standards. The Convention, which contains import and export restrictions and other rules aimed at limiting drug use to scientific and medical purposes, came into force on 16 August 1976. As of 2013, 183 member states are Parties to the treaty. Many laws have been passed to implement the Convention, including the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act. Adolf Lande, under the direction of the United Nations Office of Legal Affairs, prepared the Commentary on the Convention on Psychotropic Substances. The Commentary, published in 1976, is an invaluable aid to interpreting the treaty and constitutes a key part of its legislative history.

Provisions to end the international trafficking of drugs covered by this Convention are contained in the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. This treaty, signed in 1988, regulates precursor chemicals to drugs controlled by the Single Convention and the Convention on Psychotropic Substances. It also strengthens provisions against money laundering and other drug-related crimes.

Brief History

International drug control began with the 1912 International Opium Convention, a treaty which adopted import and export restrictions on the opium poppy’s psychoactive derivatives. Over the next half-century, several additional treaties were adopted under League of Nations auspices, gradually expanding the list of controlled substances to encompass cocaine and other drugs and granting the Permanent Central Opium Board power to monitor compliance. After the United Nations was formed in 1945, those enforcement functions passed to the UN.

In 1961, a conference of plenipotentiaries in New York adopted the Single Convention on Narcotic Drugs, which consolidated the existing drug control treaties into one document and added Cannabis to the list of prohibited plants. In order to appease the pharmaceutical interests, the Single Convention’s scope was sharply limited to the list of drugs enumerated in the Schedules annexed to the treaty and to those drugs determined to have similar effects.

During the 1960s, drug use increased in Western developed nations. Young people began using hallucinogenic, stimulant, and other drugs on a widespread scale that has continued to the present. In many jurisdictions, police had no laws under which to prosecute users and traffickers of these new drugs; LSD, for instance, was not prohibited federally in the US until 1967.

In 1968, “[d]eeply concerned at reports of serious damage to health being caused by LSD and similar hallucinogenic substances,” the United Nations Economic and Social Council (ECOSOC) passed a resolution calling on nations to limit the use of such drugs to scientific and medical purposes and to impose import and export restrictions. Later that year, the UN General Assembly requested that ECOSOC call upon its Commission on Narcotic Drugs to “give urgent attention to the problem of the abuse of the psychotropic substances not yet under international control, including the possibility of placing such substances under international control”.

Circa 1969, with use of stimulants growing, ECOSOC noted with considerable consternation that the Commission “was unable to reach agreement on the applicability of the Single Convention on Narcotic Drugs, 1961 to these substances”. The language of the Single Convention and its legislative history precluded any interpretation that would allow international regulation of these drugs under that treaty. A new convention, with a broader scope, would be required in order to bring those substances under control. Using the Single Convention as a template, the Commission prepared a draft convention which was forwarded to all UN member states. The Secretary-General of the United Nations scheduled a conference for early 1971 to finalise the treaty.

Meanwhile, countries had already begun passing legislation to implement the draft treaty. In 1969, Canada added Part IV to its Food and Drugs Act, placing a set of “restricted substances,” including LSD, DMT, and MDA, under federal control. In 1970, the United States completely revamped its existing drug control laws by enacting the Controlled Substances Act (amended in 1978 by the Psychotropic Substances Act, which allows the US drug control Schedules to be updated as needed to comply with the Convention). In 1971, the United Kingdom passed the Misuse of Drugs Act 1971. A host of other nations followed suit. A common feature shared by most implementing legislation is the establishment of several classes or Schedules of controlled substances, similarly to the Single Convention and the Convention on Psychotropic Substances, so that compliance with international law can be assured simply by placing a drug into the appropriate Schedule.

The conference convened on 11 January 1971. Nations split into two rival factions, based on their interests. According to a Senate of Canada report, “One group included mostly developed nations with powerful pharmaceutical industries and active psychotropics markets . . . The other group consisted of developing states…with few psychotropic manufacturing facilities”. The organic drugmaking states that had suffered economically from the Single Convention’s restrictions on cannabis, coca, and opium, fought for tough regulations on synthetic drugs. The synthetic drug-producing states opposed those restrictions. Ultimately, the developing states’ lobbying power was no match for the powerful pharmaceutical industry’s, and the international regulations that emerged at the conference’s close on 21 February were considerably weaker than those of the Single Convention.

The Convention’s adoption marked a major milestone in the development of the global drug control regime. Over 59 years, the system had evolved from a set of loose controls focused on a single drug into a comprehensive regulatory framework capable of encompassing almost any mind-altering substance imaginable. According to Rufus King, “It covers such a grab-bag of natural and manufactured items that at every stage of its consideration its proponents felt obliged to stress anew that it would not affect alcohol or tobacco abuse.”

Member States

As of February 2018, there are 184 state parties to the convention. This total includes 182 member states of the United Nations, the Holy See, and the State of Palestine. The 11 UN member states that are not party to the convention are East Timor, Equatorial Guinea, Haiti, Kiribati, Liberia, Nauru, Samoa, Solomon Islands, South Sudan, Tuvalu, and Vanuatu. Liberia has signed the treaty but has not ratified it.

Schedules of Controlled Substances

The list of Schedules and the substances presently therein can be found on the International Narcotics Control Board’s (INCB) website.

The Convention has four Schedules of controlled substances, ranging from Schedule I (most restrictive) to Schedule IV (least restrictive). A list of psychotropic substances, and their corresponding Schedules, was annexed to the 1971 treaty. The text of the Convention does not contain a formal description of the features of the substances fitting in each Schedule, in contrast to the US Controlled Substances Act of 1970, which gave specific criteria for each Schedule in the US system. The amphetamine-type stimulants (ATS), a legal class of stimulants – not all of which are substituted amphetamines – were defined in the 1971 treaty and in subsequent revisions. A 2002 European Parliament report and a 1996 UNODC report on ATS describe the international Schedules as listed below.

Schedule IIncludes drugs claimed to create a serious risk to public health, whose therapeutic value is not currently acknowledged by the Commission on Narcotic Drugs. It includes isomers of THC, synthetic psychedelics such as LSD, and natural psychedelics like certain substituted tryptamines. ATS such as cathinone, MDA, and MDMA (ecstasy) also fall under this category.
Schedule IIIncludes certain ATS with therapeutic uses, such as delta-9-THC (including dronabinol, its synthetic form), amphetamine and methylphenidate.
Schedule IIIIncludes barbiturate products with fast or average effects, which have been the object of serious abuse even though useful therapeutically, strongly sedative benzodiazepines like flunitrazepam and some analgesics like buprenorphine. The only ATS in this category is cathine.
Schedule IVIncludes some weaker barbiturates like (phenobarbital) and other hypnotics, anxiolytic benzodiazepines (except flunitrazepam), and some weaker stimulants (such as modafinil and armodafinil). Over a dozen ATS are included in this category, including the substituted amphetamine phentermine.

A 1999 UNODC report notes that Schedule I is a completely different regime from the other three. According to that report, Schedule I mostly contains hallucinogenic drugs such as LSD that are produced by illicit laboratories, while the other three Schedules are mainly for legally produced pharmaceuticals. The UNODC report also claims that the Convention’s Schedule I controls are stricter than those provided for under the Single Convention, a contention that seems to be contradicted by the 2002 Senate of Canada and 2003 European Parliament reports.

Although estimates and other controls specified by the Single Convention are not present in the Convention on Psychotropic Substances, the International Narcotics Control Board corrected the omission by asking Parties to submit information and statistics not required by the Convention, and using the initial positive responses from various organic drug producing states to convince others to follow. In addition, the Convention does impose tighter restrictions on imports and exports of Schedule I substances. A 1970 Bulletin on Narcotics report notes:

LSD, mescaline, etc., are controlled in a way which is more stringent than morphine under the narcotics treaties. Article 7, which sets down this regime, provides that such substances can only be moved in international trade when both exporter and importer are government authorities, or government agencies or institutions specially authorized for the purpose; in addition to this very rigid identification of supplier and recipient, in each case export and import authorization is also mandatory.

Scheduling Process

Article 2 sets out a process for adding additional drugs to the Schedules. First, the World Health Organization (WHO) must find that the drug meets the specific criteria set forth in Article 2, Section 4, and thus is eligible for control. Then, the WHO issues an assessment of the substance that includes:

  • The extent or likelihood of abuse;
  • The degree of gravity in the public health and social problem;
  • The degree of utility of the substance in legitimate medical therapy; and
  • Whether international control measures as provided in the treaty would be appropriate and useful.

Article 2, Paragraph 4:

If the World Health Organization finds: (a) That the substance has the capacity to produce (i) (1) A state of dependence, and (2) Central nervous system stimulation or depression, resulting in hallucinations or disturbances in motor function or thinking or behaviour or perception or mood, or (ii) Similar abuse and similar ill effects as a substance in Schedule I, II, III or IV, and (b) That there is sufficient evidence that the substance is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of the substance under international control, the World Health Organization shall communicate to the Commission an assessment of the substance, including the extent or likelihood of abuse, the degree of seriousness of the public health and social problem and the degree of usefulness of the substance in medical therapy, together with recommendations on control measures, if any, that would be appropriate in the light of its assessment.

The Commentary gives alcohol and tobacco as examples of psychoactive drugs that were deemed to not fit the above criteria by the 1971 Conference which negotiated the Convention. Alcohol can cause dependence and central nervous depression resulting in disturbances of thinking and behaviour, furthermore alcohol causes similar effects as barbiturates, alcohol causes very serious “public health and social problems” in many countries, and also alcohol has minimal use in modern medicine. Nevertheless, according to the Commentary:

Alcohol does not ‘warrant’ that type of control because it is not ‘suitable’ for the regime of the Vienna Convention. It appears obvious that the application of the administrative measures for which that treaty provides would not solve or alleviate the alcohol problem.

Similarly, tobacco can cause dependence and has little medical use, but it was not considered to be a stimulant or depressant or to be similar to other scheduled substances. Most important, according to the Commentary:

[Tobacco] is not suitable for the kinds of controls for which the Vienna Convention provides, and which if applied would not make any useful impact on the tobacco problem. That problem, however serious, therefore does not ‘warrant’ the placing of tobacco ‘under international’ control, i.e. under the Vienna Convention.

The Commission on Narcotic Drugs makes the final decision on whether to add the drug to a Schedule, “taking into account the communication from the World Health Organisation [WHO], whose assessments shall be determinative as to medical and scientific matters, and bearing in mind the economic, social, legal, administrative and other factors it may consider relevant”. A similar process is followed in deleting a drug from the Schedules or transferring a drug between Schedules. For instance, at its 33rd meeting, the WHO Expert Committee on Drug Dependence recommended transferring tetrahydrocannabinol to Schedule IV of the Convention, citing its medical uses and low abuse potential. However, the Commission on Narcotic Drugs has declined to vote on whether to follow the WHO recommendation and reschedule tetrahydrocannabinol. The UN Economic and Social Council, as a parent body of the Commission on Narcotic Drugs, can alter or reverse the Commission’s scheduling decisions.

In the event of a disagreement about a drug’s Scheduling, Article 2, Paragraph 7 allows a Party to, within 180 days of the communication of the Commission’s decision, give the UN Secretary-General “a written notice that, in view of exceptional circumstances, it is not in a position to give effect with respect to that substance to all of the provisions of the Convention applicable to substances in that Schedule.” This allows the nation to comply with a less stringent set of restrictions. The US Controlled Substances Act’s 21 U.S.C. § 811(d)(4) implies that placing a drug in Schedule IV or V of the Act is sufficient to “carry out the minimum United States obligations under paragraph 7 of article 2 of the Convention”. This provision, which calls for temporarily placing a drug under federal drug control in the event the Convention requires it, was invoked in 1984 with Rohypnol (flunitrazepam). Long before abuse of the drug was sufficiently widespread in the United States to meet the Act’s drug control criteria, rohypnol was added to the Schedules of the Convention on Psychotropic Substances, and the US government had to place rohypnol in Schedule IV of the Controlled Substances Act in order to meet its minimum treaty obligations.

As of March 2005, 111 substances were controlled under the Convention.

WHO Evaluations of Specific Drugs

Ephedrine

In 1998, ephedrine was recommended for control under the Convention. The Dietary Supplement Safety and Science Coalition lobbied against control, stressing the drug’s history and safety, and arguing that “ephedrine is not a controlled substance in the US today, nor should it be internationally” because it is a soft stimulant similar to caffeine. After a two-year debate, the Expert Committee on Drug Dependence decided against regulating ephedrine. However, the Commission on Narcotics Drugs and the International Narcotics Control Board listed the drug as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances because ephedrine can be used as chemical precursor for synthetize or manufacture amphetamine or methamphetamine, both which are actually controlled substances, a move that did not require WHO approval.

Ketamine

The Expert Committee on Drug Dependence cautiously began investigating ketamine at its thirty-third meeting, noting, “Its use in veterinary medicine must also be considered in relation to its control”. Ketamine remains uncontrolled internationally, although many nations (e.g. USA and UK) have enacted restrictions on the drug.

MDMA

The Expert Committee’s evaluation of MDMA during its 22nd meeting in 1985 was marked by pleas from physicians to allow further research into the drug’s therapeutic uses. Paul Grof, chairman of the Expert Committee, argued that international control was not yet warranted, and that scheduling should be delayed pending completion of more studies. The Expert Committee concluded that because there was “insufficient evidence to indicate that the substance has therapeutic usefulness,” it should be placed in Schedule I. However, its report did recommend more MDMA research:

the Expert Committee held extensive discussions concerning therapeutic usefulness of 3,4 Methylenedioxymethamphetamine. While the Expert Committee found the reports intriguing, it felt that the studies lacked the appropriate methodological design necessary to ascertain the reliability of the observations. There was, however, sufficient interest expressed to recommend that investigations be encouraged to follow up these preliminary findings. To that end, the Expert Committee urged countries to use the provisions of Article 7 of the Convention on Psychotropic Substances to facilitate research on this interesting substance.

MDMA was added to the convention as a Schedule I controlled substance in February 1986.

MBDB

MBDB (Methylbenzodioxolylbutanamine) is an entactogen with similar effects to MDMA. The thirty-second meeting of the WHO Expert Committee on Drug Dependence (September 2000) evaluated MBDB and recommended against scheduling.

From the WHO Expert Committee assessment of MBDB:

Although MBDB is both structurally and pharmacologically similar to MDMA, the limited available data indicate that its stimulant and euphoriant effects are less pronounced than those of MDMA. There have been no reports of adverse or toxic effects of MBDB in humans. Law enforcement data on illicit trafficking of MBDB in Europe suggest that its availability and abuse may now be declining after reaching a peak during the latter half of the 1990s. For these reasons, the Committee did not consider the abuse liability of MBDB would constitute a significant risk to public health, thereby warranting its placement under international control. Scheduling of MBDB was therefore not recommended.

Methcathinone

Circa 1994, the United States government notified the UN Secretary General that it supported controlling methcathinone, an addictive stimulant manufactured with common household products, as a Schedule I drug under the Convention. The FDA report warned of the drug’s dangers, even noting that addicts in Russia were observed to often have “potassium permanganate burns on their fingers” and to “tend not to pay attention to their appearance, thus looking ragged with dirty hands and hair”. With methcathinone having no medical use, the decision to place the drug in Schedule I was uncontested.

Nicotine

Traditionally, the UN has been reluctant to control nicotine and other drugs traditionally legal in Europe and North America, citing tolerance of a wide range of lifestyles. This contrasts with the regulatory regime for other highly addictive drugs. Gabriel G. Nahas, in a Bulletin on Narcotics report, noted:

Some psychotropic substances such as nicotine, myristicin, ephedrine, mitraginyne, salvinorin A, arecoline, theophylline, theobromine, kava, khat, tobacco, L-theanine, or caffeine (in moderate amounts) or in moderate and responsible consumption, or alcoholic drinks (in small amounts or limited consumption) do not produce any measurable symptoms of neuropsychological toxicity, main physical damage, acute physical damage or main physical dependence or addiction, as also acute side effects or several adverse effects. Some pharmacologists have associated the symptoms of neuropsychological toxicity with behavioural toxicity or the toxic and addictive personality, the toxicity of drugs generally and overall depends by several factors as, envinonmental factors, economic factors, the field of the drug use, the place, the date, the time and social, psicological, emotional, mental, spiritual and intelectual factors that if are weak can to contribute as a risk factor or a risk behaviour. which include in addition: suppression of normal anxiety, toxic emotions, toxic relationships, toxic behavior, negative thinkings, reduction in motivation and non-purposive or inappropriate behaviour, illegal offense or inmoral act necessary. However, the latter behavioural symptoms do not present “markers” which may be measurable in societies accepting as “normal” a wide range of life styles.

Nonetheless, in October 1996, the Expert Committee considered controlling nicotine, especially products such as gum, patches, nasal spray, and inhalers. The UN ultimately left nicotine unregulated. Since then, nicotine products have become even more loosely controlled; Nicorette gum, for instance, is now an over-the-counter drug in the United States and in Finland, readily available in Finland from grocery stores and pharmacies. Another nicotine gum sold in Finland is called Nicotinell. All kinds of nicotine products are readily available in Finnish grocery stores and pharmacies.

Tetrahydrocannabinol

Tetrahydrocannabinol (THC), the main active ingredient in cannabis, was originally placed in Schedule I when the Convention was enacted in 1971. At its twenty-sixth meeting, in response to a 1987 request from the Government of the United States that THC be transferred from Schedule I to Schedule II, the WHO Expert Committee on Drug Dependence recommended that THC be transferred to Schedule II, citing its low abuse potential and “moderate to high therapeutic usefulness” in relieving nausea in chemotherapy patients. The Commission on Narcotic Drugs rejected the proposal. However, at its twenty-seventh meeting, the WHO Expert Committee again recommended that THC be moved to Schedule II. At its 45th meeting, on 29 April 1991, the Commission on Narcotic Drugs approved the transfer of dronabinol and its stereochemical variants from Schedule I to Schedule II of the Convention, while leaving other tetrahydrocannabinols and their stereochemical variants in Schedule I.

At its thirty-third meeting (September 2002), the WHO Committee issued another evaluation of the drug and recommended that THC be moved to Schedule IV, stating:

The abuse liability of dronabinol (delta-9-tetrahydrocannabinol) is expected to remain very low so long as cannabis continues to be readily available. The Committee considered that the abuse liability of dronabinol does not constitute a substantial risk to public health and society. In accordance with the established scheduling criteria, the Committee considered that dronabinol should be rescheduled to schedule IV of the 1971 Convention on Psychotropic Substances.

No action was taken on this recommendation. And at its thirty-fourth meeting the WHO Committee recommended that THC be moved instead to Schedule III. In 2007 the Commission on Narcotic Drugs decided not to vote on whether to reschedule THC, and they requested that the WHO make another review when more information is available.

In 2019, the WHO Expert Committee recommended that all isomers of THC be withdrawn from the Schedules of the 1971 Convention and included in the 1961 Convention alongside other Cannabis-related products and pharmaceutical preparations. However, this was rejected by a vote at the United Nations Commission on Narcotic Drugs on 02 December 2020.

2C-B (4-Bromo-2,5-dimethoxyphenethylamine)

2C-B is a psychedelic phenethylamine. At its thirty-second (September 2000) meeting the WHO Expert Committee on Drug Dependence recommended that 2C-B be placed in Schedule II, rather than with other scheduled psychedelics in Schedule I.

The committee stated that “[t]he altered state of mind induced by hallucinogens such as 2C-B may result in harm to the user and to others”, but did not cite any evidence.

From the WHO Expert Committee assessment of 2C-B:

At high doses it is a strong hallucinogen, producing particularly marked visual hallucinations with an intense colour play, intriguing patterns emerging on surfaces and distortions of objects and faces. 2C-B is also reported to enhance sexual feelings, perception and performance…. Apart from its controversial experimental use in psychotherapy, 2C-B, like most other hallucinogens, does not have any known therapeutic usefulness…. The Committee noted, however, that hallucinogens are rarely associated with compulsive use and that abuse of 2C-B has been infrequent, suggesting that the drug is likely to constitute a substantial, rather than an especially serious, risk to public health. For these reasons, the Committee recommended that 2C-B be placed in Schedule II of the 1971 Convention.

Medical and Scientific Uses

Like the Single Convention on narcotic medicines, the Convention on Psychotropic Substances recognizes scientific and medical use of psychoactive drugs, while banning other uses. Article 7 provides that:

In respect of substances in Schedule I, the Parties shall: (a) Prohibit all use except for scientific and very limited medical purposes by duly authorized persons, in medical or scientific establishments which are directly under the control of their Governments or specifically approved by them.

In this sense, the US Controlled Substances Act is stricter than the Convention requires. Both have a tightly restricted category of drugs called Schedule I, but the US Act restricts medical use of Schedule I substances to research studies, while the Convention allows broader, but limited and restriged, medical use of Schedule I controlled substances but scientific or industrial use of controlled substances is normally permitted.

Psychedelic Plants and Fungi

Several of the substances originally placed in Schedule I are psychedelic drugs which are contained in natural plants and fungi (such as peyote and psilocybin mushrooms) and which have long been used in religious or healing rituals. The Commentary notes the “Mexican Indian Tribes Mazatecas, Huicholes and Tarahumaras” as well as the “Kariri and Pankararu of eastern Brazil” as examples of societies that use such plants.

Article 32, paragraph 4 allows for States, at the time of signature, ratification or accession, to make a reservation noting an exemption for:

plants growing wild which contain psychotropic substances from among those in Schedule I and which are traditionally used by certain small, clearly determined groups in magical or religious rites.

However, the official Commentary on the Convention on Psychotropic Substances makes it clear that psychedelic plants (and indeed any plants) were not included in the original Schedules and are not covered or included at all by the Convention. This includes “infusion of the roots” of Mimosa tenuiflora (M. hostilis; which contains DMT) and “beverages” made from psilocybin mushrooms or psychotropic acacias, the latter of which are used in the DMT-containing beverage known colloquially as Ayahuasca. The purpose of Paragraph 4 of Article 32 was to allow States to “make a reservation assuring them the right to permit the continuation of the traditional use in question” in the case that plants were in the future added to the Schedule I. Currently, naught plants or plant products are included in the Schedules of the 1971 Convention.

Commentary 32-12: It may be pointed out that at the time of this writing the continued toleration of the use of hallucinogenic substances which the 1971 Conference had in mind would not require a reservation under paragraph 4. Schedule I does not list any of the natural hallucinogenic materials in question, but only chemical substances which constitute the active principles contained in them. The inclusion in Schedule I of the active principle of a substance does not mean that the substance itself is also included therein if it is a substance clearly distinct from the substance constituting its active principle. This view is in accordance with the traditional understanding of that question in the field of international drug control. Neither the crown (fruit, mescal button) of the Peyote cactus nor the roots of the plant Mimosa hostilis, Peganum Harmala that contains Harmala alkaloids or Syrian Rue, or Hawaiian Baby Woodrose plant and morning glory flowers that contains LSA or Lysergic Acid Amide or the Chacruna, a psychotropic shrub or plant which is used for make the Ayahuasca brew, [Footnote: “An infusion of the roots is used”] nor Psilocybe mushrooms [Footnote: “Beverages made from such mushrooms are used”] themselves are included in Schedule I, but only their respective active principles, mescaline, DMT and psilocybine (psilocine, psilotsin).

Commentary 32-13: It can however not be excluded that the fruit of the Peyote cactus, the roots of Mimosa hostilis, Psilocybe mushrooms or other hallucinogenic plant parts used in traditional magical or religious rites will in the future be placed in Schedule I by the operation of article 2, at a time at which the State concerned, having already deposited its instrument of ratification or accession, could no longer make the required reservation. It is submitted that Parties may under paragraph 4 make a reservation assuring them the right to permit the continuation of the traditional use in question in the case of such future actions by the Commission.

Furthermore, in a letter, dated 13 September 2001, to the Dutch Ministry of Health, Herbert Schaepe, Secretary of the UN International Narcotics Control Board, clarified that the UN Conventions do not cover “preparations” of psilocybin mushrooms:

As you are aware, mushrooms containing the above substances are collected and abused for their hallucinogenic effects. As a matter of international law, no plants (natural material) containing psilocine and psilocybin are at present controlled under the Convention on Psychotropic Substances of 1971. Consequently, preparations made of these plants are not under international control and, therefore, not subject of the articles of the 1971 Convention. However, criminal cases are decided with reference to domestic law, which may otherwise provide for controls over mushrooms containing psilocine and psilocybin. As the Board can only speak as to the contours of the international drug conventions, I am unable to provide an opinion on the litigation in question.

Nonetheless, in 2001 the US Government, in Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, argued that ayahuasca, an infusion of Mimosa hostilis and other psychoactive plants that is used in religious rituals, was prohibited in the US because of the 1971 Convention. That case involved a seizure by US Customs and Border Protection of several drums of DMT-containing liquid. Plaintiffs sued to have the drugs returned to them, claiming that they used it as a central part of their religion.

In the discussions on Article 32, paragraph 4, noted in the Official Record of the 1971 Conference, the representative from the United States supported the explicit exemption of sacred psychoactive substances, stating: “Substances used for religious services should be placed under national rather than international control”, while the representative of the Holy See observed: “If exemptions were made in favour of certain ethnic groups, there would be nothing to prevent certain organizations of hippies from trying to make out, on religious grounds, that their consumption of psychotropic substances was permissible.”

Organic Plants

The Commentary on the Convention on Psychotropic Substances notes that while many plant-derived chemicals are controlled by the treaty, the plants themselves are not:

The term “synthetic” appears to refer to a psychotropic substance manufactured by a process of full chemical synthesis. One may also assume that the authors of the Vienna Convention intended to apply the term “natural material” to parts of a plant which constitute a psychotropic substance, and the term “natural psychotropic substance” to a substance obtained directly from a plant by some process of manufacturing which was relatively simple, and in any event much simpler than a process of full chemical synthesis.
(…)
Cultivation of plants for the purpose of obtaining psychotropic substances or raw materials for the manufacture of such substances is not “manufacture” in the sense of Article 1, paragraph (i). Many provisions of the Vienna Convention governing psychotropic substances would be unsuitable for application to cultivation. The harvesting of psychotropic substances, i.e. separation of such substances from the plants from which they are obtained, is “manufacture”.
(…)
The cultivation of plants from which psychotropic substances are obtained is not controlled by the Vienna Convention. (…) Neither the crown (fruit, mescal button) of the Peyote cactus nor the roots of the plant Mimosa hostilis nor Psilocybe mushrooms themselves are included in Schedule 1, but only their respective principles, Mescaline, DMT and Psilocybin.

Mexico, in particular, argued that “production” of psychotropic drugs should not apply to wild-growing plants such as peyote cacti or psilocybin mushrooms. The Bulletin on Narcotics noted that “Mexico could not undertake to eradicate or destroy these plants”. Compared to the Single Convention on Narcotic Drugs (which calls for “uprooting of all coca bushes which grow wild” and governmental licensing, purchasing, and wholesaling of licit opium, coca, and cannabis crops), the Convention on Psychotropic Substances devotes few words to the subject of psychoactive plants.

On 02 July 1987, the United States Assistant Secretary of Health recommended that the Drug Enforcement Administration initiate scheduling action under the Controlled Substances Act in order to implement restrictions required by cathinone’s Schedule I status under the Convention. The 1993 DEA rule placing cathinone in the CSA’s Schedule I noted that it was effectively also banning khat:

Cathinone is the major psychoactive component of the plant Catha edulis (khat). The young leaves of khat are chewed for a stimulant effect. Enactment of this rule results in the placement of any material which contains cathinone into Schedule I.

Precursors

A 1971 Bulletin on Narcotics notes:

Article 2, in paragraph 4 of the original text, carried over the concept in Article 3 (3) (iii) of the Single Convention, and required the application to a “precursor ” – i.e. a substance “readily convertible” into a substance under control – of measures of control. In Vienna the complexity of controlling precursors of psychotropic substances was agreed to be so overwhelming that no absolute obligation to control them was provided. The new article 2 in paragraph 9 asks Parties “to use their best endeavours” to apply “such measures of supervision as may be practicable” to substances which may be used in the illicit manufacture of psychotropic substances, i.e. their precursors and possibly also substances essential in the chemistry of manufacture.

This provision was eventually judged to be inadequate, and was strengthened by the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances’ precursor control regime, which established two Tables of controlled precursors. The Commission on Narcotic Drugs and International Narcotics Control Board were put in charge of adding, removing, and transferring substances between the Tables.

Analogues

Circa 1999, the Government of Spain proposed amending Schedules I and II to include isomers, esters, ethers, salts of isomers, esters and ethers, and any “substance resulting from modification of the chemical structure of a substance already in Schedule I or II and which produced pharmacological effects similar to those produced by the original substances”. The WHO opposed this change. The Commission on Narcotic Drugs did amend the Schedules to include stereoisomerisms, however, with the understanding that “specific isomers that did not have hazardous pharmacological activity and that posed no danger to society could be excluded from control, as dextromethorphan had been in the case of Schedule I of the 1961 Convention.”

Penal Provisions

Article 22 provides:

  1. (a) Subject to its constitutional limitations, each Party shall treat as a punishable offence, when committed intentionally, any action contrary to a law or regulation adopted in pursuance of its obligations under this Convention, and shall ensure that serious offences shall be liable to adequate punishment, particularly by imprisonment or other penalty of deprivation of liberty.
  2. (b) Notwithstanding the preceding sub-paragraph, when abusers of psychotropic substances have committed such offences, the Parties may provide, either as an alternative to conviction or punishment or in addition to punishment, that such abusers undergo measures of treatment, education, after-care, rehabilitation and social reintegration in conformity with paragraph 1 of article 20.

Conspiracy, attempts, preparatory acts, and financial operations related to drug offenses are also called on to be criminalised. Parties are also asked to count convictions handed down by foreign governments in determining recidivism. Article 22 also notes that extradition treaties are “desirable”, although a nation retains the right to refuse to grant extradition, including “where the competent authorities consider that the offence is not sufficiently serious.”

As with all articles of the Convention on Psychotropic Substances, the provisions of Article 22 are only suggestions which do not override the domestic law of the member countries:

  • The provisions of this article shall be subject to the provisions of the domestic law of the Party concerned on questions of jurisdiction.
  • Nothing contained in this article shall affect the principle that the offences to which it refers shall be defined, prosecuted and punished in conformity with the domestic law of a Party.

Treatment and Prevention

Article 22 allows Parties, in implementing the Convention’s penal provisions, to make exceptions for drug abusers by substituting “treatment, education, after-care, rehabilitation and social reintegration” for imprisonment. This reflects a shift in focus in the war on drugs from incarceration to treatment and prevention that had already begun to take hold by 1971. Indeed, in 1972, a parallel provision allowing treatment for drug abusers was added to the Single Convention on Narcotic Drugs by the Protocol Amending the Single Convention on Narcotic Drugs.

Article 20 mandates drug treatment, education, and prevention measures and requires Parties to assist efforts to “gain an understanding of the problems of abuse of psychotropic substances and of its prevention” and to “promote such understanding among the general public if there is a risk that abuse of such substances will become widespread.” To comply with these provisions, most Parties financially support organisations and agencies dedicated to these goals. The United States, for instance, established the National Institute on Drug Abuse in 1974 to comply with the research requirement and began sponsoring Drug Abuse Resistance Education in 1983 to help fulfil the educational and prevention requirements.

Rise in Stimulant Trafficking

Control of stimulants has become a major challenge for the UN. In 1997, the World Drug Report warned:

Since the mid-1980s the world has faced a wave of synthetic stimulant abuse, with approximately nine times the quantity seized in 1993 than in 1978, equivalent to an average annual increase of 16 per cent. The principle synthetic drugs manufactured clandestinely are the amphetamine-type stimulants (ATS) which include the widely abused amphetamine and methamphetamine, as well as the more recently popularized methylenedioxymethamphetamine (MDMA), known as ecstasy.” It is estimated that throughout the world 30,000,000, people use ATS. This is 0.5 per cent of the global population and exceeds the number using heroin and probably those using cocaine.

A 1998 UN General Assembly Special Session on the World Drug Problem report noted:

Between 1971 and 1995, there was a nearly fivefold increase in the number of amphetamine-type stimulants under international control. . . ecstasy and related designer drugs are under schedule one of the 1971 Convention, because they have virtually no medical use, while amphetamine and methamphetamine are under schedule 2 because they began life with medical use. But even though they are scheduled, the system is not really working for these illegally produced drugs. One of the main limitations of the control system is that the Psychotropic Convention was not designed to control illicit markets. It was designed to control and regulate legitimate pharmaceutical markets to prevent their diversion into illicit markets.

The report mentioned proposals to increase the flexibility of scheduling drugs under the Convention and to amend the drug-control treaties to make them more responsive to the current situation. Neither proposal has gained traction, however. Due to the ease of manufacturing methamphetamine, methcathinone, and certain other stimulants, control measures are focusing less on preventing drugs from crossing borders. Instead, they are centring on increasingly long prison sentences for manufacturers and traffickers as well as regulations on large purchases of precursors such as ephedrine and pseudoephedrine. The International Narcotics Control Board and Commission on Narcotic Drugs help coordinate this fight by adding additional precursors to the Tables of chemicals controlled under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

In 1997, ECOSOC called on nations to help enforce international law by cooperating “with relevant international organizations, such as Interpol and the World Customs Organization . . . in order to promote coordinated international action in the fight against illicit demand for and supply of amphetamine-type stimulants and their precursors.” That resolution also called on governments overseeing precursor exports “to inquire with the authorities of importing States about the legitimacy of transactions of concern, and to inform the International Narcotics Control Board of the action taken, particularly when they do not receive any reply to their inquiries”.

Pockets of high-intensity clandestine production and trafficking, such as rural southwest Virginia, exist in most industrialised nations. However, the United Nations Office on Drugs and Crime believes that East Asia (particularly Thailand) now has the most serious amphetamine-type stimulant (ATS) problem in the world. A 2002 report by that agency noted:

For many countries the problem of ATS is relatively new, growing quickly and unlikely to go away. The geographical spread is widening. . . Abuse is increasingly concentrated among younger populations, who generally and erroneously believe that the substances are safe and benign. The abuse of ATS is threatening to become part of mainstream culture. The less optimistic suggest that ATS is already embedded in normative young adult behavior to such an extent that it will be very difficult to change, notwithstanding the issues of physical, social and economic damage.

The Office called on nations to bring more resources to bear in the demand reduction effort, improving treatment and rehabilitation processes, increasing private sector participation in eliminating drugs from the workplace, and expanding the drug information clearing house to share information more effectively.

Canadian Noncompliance

In 2000, the International Narcotics Control Board chastised Canada for refusing to comply with the Convention’s requirement that international transactions in controlled psychotropics be reported to the Board. INCB Secretary Herbert Schaepe said:

From Canada there is just a big, black hole. We don’t know what is going into the country, nor coming out. We cannot monitor the international movement of these substances, which is our mandate. The lack of controls in Canada means that they could be destined for fake companies that will divert them into the hands of traffickers. Traffickers in third countries could be getting them through Canada. Normally, Canada has a very good reputation for fulfilling its international obligations, but here it is just breaking the treaty – a treaty that it ratified a long time ago. It is very disturbing.

Licit Drug Problems

In an unusual departure from its normally pro-industry leanings, the INCB issued a press release in 2001 warning of excessive use of licit psychotropics:

. . . the Board points to loose regulation, unreliable estimates and information regarding medical needs, aggressive marketing techniques and improper or even unethical prescription practices as the main reasons for the oversupply of such controlled substances as benzodiazepines and various amphetamine type stimulants. Easy availability leads to overconsumption of such substances, either in the form of drug abuse or by fuelling a culture of drug-taking to deal with a variety of non-medical problems. . . Insomnia, anxiety, obesity and child hyperactivity as well as various kinds of pain are listed among the most common problems to be treated by prescribing psychotropic substances. The Board is especially concerned that preference is given to quick solutions without looking at the long-term effects, as prolonged, excessive consumption of such drugs could result in dependency and other physical and mental suffering.

The Board also warned that the Internet provides “easy access to information on drug production and drug-taking,” calling it “a growing source of on-line drug trafficking.” The Board pointed out that some Internet suppliers sell controlled drugs without regard to the Convention’s medical prescription requirements.

List of Controlled Psychotropic Substances

Statistics

All Schedules consist of 116 positions and common generalization clause for salts. Schedule I also contains generalization clause for stereoisomers. There are also 2 specific generalizations, both for tetrahydrocannabinol stereochemical variants. There are no exclusions.

  • 116 positions:
    • 20 psychedelics.
      • 14 phenethylamine psychedelics.
      • 5 tryptamine psychedelics.
      • 1 ergoline.
    • 28 stimulants (excluding lefetamine).
    • 2 synthetic cannabinoids.
    • 2 positions representing 7 tetrahydrocannabinol isomers and their stereochemical variants.
    • 4 dissociatives.
    • 56 depressants.
      • 12 barbiturates.
      • 36 benzodiazepines (including 1 z-drug).
      • 2 carbamates.
      • 2 qualones.
      • 4 other depressants.
    • 1 position – zipeprol.
    • 1 position – lefetamine (with stimulant and opioid effects).
    • 1 semisynthetic opioid.
    • 1 synthetic benzomorphan opioid.

Schedule I

Contains 62 positions (including 1 position for six tetrahydrocannabinol isomers), generalisation clause for stereoisomers, specific generalisation for tetrahydrocannabinol stereochemical variants and common generalisation clause for salts.

  • 28 positions:
    • 19 psychedelics.
      • 13 phenethylamine psychedelics.
      • 5 tryptamine psychedelics.
      • 1 ergoline.
    • 3 stimulants.
    • 2 synthetic cannabinoids.
    • 1 position representing 6 isomers of tetrahydrocannabinol and their stereochemical variants.
    • 3 dissociatives.
  • Phenethylamine psychedelics:
    • 2,5-Dimethoxy-4-bromoamphetamine (DOB).
    • Dimethoxyamphetamine (DMA).
    • 2,5-Dimethoxy-4-ethylamphetamine(DOET).
    • methylenedioxyhydroxyamphetamine (MDOH).
    • methylenedioxyethylamphetamine (MDEA).
    • 3,4-methylenedioxy-N-methylamphetamine (MDMA).
    • Mescaline.
    • MMDA.
    • 4-MTA.
    • Para-methoxyamphetamine (PMA).
    • DOM (STP).
    • Tenamfetamine (MDA).
    • Trimethoxyamphetamine (TMA).
  • Tryptamine psychedelics:
    • Diethyltryptamine (DET).
    • Dimethyltryptamine (DMT).
    • Etryptamine (αET).
    • Psilocin.
    • Psilocybin.
  • Stimulants:
    • Cathinone.
    • Methcathinone.
    • 4-methylaminorex.
  • Synthetic cannabinoids:
    • Dimethylheptylpyran (DMHP).
    • Parahexyl.
  • Isomers of natural tetrahydrocannabinol:
    • Tetrahydrocannabinol, the following isomers and their stereochemical variants:
      • (9R)-Δ6a(10a)-tetrahydrocannabinol – 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
      • (9R,10aR)-Δ6a(7)-tetrahydrocannabinol – (9R,10aR)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
      • (6aR,9R,10aR)-Δ7-tetrahydrocannabinol – (6aR,9R,10aR)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
      • (6aR,10aR)-Δ8-tetrahydrocannabinol – (6aR,10aR)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
      • (6aR,9R)-Δ10-tetrahydrocannabinol – 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
      • (6aR,10aR)-Δ9(11)-tetrahydrocannabinol – (6aR,10aR)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.
  • Dissociatives:
    • Eticyclidine (PCE).
    • Rolicyclidine (PHP, PCPy).
    • Tenocyclidine (TCP).
  • Ergolines:
    • LSD.

The stereoisomers of substances in Schedule I are also controlled, unless specifically excepted, whenever the existence of such stereoisomers is possible within the specific chemical designation.

Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.

Schedule II

Contains 17 positions, specific generalisation for tetrahydrocannabinol stereochemical variants and common generalisation clause for salts.

  • 19 positions:
    • 12 stimulants.
    • 1 phenethylamine psychedelic.
    • 1 position representing an isomer of tetrahydrocannabinol and its stereochemical variants.
    • 3 depressants.
      • 1 barbiturate.
      • 2 qualones.
    • 1 dissociative.
    • 1 position – zipeprol.
  • Stimulants:
    • Amineptine.
    • Amphetamine and its isomers (dextroamphetamine and levoamphetamine).
    • Fenethylline.
    • Methamphetamine and its isomers (dextromethamphetamine and levomethamphetamine).
    • Methylphenidate and its isomers (dextromethylphenidate and levomethylphenidate).
    • Phenmetrazine.
    • a-PVP.
    • N-Ethylpentylone.
  • Phenethylamine psychedelics:
    • 2C-B.
  • Natural cannabinols:
    • Δ9-tetrahydrocannabinol – (6aR,10aR)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, and its stereochemical variants (dronabinol is the international non-proprietary name, although it refers to only one of the stereochemical variants of delta-9-tetrahydrocannabinol, namely (−)-trans-delta-9-tetrahydrocannabinol).
  • Depressants (qualones):
    • Mecloqualone.
    • Methaqualone.
  • Dissociatives:
    • Phencyclidine (PCP).
  • Other:
    • Zipeprol.

Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.

Schedule III

Contains 9 positions and common generalisation clause for salts.

  • 9 positions:
    • 6 depressants.
      • 4 barbiturates.
      • 1 benzodiazepine.
      • 1 other depressant.
    • 1 semisynthetic opioid.
    • 1 synthetic benzomorphan opioid.
    • 1 stimulant.
  • Depressants (barbiturates):
    • Amobarbital.
    • Butalbital.
    • Cyclobarbital.
    • Pentobarbital.
  • Depressants (other):
    • Glutethimide.
  • Semisynthetic agonist-antagonist opioids:
    • Buprenorphine.
  • Synthetic agonist-antagonist opioids – benzomorphans:
    • Pentazocine.
  • Stimulants:
    • Cathine.

Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.

Schedule IV

Contains 62 positions and common generalisation clause for salts.

  • Schedule IV (62):
    • 47 depressants.
      • 7 barbiturates.
      • 35 benzodiazepines (including 1 z-drug).
      • 2 carbamates.
      • 3 other depressants.
    • 14 stimulants.
    • 1 position – lefetamine (with stimulant and opioid effects).
  • Depressants (barbiturates):
    • Allobarbital.
    • Barbital.
    • Butobarbital.
    • Methylphenobarbital.
    • Phenobarbital.
    • Butabarbital.
    • Vinylbital.
  • Depressants (carbamates):
    • Ethinamate.
    • Meprobamate.
  • Depressants (other):
    • Ethchlorvynol.
    • Gamma-hydroxybutyric acid (GHB).
    • Methyprylon.
  • Stimulants:
    • Amfepramone.
    • Aminorex.
    • Benzphetamine.
    • Etilamfetamine.
    • Fencamfamine.
    • Fenproporex.
    • Mazindol.
    • Mefenorex.
    • Mesocarb.
    • Pemoline.
    • Phendimetrazine.
    • Phentermine.
    • Pipradrol.
    • Pyrovalerone.
  • Drugs with both stimulant and opioid effects:
    • Lefetamine (SPA) – open chain opioid having also stimulant effects.

Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.

Regulated Elsewhere

  • Ephedrine (as well as pseudoephedrine and norephedrine) is regulated as an UN-controlled drug precursor.

The following are scheduled by Single Convention on Narcotic Drugs.

  • Cannabis:
    • Cannabis – the flowering or fruiting tops of the cannabis plant (resin not extracted).
    • Cannabis resin – the separated resin, crude or purified, obtained from the cannabis plant.
    • Extracts and tinctures of cannabis.
  • Coca leaf, cocaine and ecgonine:
    • Coca leaf – the leaf of the coca bush (plant material), except a leaf from which all ecgonine, cocaine and any other ecgonine alkaloids have been removed.
    • Cocaine (methyl ester of benzoylecgonine) – an alkaloid found in coca leaves or prepared by synthesis from ecgonine.
    • Ecgonine – its esters and derivatives which are convertible to ecgonine and cocaine.

All other drugs scheduled by the narcotic convention are agonist-only opioids (and natural sources of them).

Not Scheduled by UN Conventions

Plants being the source of substances scheduled by this convention are not scheduled (see Psychedelic plants and fungi and Organic plants sections).

Partial list of psychotropic substances currently or formerly used in medicine, but not scheduled:

  • Ketamine (dissociative) and its stereoisomer esketamine.
  • Modafinil (stimulant), its stereoisomer armodafinil, and a similar drug adrafinil.
  • Dextromethorphan (dissociative, used medically as a cough suppressant) and its metabolite dextrorphan.
  • Diphenhydramine and dimenhydrinate (deliriants).
  • Benzydamine (deliriant and stimulant, used medically as a non-steroidal anti-inflammatory drug).
  • Propofol and fospropofol (anaesthetics).
  • Sodium thiopental (barbiturate).
  • Zaleplon (depressant z-drug).
  • Zopiclone (depressant z-drug) and its stereoisomer eszopiclone.
  • Nalbuphine (agonist-antagonist opioid).
  • Butorphanol (agonist-antagonist opioid).

Of course there are also many designer drugs, not used in medicine.

What is an Antipsychotic?

Introduction

Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders.

They are also the mainstay together with mood stabilisers in the treatment of bipolar disorder.

Recent research has shown that use of any antipsychotic results in smaller brain tissue volumes and that this brain shrinkage is dose dependent and time dependent. A review of the research has also reinforced this effect.

The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome. Long-term use can produce adverse effects such as tardive dyskinesia.

First-generation antipsychotics, known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s. Second-generation drugs, known as atypical antipsychotics, were introduced firstly with clozapine in the early 1970s followed by others. Both generations of medication block receptors in the brain for dopamine, but atypicals tend to act on serotonin receptors as well. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of) – thus meaning “which takes the nerve” – refers to both common neurological effects and side effects.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent “pharmacological lobotomy”. Lobotomy at the time was used to treat many behavioural disorders, including psychosis, although its effect was to markedly reduce behaviour and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been discovered by an approach that incorporates this sort of information.

The discovery of chlorpromazine’s psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, non-manic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquiliser to differentiate reserpine from the older sedatives. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term “ataraxy” was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective “ἀτάρακτος” (ataraktos), which means “not disturbed, not excited, without confusion, steady, calm”. In the use of the terms “tranquiliser” and “ataractic”, medical practitioners distinguished between the “major tranquilizers” or “major ataractics”, which referred to drugs used to treat psychoses, and the “minor tranquilizers” or “minor ataractics”, which referred to drugs used to treat neuroses. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favour of “antipsychotic”, which refers to the drug’s desired effects. Today, “minor tranquiliser” can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which have some antipsychotic properties and are recommended for concurrent use with antipsychotics, and are useful for insomnia or drug-induced psychosis. They are potentially addictive sedatives.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The difference between first- and second-generation antipsychotics is a subject of debate. The second-generation antipsychotics are generally distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.

Medical Uses

Antipsychotics are most frequently used for the following conditions:

  • Schizophrenia.
  • Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabiliser (in the case of the bipolar subtype).
  • Bipolar disorder (acute mania and mixed episodes) may be treated with either typical or atypical antipsychotics, although atypical antipsychotics are usually preferred because they tend to have more favourable adverse effect profiles and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.
  • Psychotic depression. In this indication it is a common practice for the psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.
  • Treatment resistant depression as an adjunct to standard antidepressant therapy.

Antipsychotics are generally not recommended for treating behavioural problems associated with dementia, given that the risk of use tends to be greater than the potential benefit. The same can be said for insomnia, in which they are not recommended as first-line therapy. There are evidence-based indications for using antipsychotics in children (e.g. tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g. to treat behavioural problems) warrants significant caution.

Schizophrenia

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (memory impairments, reduced ability to plan and execute tasks). In general, the efficacy of antipsychotic treatment in reducing both positive and negative symptoms appears to increase with increasing severity of baseline symptoms. All antipsychotic medications work relatively the same way, by antagonising D2 dopamine receptors. However, there are some differences when it comes to typical and atypical antipsychotics. For example, atypical antipsychotic medications have been seen to lower the neurocognitive impairment associated with schizophrenia more so than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis in those showing symptoms that suggest that they are at high risk of developing psychosis, treatment of first episode psychosis, maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse), and treatment of recurrent episodes of acute psychosis.

Prevention of Psychosis and Symptom Improvement

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low-level psychotic symptoms and cognitive disturbances, are used to evaluate people with early, low-level symptoms of psychosis. Test results are combined with family history information to identify patients in the “high-risk” group; they are considered to have a 20-40% risk of progression to frank psychosis within two years. These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, clinical trials to date show little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms, either alone or in combination with cognitive behavioural therapy (CBT).

First Episode Psychosis

First episode psychosis (FEP), is the first time that psychotic symptoms are presented. NICE recommends that all persons presenting with first episode psychosis be treated with both an antipsychotic drug, and CBT. NICE further recommends that those expressing a preference for CBT alone are informed that combination treatment is more effective. A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.

The conversion rate for a first episode drug induced psychosis to bipolar disorder or schizophrenia are lower, with 30% of people converting to either bipolar disorder or schizophrenia. NICE makes no distinction between a substance-induced psychosis, and any other form of psychosis. The rate of conversion differs for different classes of drug.

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews. The goals of treatment for FEP include reducing symptoms and potentially improving long-term treatment outcomes. Randomised clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. Evidence that early treatment has a favourable effect on long term outcomes is equivocal.

Recurrent Psychotic Episodes

Placebo controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5. There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents. The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.

Maintenance Therapy

The majority of patients treated with an antipsychotic drug will experience a response within four weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.

Maintenance therapy with antipsychotic drugs is clearly superior to placebo in preventing relapse but is associated with weight gain, movement disorders, and high dropout rates. A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.

While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalisation compared to those that stopped taking antipsychotics. The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomised clinical trials, suggest that most patients who discontinue treatment do so because of suboptimal efficacy. If someone experiences psychotic symptoms due to nonadherence, they may be compelled to treatment through a process called involuntary commitment, in which they can be forced to accept treatment (including antipsychotics). A person can also be committed to treatment outside of a hospital, called outpatient commitment.

Antipsychotics in long-acting injectable (LAI), or “depot”, form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance). NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority. LAIs are used to ensure adherence in outpatient commitment. A meta-analysis found that LAIs resulted in lower rates of rehospitalisation with a hazard ratio of 0.83, however these results were not statistically significant (the 95% confidence interval was 0.62 to 1.11).

Bipolar Disorder

Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder. The reason for this combination is the therapeutic delay of the aforementioned mood stabilisers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs. The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.

Three atypical antipsychotics (lurasidone, olanzapine and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine and quetiapine have been proven to be effective broad-spectrum (i.e. against all three types of relapse – manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.

The American Psychiatric Association and the UK National Institute for Health and Care Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes. They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of “compliance” or “adherence” with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalisation.

Dementia

Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of Federal Drug Administration (FDA) approval and black-box warnings, atypical antipsychotics are often prescribed to people with dementia. An assessment for an underlying cause of behaviour is needed before prescribing antipsychotic medication for symptoms of dementia. Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others. Psychosocial interventions may reduce the need for antipsychotics. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Major Depressive Disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder. Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received FDA labelling for this indication. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants. The greater risk of serious side effects with antipsychotics is why, e.g. quetiapine was denied approval as monotherapy for major depressive disorder or generalised anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.

Other

Besides the above uses antipsychotics may be used for obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder. The atypical antipsychotic risperidone may be useful for OCD. The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit and concerns regarding adverse effects. Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.

In children they may be used in those with disruptive behaviour disorders, mood disorders and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common. The situation is similar for those on the autism spectrum. Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, personality disorders, Tourette’s) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the FDA for the treatment of irritability in autistic children and adolescents.

Aggressive challenging behaviour in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomised controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behaviour when other treatments have not worked. They have not been found to be useful for the prevention of delirium among those admitted to hospital.

Typicals vs Atypicals

It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics. Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.

Clozapine is an effective treatment for those who respond poorly to other drugs (“treatment-resistant” or “refractory” schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project). No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes. In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter. NICE recently revised its recommendation favouring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient’s preferences.

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypical

Adverse Effects

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.

Very rarely antipsychotics may cause tardive psychosis.

By Rate

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

  • Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine).
  • Headaches.
  • Dizziness.
  • Diarrhoea.
  • Anxiety.
  • Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
    • Akathisia, an often distressing sense of inner restlessness.
    • Dystonia, an abnormal muscle contraction.
    • Pseudoparkinsonism, symptoms that are similar to what people with Parkinson’s disease experience, including tremulousness and drooling.
  • Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
    • Galactorrhoea, the unusual secretion of breast milk.
    • Gynaecomastia, abnormal growth of breast tissue.
    • Sexual dysfunction (in both sexes).
    • Osteoporosis.
  • Orthostatic hypotension.
  • Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine).
  • Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone) such as:
    • Blurred vision.
    • Constipation.
    • Dry mouth (although hypersalivation may also occur).
    • Reduced perspiration.
  • Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterised by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs, or torso, which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used).

Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

  • Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropoenia), which is more common in patients on clozapine.
  • Metabolic syndrome and other metabolic problems such as type II diabetes mellitus – particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus. Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appear to be mediated by the following mechanisms:
    • Causing weight gain by antagonising the histamine H1 and serotonin 5-HT2Creceptors] and perhaps by interacting with other neurochemical pathways in the central nervous system.
  • Neuroleptic malignant syndrome, a potentially fatal condition characterised by:
    • Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
    • Hyperthermia – elevated body temperature.
    • Mental status change (confusion, hallucinations, coma, etc.).
    • Muscle rigidity.
    • Laboratory abnormalities (e.g. elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.).
  • Pancreatitis.
  • QT interval prolongation – more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
  • Torsades de pointes.
  • Seizures, particularly in people treated with chlorpromazine and clozapine.
  • Thromboembolism.
  • Myocardial infarction.
  • Stroke.

Long-Term Effects

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder. Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it. Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.

Loss of grey matter and other brain structural changes over time are observed amongst people diagnosed with schizophrenia. Meta-analyses of the effects of antipsychotic treatment on grey matter volume and the brain’s structure have reached conflicting conclusions. A 2012 meta-analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation. A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss. Animal studies found that monkeys exposed to both first- and second-generation antipsychotics experience significant reduction in brain volume, resulting in an 8-11% reduction in brain volume over a 17-27 month period.

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extrapyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia.

Adverse effect on cognitive function and increased risk of death in people with dementia along with worsening of symptoms has been describe in the literature.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (it is presumed due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects. The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.

City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.

List of Agents

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses. A 2013 review has stated that the division of antipsychotics into first and second generation is perhaps not accurate.

Notes:

  • † indicates drugs that are no longer (or were never) marketed in English-speaking countries.
  • ‡ denotes drugs that are no longer (or were never to begin with) marketed in the United States. Some antipsychotics are not firmly placed in either first-generation or second-generation classes.
  • # denotes drugs that have been withdrawn worldwide.

First-Generation (Typical)

  • Butyrophenones:
    • Benperidol‡
    • Bromperidol†
    • Droperidol‡
    • Haloperidol
    • Moperone (discontinued)†
    • Pipamperone (discontinued)†
    • Timiperone †
  • Diphenylbutylpiperidines:
    • Fluspirilene ‡
    • Penfluridol ‡
    • Pimozide
  • Phenothiazines:
    • Acepromazine † – although it is mostly used in veterinary medicine.
    • Chlorpromazine
    • Cyamemazine †
    • Dixyrazine †
    • Fluphenazine
    • Levomepromazine‡
    • Mesoridazine (discontinued)†
    • Perazine
    • Pericyazine‡
    • Perphenazine
    • Pipotiazine ‡
    • Prochlorperazine
    • Promazine (discontinued)
    • Promethazine
    • Prothipendyl †
    • Thioproperazine‡ (only English-speaking country it is available in is Canada)
    • Thioridazine (discontinued)
    • Trifluoperazine
    • Triflupromazine (discontinued)†
  • Thioxanthenes:
    • Chlorprothixene †
    • Clopenthixol
    • Flupentixol ‡
    • Thiothixene
    • Zuclopenthixol ‡

Disputed/Unknown

This category is for drugs that have been called both first and second-generation, depending on the literature being used.

  • Benzamides:
    • Sulpiride ‡
    • Sultopride †
    • Veralipride †
  • Tricyclics:
    • Carpipramine †
    • Clocapramine †
    • Clorotepine †
    • Clotiapine ‡
    • Loxapine
    • Mosapramine †
  • Others:
    • Molindone #

Second-Generation (Atypical)

  • Benzamides:
    • Amisulpride ‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
    • Nemonapride † – Used in Japan.
    • Remoxipride # – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D2 receptor.
    • Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.
  • Benzisoxazoles/benzisothiazoles:
    • Iloperidone – Approved by the FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
    • Lurasidone – Approved by the FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.
    • Paliperidone – Primary, active metabolite of risperidone that was approved in 2006.
    • Paliperidone palmitate – Long-acting version of paliperidone for once-monthly injection.
    • Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
    • Risperidone – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
    • Ziprasidone – Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
  • Butyrophenones:
    • Melperone † – Only used in a few European countries. No English-speaking country has licensed it to date.
    • Lumateperone.
  • Phenylpiperazines/quinolinones:
    • Aripiprazole – Partial agonist at the D2 receptor unlike almost all other clinically-utilized antipsychotics.
    • Aripiprazole lauroxil – Long-acting version of aripiprazole for injection.
    • Brexpiprazole – Partial agonist of the D2 receptor. Successor of aripiprazole.
    • Cariprazine – A D3-preferring D2/D3 partial agonist.
  • Tricyclics:
    • Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
    • Clozapine – Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
    • Olanzapine – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
    • Quetiapine – Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, the United Kingdom and the United States) as an adjunct to antidepressant therapy in patients with major depressive disorder. It is the only antipsychotic that has demonstrated efficacy as a monotherapy for the treatment of major depressive disorder. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
    • Zotepine – An atypical antipsychotic indicated for acute and chronic schizophrenia. It is still used in Japan and was once used in Germany but it was discontinued.†
  • Others:
    • Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
    • Pimavanserin – A selective 5-HT2A receptor antagonist approved for the treatment of Parkinson’s disease psychosis in 2016.
    • Sertindole ‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.

Mechanism of Action

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder. In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonise 5-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors; however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.

Society and Culture

Terminology

The term major tranquiliser was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.

Antipsychotics are a type of psychoactive or psychotropic medication.

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.

Overprescription

Antipsychotics in the nursing home population are often overprescribed, often for the purposes of making it easier to handle dementia patients. Federal efforts to reduce the use of antipsychotics in US nursing homes has led to a nationwide decrease in their usage in 2012.

Legal

Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment.

Formulations

They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle. Short-acting parenteral formulations also exist, which are generally reserved for emergencies or when oral administration is otherwise impossible. The oral formulations include immediate release, extended release, and orally disintegrating products (which are not sublingual, and can help ensure that medications are swallowed instead of “cheeked”). Sublingual products (e.g. asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.

Recreational Use

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilising, and (paradoxically) “hallucinogenic” effects. The most commonly second-generation antipsychotic implicated is quetiapine. In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons. There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g. aripiprazole) has been used.

Controversy

Joanna Moncrieff has argued that antipsychotic drug treatment is often undertaken as a means of control rather than to treat specific symptoms experienced by the patient.

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff. In an official review commissioned by UK government ministers it was reported that the needless use of antipsychotic medication in dementia care was widespread and was linked to 1800 deaths per year. In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations. One case involved Eli Lilly and Company’s antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, Astrazeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices. By expanding the conditions for which they were indicated, Astrazeneca’s Seroquel and Eli Lilly’s Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.

Harvard medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007 – some of them undisclosed to Harvard – from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research centre that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company’s antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.

Special Populations

It is recommended that persons with dementia who exhibit behavioural and psychological symptoms should not be given antipsychotics before trying other treatments. When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.

MedSupport: Patient Perceptions & Perceived Support

Research Paper Title

Enabling patients to cope with psychotropic medication in mental health care: Evaluation and reports of the new inventory MedSupport.

Background

This cross sectional study examined patients’ perceptions of professional support regarding use of psychotropic medication in a specialist mental health care setting.

The aims were to evaluate reliability and validity of the MedSupport inventory, and investigate possible associations between MedSupport scores and patient characteristics.

Methods

A cross-sectional study was performed. The patients completed the MedSupport, a newly developed self-reported 6 item questionnaire on a Likert scale ranged 1 to 5 (1 = strongly disagree to 5 = strongly agree), and the Beliefs about Medicines Questionnaire.

Diagnosis and treatment information were obtained at the clinical visits and from patient records.

Among the 992 patients recruited, 567 patients (57%) used psychotropic medications, and 514 (91%) of these completed the MedSupport and were included in the study.

Results

The MedSupport showed an adequate internal consistency (Cronbach alpha.87; 95% CI.86-89) and a convergent validity toward the available variables.

The MedSupport mean score was 3.8 (standard deviation.9, median 3.8).

Increasing age and the experience of stronger needs for psychotropic medication were associated with perception of more support to cope with medication, whereas higher concern toward use of psychotropic medication was associated with perception of less support.

Patients diagnosed with behavioural and emotional disorders, onset in childhood and adolescence perceived more support than patients with Mood disorders.

Conclusions

The MedSupport inventory was suitable for assessing the patients’ perceived support from health care service regarding their medication.

Awareness of differences in patients’ perceptions might enable the service to provide special measures for patients who perceive insufficient medication support.

Reference

Drivenes, K., Vederhus, J.K., Haaland, V.Ø., Ruud, T., Hauge, Y.L., Regevik, H., Falk, R.S. & Tanum, L. (2020) Enabling patients to cope with psychotropic medication in mental health care: Evaluation and reports of the new inventory MedSupport. Medicine (Baltimore). 99(1):e18635. doi: 10.1097/MD.0000000000018635.

Do We Need to be Aware of Differences in Patients’ Perceptions of Medication Support?

Research Paper Title

Enabling patients to cope with psychotropic medication in mental health care: Evaluation and reports of the new inventory MedSupport.

Background

This cross sectional study examined patients’ perceptions of professional support regarding use of psychotropic medication in a specialist mental health care setting.

The aims were to evaluate reliability and validity of the MedSupport inventory, and investigate possible associations between MedSupport scores and patient characteristics.

Methods

A cross-sectional study was performed.

The patients completed the MedSupport, a newly developed self-reported 6 item questionnaire on a Likert scale ranged 1 to 5 (1 = strongly disagree to 5 = strongly agree), and the Beliefs about Medicines Questionnaire.

Diagnosis and treatment information were obtained at the clinical visits and from patient records.

Among the 992 patients recruited, 567 patients (57%) used psychotropic medications, and 514 (91%) of these completed the MedSupport and were included in the study.

Results

The MedSupport showed an adequate internal consistency (Cronbach alpha.87; 95% CI.86-89) and a convergent validity toward the available variables.

The MedSupport mean score was 3.8 (standard deviation.9, median 3.8).

Increasing age and the experience of stronger needs for psychotropic medication were associated with perception of more support to cope with medication, whereas higher concern toward use of psychotropic medication was associated with perception of less support.

Patients diagnosed with behavioural and emotional disorders, onset in childhood and adolescence perceived more support than patients with Mood disorders.

Conclusions

The MedSupport inventory was suitable for assessing the patients’ perceived support from health care service regarding their medication.

Awareness of differences in patients’ perceptions might enable the service to provide special measures for patients who perceive insufficient medication support.

Reference

Drivenes, K., Vederhus, J.K., Haaland, V.Ø., Ruud, T., Hauge, Y.L., Regevik, H., Falk, R.S. & Tanum, L. (2020) Enabling patients to cope with psychotropic medication in mental health care: Evaluation and reports of the new inventory MedSupport. Medicine (Baltimore). 99(1):e18635. doi: 10.1097/MD.0000000000018635.