Phenobarbital, also known as phenobarbitone or phenobarb, or by the trade name Luminal, is a medication of the barbiturate type.
It is recommended by the World Health Organisation (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It may be used intravenously, injected into a muscle, or taken by mouth. The injectable form may be used to treat status epilepticus. Phenobarbital is occasionally used to treat trouble sleeping, anxiety, and drug withdrawal and to help with surgery. It usually begins working within five minutes when used intravenously and half an hour when administered by mouth. Its effects last for between four hours and two days.
Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long-term use. It may also increase the risk of suicide. It is pregnancy category B or D (depending on how it is taken) in the United States and category D in Australia, meaning that it may cause harm when taken by pregnant women. If used during breastfeeding it may result in drowsiness in the baby. A lower dose is recommended in those with poor liver or kidney function, as well as elderly people. Phenobarbital, like other barbiturates works by increasing the activity of the inhibitory neurotransmitterGABA.
Phenobarbital was discovered in 1912 and is the oldest still commonly used anti-seizure medication. It is on the WHO’s List of Essential Medicines.
The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering and was first marketed as Veronal by Friedr. Bayer et comp. By 1904, several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.
Phenobarbital’s soporific, sedative and hypnotic properties were well known in 1912, but it was not yet known to be an effective anti-convulsant. The young doctor Alfred Hauptmann gave it to his epilepsy patients as a tranquiliser and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: The worst patients suffered fewer and lighter seizures and some patients became seizure-free. In addition, they improved physically and mentally as bromides were removed from their regimen. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptmann dismissed concerns that its effectiveness in stalling seizures could lead to patients suffering a build-up that needed to be “discharged”. As he expected, withdrawal of the drug led to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anti-convulsant, though World War I delayed its introduction in the US.
In 1939, a German family asked Adolf Hitler to have their disabled son killed; the five-month-old boy was given a lethal dose of Luminal after Hitler sent his own doctor to examine him. A few days later 15 psychiatrists were summoned to Hitler’s Chancellery and directed to commence a clandestine programme of involuntary euthanasia.
In 1940, at a clinic in Ansbach, Germany, around 50 intellectually disabled children were injected with Luminal and killed that way. A plaque was erected in their memory in 1988 in the local hospital at Feuchtwanger Strasse 38, although a newer plaque does not mention that patients were killed using barbiturates on site. Luminal was used in the Nazi children’s euthanasia programme until at least 1943.
Phenobarbital was used to treat neonatal jaundice by increasing liver metabolism and thus lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the standard treatment.
Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures. Although an effective treatment in preventing recurrent febrile seizures, it had no positive effect on patient outcome or risk of developing epilepsy. The treatment of simple febrile seizures with anticonvulsant prophylaxis is no longer recommended.
Phenobarbital is used in the treatment of all types of seizures, except absence seizures. It is no less effective at seizure control than phenytoin, however phenobarbital is not as well tolerated. Phenobarbital may provide a clinical advantage over carbamazepine for treating partial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital for generalised onset tonic-clonic seizures. Its very long active half-life (53-118 hours) means for some people doses do not have to be taken every day, particularly once the dose has been stabilised over a period of several weeks or months, and seizures are effectively controlled.
The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The WHO gives phenobarbital a first-line recommendation in the developing world and it is commonly used there.
Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.
Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.
Phenobarbital is useful for insomnia and anxiety.
Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines.
Phenobarbital is a cytochrome P450 inducer, and is used to reduce the toxicity of some drugs.
Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler-Najjar syndrome, type II, or in people with Gilbert’s syndrome. Phenobarbital can also be used to relieve cyclic vomiting syndrome symptoms.
Phenobarbital is a commonly used agent in high purity and dosage for lethal injection of “death row” criminals.
In infants suspected of neonatal biliary atresia, phenobarbital is used in preparation for a 99mTc-IDA hepatobiliary (HIDA; hepatobiliary 99mTc-iminodiacetic acid) study that differentiates atresia from hepatitis or cholestasis.
Phenobarbital is used as a secondary agent to treat newborns with neonatal abstinence syndrome, a condition of withdrawal symptoms from exposure to opioid drugs in utero.
In massive doses, phenobarbital is prescribed to terminally ill people to allow them to end their life through physician-assisted suicide.
Like other barbiturates, phenobarbital can be used recreationally, but this is reported to be relatively infrequent.
Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital. Central nervous system effects, such as dizziness, nystagmus and ataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result in paradoxical hyperactivity.
Phenobarbital is a cytochrome P450 hepatic enzyme inducer. It binds transcription factor receptors that activate cytochrome P450 transcription, thereby increasing its amount and thus its activity. Due to this higher amount of CYP450, drugs that are metabolised by the CYP450 enzyme system will have decreased effectiveness. This is because the increased CYP450 activity increases the clearance of the drug, reducing the amount of time they have to work.
Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.
Acute intermittent porphyria, hypersensitivity to any barbiturate, prior dependence on barbiturates, severe respiratory insufficiency (as with chronic obstructive pulmonary disease), severe liver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.
Phenobarbital causes a depression of the body’s systems, mainly the central and peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a “slowing” of bodily functions, including decreased consciousness (even coma), bradycardia, bradypnea, hypothermia, and hypotension (in massive overdoses). Overdose may also lead to pulmonary oedema and acute renal failure as a result of shock, and can result in death.
The electroencephalogram (EEG) of a person with phenobarbital overdose may show a marked decrease in electrical activity, to the point of mimicking brain death. This is due to profound depression of the central nervous system, and is usually reversible.
Treatment of phenobarbital overdose is supportive, and mainly consists of the maintenance of airway patency (through endotracheal intubation and mechanical ventilation), correction of bradycardia and hypotension (with intravenous fluids and vasopressors, if necessary), and removal of as much drug as possible from the body. In very large overdoses, multi-dose activated charcoal is a mainstay of treatment as the drug undergoes enterohepatic recirculation. Urine alkalisation (achieved with sodium bicarbonate) enhances renal excretion. Haemodialysis is effective in removing phenobarbital from the body, and may reduce its half-life by up to 90%. No specific antidote for barbiturate poisoning is available.
Mechanism of Action
Phenobarbitol is as an allosteric modulator which extends the amount of time the chloride ion channel is open by interacting with GABAA receptor subunits. Through this action, phenobarbital increases the flow of chloride ions into the neuron which decreases the excitability of the post-synaptic neuron. Hyperpolarising this post-synaptic membrane leads to a decrease in the general excitatory aspects of the post-synaptic neuron. By making it harder to depolarise the neuron, the threshold for the action potential of the post-synaptic neuron will be increased. Phenobarbital stimulates GABA to accomplish this hyperpolarisation. Direct blockade of excitatory glutamate signalling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.
Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (Cmax) are reached eight to 12 hours after oral administration. It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of two to seven days) and has very low protein binding (20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation and glucuronidation, and induces many isozymes of the cytochrome P450 system. Cytochrome P450 2B6 (CYP2B6) is specifically induced by phenobarbital via the CAR/RXR nuclear receptor heterodimer. It is excreted primarily by the kidneys.
Phenobarbital is one of the initial drugs of choice to treat epilepsy in dogs, as well as cats. It is also used to treat feline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.
It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.
Society and Culture
Phenobarbital is the INN and phenobarbitone is the BAN.
Barbiturate drugs are obtained via condensation reactions between a derivative of diethyl malonate and urea in the presence of a strong base. The synthesis of phenobarbital uses this common approach as well but differs in the way in which this malonate derivative is obtained. The reason for this difference is due to the fact that aryl halides do not typically undergo nucleophilic substitution in Malonic ester synthesis in the same way as aliphatic organosulfates or halocarbons do. To overcome this lack of chemical reactivity two dominant synthetic approaches using benzyl cyanide as a starting material have been developed:
The first of these methods consists of a Pinner reaction of benzyl cyanide, giving phenylacetic acid ethyl ester. Subsequently, this ester undergoes cross Claisen condensation using diethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide, yielding diethyl phenylmalonate. Malonic ester synthesis using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally a condensation reaction with urea gives phenobarbital.
The second approach utilises diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester. Alkylation of this ester using ethyl bromide proceeds via a nitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester. This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidic hydrolysis of the resulting product gives phenobarbital.
Regulation The level of regulation includes Schedule IV non-narcotic (depressant) (ACSCN 2285) in the United States under the Controlled Substances Act 1970—but along with a few other barbiturates and at least one benzodiazepine, and codeine, dionine, or dihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for its ephedrine content. The phenobarbitone/phenobarbital exists in subtherapeutic doses which add up to an effective dose to counter the overstimulation and possible seizures from a deliberate overdose in ephedrine tablets for asthma, which are now regulated at the federal and state level as: a restricted OTC medicine and/or watched precursor, uncontrolled but watched/restricted prescription drug & watched precursor, a Schedule II, III, IV, or V prescription-only controlled substance & watched precursor, or a Schedule V (which also has possible regulations at the county/parish, town, city, or district as well aside from the fact that the pharmacist can also choose not to sell it, and photo ID and signing a register is required) exempt Non-Narcotic restricted/watched OTC medicine.
The Japanese officers aboard the German submarine U-234 killed themselves with phenobarbital while the German crew members were on their way to the US to surrender (but before Japan had surrendered).
A mysterious woman, known as the Isdal Woman, was found dead in Bergen, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, and carbon monoxide poisoning; many theories about her death have been posited, and it is believed that she may have been a spy.
British veterinarian Donald Sinclair, better known as the character Siegfried Farnon in the “All Creatures Great and Small” book series by James Herriot, committed suicide at the age of 84 by injecting himself with an overdose of phenobarbital. Activist Abbie Hoffman also committed suicide by consuming phenobarbital, combined with alcohol, on 12 April 1989; the residue of around 150 pills was found in his body at autopsy. Also dying from an overdose was British actress Phyllis Barry in 1954 and actress/model Margaux Hemingway in 1996.
Thirty-nine members of the Heaven’s Gate UFO religious group committed mass suicide in March 1997 by drinking a lethal dose of phenobarbital and vodka “and then lay down to die” hoping to enter an alien spacecraft.
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.
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.”
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.
Includes 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.
Includes certain ATS with therapeutic uses, such as delta-9-THC (including dronabinol, its synthetic form), amphetamine and methylphenidate.
Includes 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.
Includes 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.
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
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.
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.
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 (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.
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.
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 (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 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.”
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.
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.
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.”
Article 22 provides:
(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.
(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.
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
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.
14 phenethylamine psychedelics.
5 tryptamine psychedelics.
28 stimulants (excluding lefetamine).
2 synthetic cannabinoids.
2 positions representing 7 tetrahydrocannabinol isomers and their stereochemical variants.
36 benzodiazepines (including 1 z-drug).
4 other depressants.
1 position – zipeprol.
1 position – lefetamine (with stimulant and opioid effects).
1 semisynthetic opioid.
1 synthetic benzomorphan opioid.
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.
13 phenethylamine psychedelics.
5 tryptamine psychedelics.
2 synthetic cannabinoids.
1 position representing 6 isomers of tetrahydrocannabinol and their stereochemical variants.
Isomers of natural tetrahydrocannabinol:
Tetrahydrocannabinol, the following isomers and their stereochemical variants:
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.
Contains 17 positions, specific generalisation for tetrahydrocannabinol stereochemical variants and common generalisation clause for salts.
1 phenethylamine psychedelic.
1 position representing an isomer of tetrahydrocannabinol and its stereochemical variants.
1 position – zipeprol.
Amphetamine and its isomers (dextroamphetamine and levoamphetamine).
Methamphetamine and its isomers (dextromethamphetamine and levomethamphetamine).
Methylphenidate and its isomers (dextromethylphenidate and levomethylphenidate).
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).
Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary oedema. If death occurs this is typically due to a lack of breathing.
Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a person’s tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.
Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.
Mechanism of Action
Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABA’s potency.
Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.
If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.
People who are known to have committed suicide by barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction). Maurice Chevalier unsuccessfully attempted suicide in March 1971 by swallowing a large amount of barbiturates and slitting his wrists; however, he suffered severe organ damage as a result and died from multiple organ failure nine months later.
The differential diagnosis should include intoxication by other substances with sedative effects, such as benzodiazepines, anticonvulsants (carbamazepine), alcohols (ethanol, ethylene glycol, methanol), opioids, carbon monoxide, sleep aids, and gamma-Hydroxybutyric acid (GHB – a known date rape drug). Natural disease that can result in disorientation may be in the differential, including hypoglycaemia and myxoedema coma. In the right setting, hypothermia should be ruled out.
Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.
Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.
The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.
The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.
A barbiturate is a drug that acts as a central nervous system depressant.
Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have largely been replaced by benzodiazepines and nonbenzodiazepines (“Z-drugs”) in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and overdose and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anaesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.
The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.
Barbituric acid was first synthesized 27 November 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town’s artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Another story was barbiturate was invented on the feast day of St. Barbara. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.
It was not until the 1950s that the behavioural disturbances and physical dependence potential of barbiturates became recognised.
Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anaesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient “under” in emergency surgery situations. Doctors can also bring a patient out of anaesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title “short/intermediate-acting.” These barbiturates are also employed for anaesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual “hang-over” effect and feel groggy.
Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative-hypnotic.
Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug overdose. However, barbiturates are still used as anticonvulsants (e.g. phenobarbital and primidone) and general anaesthetics (e.g. sodium thiopental).
Barbiturates in high doses are used for medical aid in dying, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanising agents in small-animal veterinary medicine.
Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for “truth serum”, or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal “interviews” where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.
The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject’s ability to invent and remember lies. This practice is no longer considered legally admissible in court due to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defence and law enforcement agencies as a “humane” alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.
In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published. Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.
Sodium barbital and barbital have also been used as pH buffers for biological research, e.g. in immuno-electrophoresis or in fixative solutions.
There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the placenta to the foetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.
With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.
The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, due to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit “cold turkey” may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.
Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.
Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (e.g. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels’ overall function by 900%, not 600%).
The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug’s effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.
Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolised by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolised by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.
People who are known to have committed suicide by barbiturate overdose include Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C.P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction).
Mechanism of Action
Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABAA receptors. GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABAA receptor at multiple homologous transmembrane pockets located at subunit interfaces, which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca2+-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.
Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT3 receptor channel, and the glycine receptor channel. However, while GABAA receptor currents are increased by barbiturates (and other general anaesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anaesthetic concentrations of both thiopental and pentobarbital. Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. This is the mechanism responsible for the (mild to moderate) anaesthetic effect of barbiturates in high doses when used in anaesthetic concentration.
Society and Culture
During World War II, military personnel in the Pacific region were given “goofballs” to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.
In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.
In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.
There is a small group of List II drugs for which doctors have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.
In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances – and they remain so as of September 2020. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and “Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid” (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.
In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014, regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its “Green List”. The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.
Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use. Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam. Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.
People who use substances tend to prefer short-acting and intermediate-acting barbiturates. The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.
Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, ‘reds & blues’, and tooties.
A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.
Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).
Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.
The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.
In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.
Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.
Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.
Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.
Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.
Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.
In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.
Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.
Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.
Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.
The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.
There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.
There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.
An anxiolytic (also anti-panic or anti-anxiety agent) is a medication or other intervention that reduces anxiety.
This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorder and its related psychological and physical symptoms.
Barbiturates are powerful anxiolytics but the risk of abuse and addiction is high. Many experts consider these drugs obsolete for treating anxiety but valuable for the short-term treatment of severe insomnia, though only after benzodiazepines or non-benzodiazepines have failed.
Benzodiazepines are prescribed to quell panic attacks. Benzodiazepines are also prescribed in tandem with an antidepressant for the latent period of efficacy associated with many ADs for anxiety disorder. There is risk of benzodiazepine withdrawal and rebound syndrome if BZDs are rapidly discontinued. Tolerance and dependence may occur. The risk of abuse in this class of medication is smaller than in that of barbiturates. Cognitive and behavioural adverse effects are possible.
Selective serotonin reuptake inhibitors (SSRIs) are a class of medications used in the treatment of depression, anxiety disorders, OCD and some personality disorders. SSRIs can increase anxiety initially due to negative feedback through the serotonergic autoreceptors, for this reason a concurrent benzodiazepine can be used until the anxiolytic effect of the SSRI occurs.
Serotonin-Norepinephrine Reuptake Inhibitors
Serotonin-norepinephrine reuptake inhibitor (SNRIs) include venlafaxine and duloxetine drugs. Venlafaxine, in extended release form, and duloxetine, are indicated for the treatment of GAD. SNRIs are as effective as SSRIs in the treatment of anxiety disorders.
Tricyclic antidepressants (TCAs) have anxiolytic effects; however, side effects are often more troubling or severe and overdose is dangerous. They’re effective, but they’ve generally been replaced by antidepressants that cause fewer adverse effects. Examples include imipramine, doxepin, amitriptyline, nortriptyline and desipramine.
Tetracyclic antidepressants, such as Mirtazapine, have demonstrated anxiolytic effect comparable to SSRIs while rarely causing or exacerbating anxiety. Mirtazapine’s anxiety reduction tends to occur significantly faster than SSRIs.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) are first generation antidepressants effective for anxiety treatment but their dietary restrictions, adverse effect profile and availability of newer medications have limited their use. MAOIs include phenelzine, isocarboxazid and tranylcypromine. Pyrazidol is a reversible MAOI that lacks dietary restriction.
Sympatholytics are a group of anti-hypertensives which inhibit activity of the sympathetic nervous system. Beta blockers reduce anxiety by decreasing heart rate and preventing shaking. Beta blockers include propranolol, oxprenolol, and metoprolol. The Alpha-1 agonist prazosin could be effective for PTSD. The Alpha-2 agonists clonidine and guanfacine have demonstrated both anxiolytic and anxiogenic effects.
Buspirone (Buspar) is a 5-HT1A receptor agonist used to treated generalised anxiety disorder. If an individual has taken a benzodiazepine, buspirone will be less effective.
Pregabalin (Lyrica) produces anxiolytic effect after one week of use comparable to lorazepam, alprazolam, and venlafaxine with more consistent psychic and somatic anxiety reduction. Unlike BZDs, it does not disrupt sleep architecture nor does it cause cognitive or psychomotor impairment.
Hydroxyzine (Atarax) is an antihistamine originally approved for clinical use by the FDA in 1956. Hydroxyzine has a calming effect which helps ameliorate anxiety. Hydroxyzine efficacy is comparable to benzodiazepines in the treatment of generalised anxiety disorder. Hydroxyzine is typically only used for short term anxiety relief.
Phenibut (Anvifen, Fenibut, Noofen) is an anxiolytic used in Russia. Phenibut is a GABAB receptor agonist, as well as an antagonist at α2δ subunit-containing voltage-dependent calcium channels (VDCCs), similarly to gabapentinoids like gabapentin and pregabalin. The medication is not approved by the FDA for use in the United States, but is sold online as a supplement.
Mebicar is an anxiolytic produced in Latvia and used in Eastern Europe. Mebicar has an effect on the structure of limbic-reticular activity, particularly on the hypothalamus, as well as on all 4 basic neuromediator systems – γ aminobutyric acid (GABA), choline, serotonin and adrenergic activity. Mebicar decreases noradrenaline, increases serotonin, and exerts no effect on dopamine.
Fabomotizole (Afobazole) is an anxiolytic drug launched in Russia in the early 2000s. Its mechanism of action is poorly defined, with GABAergic, NGF and BDNF release promoting, MT1 receptor agonism, MT3 receptor antagonism, and sigma agonism thought to have some involvement.
Bromantane is a stimulant drug with anxiolytic properties developed in Russia during the late 1980s. Bromantane acts mainly by facilitating the biosynthesis of dopamine, through indirect genomic upregulation of relevant enzymes (tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD).
Emoxypine is an antioxidant that is also a purported anxiolytic. Its chemical structure resembles that of pyridoxine, a form of vitamin B6.
Menthyl isovalerate is a flavouring food additive marketed as a sedative and anxiolytic drug in Russia under the name Validol.
Some racetam based drugs such as aniracetam can have an antianxiety effect.
Having similar anxiolytic effects as benzodiazepine drugs, etifoxine does not produce the same levels of sedation and ataxia. Further, etifoxine does not affect memory and vigilance, and does not induce rebound anxiety, drug dependence, or withdrawal symptoms.
Ethanol is sometimes used as an anxiolytic by self-medication. fMRI can measure the anxiolytic effects of alcohol in the human brain.
Alternatives to Medication
Cognitive behavioural therapy (CBT) is an effective treatment for panic disorder, social anxiety disorder, generalized anxiety disorder, and obsessive-compulsive disorder, while exposure therapy is the recommended treatment for anxiety related phobias. Healthcare providers can guide those with anxiety disorder by referring them to self-help resources. Sometimes medication is combined with psychotherapy but research has not found a benefit of combined pharmacotherapy and psychotherapy versus monotherapy.
If CBT is found ineffective, both the Canadian and American medical associations then suggest the use of a potent, long lasting benzodiazepine such as clonazepam and an antidepressant, usually Prozac for its effectiveness.