Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (study of effects of drugs on the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behaviour.
It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of “how” and “why”, and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behaviour, and sleep behaviour.
Drugs such as opium, alcohol, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually worked was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw psychology and psychiatry as largely phenomenological, in that behaviours or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the behavioural branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as “software” errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields – until several developments after World War II began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as MAO inhibitors, tricyclic antidepressants, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the prefrontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury.
The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.
An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neurochemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10-10 M such as found with extrastriatal D1 receptor for dopamine.
One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuropathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These “hyperselective-action” drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximising the efficacy (or technically the potency) of the drug within the clinical target and minimising adverse effects. However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is Vortioxetine, a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of relapse) and greatly reduced incidence of sexual dysfunction, without loss in antidepressant efficacy.
The groundwork is currently being paved for the next generation of pharmacological treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons – the study of which, in addition to neurotrophic factors, may hold hope for neurodegenerative diseases like Alzheimer’s, Parkinson’s, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.
So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device.
By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:
The transport of synaptic vesicles and subsequent release into the synapse;
Receptor activation and cascade function; and
Transport mechanisms (reuptake) and/or enzyme degradation.
The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterisation of a large number of very specific subtypes of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further “sub-subtypes” exist together with variants, totalling in the hundreds for just these 6 transmitters (refer to serotonin receptor, for example). It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.
It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl−. The concentration differences between the inside and outside of the cell determine the membrane voltage.
Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein coupled processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.
The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expression determines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.
Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.
The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. “dirty drug”) and safe to consume. The 2005 Physicians’ Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with “selective serotonin reuptake inhibitors“, or SSRIs which exemplify modern pharmaceuticals. These SSRI antidepressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker anti-psychotics, and GABA agonist tranquilisers (benzodiazepines).
New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the antinarcoleptic action of the drug modafinil which was already being used only a year prior.
The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1 antagonists, and 5HT2c antagonists. Another is the proposal of new routes of exploration for antipsychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.
Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. Phencyclidine has been found to cause cell death in striatopallidal cells and abnormal vacuolisation in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons (Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself). As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.
It is a not-so-recent discovery that many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioural, and genetic correlates of receptor action, completing the knowledge of neural signalling (refer to Human Cognome Project). The signal paths of neurons are hyperorganised beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts.
Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviours with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signalling, even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviours as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation.
Significant progress has been made on central mechanisms of certain hallucinogenic drugs. It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the “classical psychedelics”, can be attributed largely to agonism of serotonin receptors. The 5HT2A receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT2C receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. 5HT2A activity has a net pro-dopaminergic effect, whereas 5HT2C receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory postsynaptic potentials, a process antagonised by serotonin itself through 5HT1 receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT1 receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT2A-mGlu2 heterodimer is also necessary for classical psychedelic activity. This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of “hallucination”.
Circadian rhythm, or sleep/wake cycling, is centred in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsin cells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABAergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibres. The output of the SCG, stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of melatonin which “entrains” the 24-hour cycle of SCN activity. The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.
Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioural effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signalling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual’s specific reactions or degree of response to a drug or their tendency to develop addictions in the future. These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson’s disease and schizophrenia while still others are attempting to establish previously unknown neural correlates underlying certain phenomena.
Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes European Neuropsychopharmacology, and as part of the Reed Elsevier Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002, a recent comprehensive collected work of the ACNP, “Neuropsychopharmacology: The Fifth Generation of Progress” was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain.
Many other journals exist which contain relevant information such as Neuroscience. Some of them are listed at Brown University Library.
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Dosage forms (also called unit doses) are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a capsule shell, for example), and apportioned into a particular dose. For example, two products may both be amoxicillin, but one is in 500 mg capsules and another is in 250 mg chewable tablets.
The term unit dose can also sometimes encompass non-reusable packaging as well (especially when each drug product is individually packaged), although the US Food and Drug Administration (FDA) distinguishes that by unit-dose “packaging” or “dispensing”. Depending on the context, multi(ple) unit dose can refer to distinct drug products packaged together, or to a single drug product containing multiple drugs and/or doses. The term dosage form can also sometimes refer only to the pharmaceutical formulation of a drug product’s constituent drug substance(s) and any blends involved, without considering matters beyond that (like how it is ultimately configured as a consumable product such as a capsule, patch, etc.). Because of the somewhat vague boundaries and unclear overlap of these terms and certain variants and qualifiers within the pharmaceutical industry, caution is often advisable when conversing with someone who may be unfamiliar with another person’s use of the term.
Depending on the method/route of administration, dosage forms come in several types. These include many kinds of liquid, solid, and semisolid dosage forms. Common dosage forms include pill, tablet, or capsule, drink or syrup, among many others. In naturopathy, dosages can take the form of decoctions and herbal teas, as well as the more conventional methods previously mentioned. A liquid dosage form is the liquid form of a dose of a chemical compound used as a drug or medication intended for administration or consumption.
The route of administration (ROA) for drug delivery is dependent on the dosage form of the substance in question. Various dosage forms may exist for a single particular drug, since some medical conditions such as being unconscious can restrict ROA. For example, persistent nausea, especially with vomiting, may make it difficult to use an oral dosage form, and in such a case, it may be necessary to use an alternative route such as inhalational, buccal, sublingual, nasal, suppository or parenteral instead. Additionally, a specific dosage form may be a requirement for certain kinds of drugs, as there may be issues with various factors like chemical stability or pharmacokinetics. As an example, insulin cannot be given orally because upon being administered in this manner, it is extensively metabolized in the gastrointestinal tract (GIT) before reaching the blood stream, and is thereby incapable of sufficiently reaching its therapeutic target destinations. The oral and intravenous doses of a drug such as paracetamol will differ for the same reason.
Pills, i.e. tablets or capsules.
Liquids such as syrups, solutions, elixers, emulsions, and tinctures.
Liquids such as decoctions and herbal teas.
Orally disintegrating tablets.
Lozenges or candy (electuaries).
Thin films (e.g. Listerine Pocketpaks, nitroglycerin) to be placed on top of or underneath the tongue as well as against the cheek.
Powders or effervescent powder or tablets, often instructed to be mixed into a food item.
Plants or seeds prepared in various ways such as a cannabis edible.
Pastes such as high fluoride toothpastes.
Gases such as oxygen (can also be delivered through the nose).
Dry-powder Inhalers or metered dose inhalers.
Talc is an excipient often used in pharmaceutical tablets that may end up being crushed to a powder against medical advice or for recreational use. Also, illicit drugs that occur as white powder in their pure form are often cut with cheap talc. Natural talc is cheap but contains asbestos while asbestos-free talc is more expensive. Inhaled talc that has asbestos is generally accepted as being able to cause lung cancer if it is inhaled. The evidence about asbestos-free talc is less clear, according to the American Cancer Society.
Intraosseous administration (IO).
These are usually solutions and suspensions.
Eye drops (normal saline in disposable packages) are distributed to syringe users by needle exchange programs.
The injection of talc from crushed pills has been associated with pulmonary talcosis in intravenous drug users.
Creams, liniments, balms (such as lip balm or antiperspirants and deodorants), lotions, or ointments, etc.
Gels and hydrogels.
Transdermal and dermal patches to be applied to the skin.
It is not safe to calculate divided doses by cutting and weighing medical skin patches, because there’s no guarantee that the substance is evenly distributed on the patch surface. For example, fentanyl transdermal patches are designed to slowly release the substance over 3 days. It is well known that cut fentanyl transdermal consumed orally have cause overdoses and deaths.
Single blotting papers for illicit drugs injected from solvents in syringes may also cause uneven distribution across the surface.
Capsules and tablets.
Rectal administration (enteral):
Suspensions and solutions in the form of enemas.
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The inverse benefit law states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively a drug is marketed. Two Americans, Howard Brody and Donald Light, have defined the inverse benefit law, inspired by Tudor Hart’s inverse care law.
A drug effective for a serious disorder is less and less effective as it is promoted for milder cases and for other conditions for which the drug was not approved. Although effectiveness becomes more diluted, the risks of harmful side effects persist, and thus the benefit-harm ratio worsens as a drug is marketed more widely. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.
State of Affairs
The law is manifested through 6 basic marketing strategies:
Reducing thresholds for diagnosing disease;
Relying on surrogate endpoints;
Exaggerating safety claims;
Exaggerating efficacy claims;
Creating new diseases; and
Encouraging unapproved uses.
This is the reason why organisations like “Worst Pill, Best Pill” recommend not to use/prescribe new medications before being in the market for at least ten years (except in the case of important new drugs that treat previously unsolved problems).
Agencies of drugs, committee of ethics and organisations of patients’ safety should consider:
Requiring that clinical trials run long enough to pick up evidence of side effects and record all adverse reactions, including in subjects who drop out.
Paying companies more for new drugs in proportion to how much better they are for patients than existing drugs, and marketing according to the value of the new drugs (ratio of benefits to harms and marketing).
Considering that market could be a force against the best use of medications.
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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).
Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs (as many of them begin with the letter “z”), are a class of psychoactive drugs that are very benzodiazepine-like in nature.
They are used in the treatment of sleep problems.
Nonbenzodiazepine pharmacodynamics are almost entirely the same as benzodiazepine drugs and therefore exhibit similar benefits, side-effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different chemical structures and are therefore unrelated to benzodiazepines on a molecular level.
Z-drugs emerged in the last years of the 1980s and early 1990s, with zopiclone (Imovane) approved by the British National Health Service (NHS) as early as 1989, quickly followed by Sanofi with zolpidem (Ambien). By 1999, King Pharmaceuticals had finalised approval with the US Food and Drug Administration (FDA) to market zaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (Lunesta) the (S)-enantiomer of zopiclone. That same year, 2005, the FDA finalised approval for Ambien CR, or extended-release zolpidem. Most recently, in 2012 the FDA approved Intermezzo (zolpidem tartate sublingual), which is marketed for middle-of-the-night insomnia, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-day sedation.
Currently, the major chemical classes of nonbenzodiazepines are:
The nonbenzodiazepines are positive allosteric modulators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex. Many of these compounds are subtype selective providing novel anxiolytics with little to no hypnotic and amnesiac effects and novel hypnotics with little or no anxiolytic effects.
Nonbenzodiazepines have demonstrated efficacy in treating sleep disorders. There is some limited evidence that suggests that tolerance to nonbenzodiazepines is slower to develop than with benzodiazepines. However, data is limited so no conclusions can be drawn. Data is also limited into the long-term effects of nonbenzodiazepines. Further research into the safety of nonbenzodiazepines and long-term effectiveness of nonbenzodiazepines has been recommended in a review of the literature. Some differences exist between the Z-drugs, for example tolerance and rebound effects may not occur with zaleplon.
The first three nonbenzodiazepine drugs to enter the market were the “Z-drugs”, zopiclone, zolpidem and zaleplon. These three drugs are all sedatives used exclusively for the treatment of mild insomnia. They are safer than the older barbiturates especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to induce physical dependence and addiction, although these issues can still become a problem. This has led to the Z-drugs becoming widely prescribed for the treatment of insomnia particularly in elderly patients. A little under a third (31%) of all Americans over 65 years of age are taking Z-drugs.
Long-term use is not recommended as tolerance and addiction can occur. A survey of patients using nonbenzodiazepine Z drugs and benzodiazepine hypnotic users found that there was no difference in reports of adverse effects that were reported in over 41% of users and, in fact, Z drug users were more likely to report that they had tried to quit their hypnotic drug and were more likely to want to stop taking Z drugs than benzodiazepine users. Efficacy also did not differ between benzodiazepine and Z drug users.
The Z-drugs are not without disadvantages, and all three compounds are notable for producing side-effects such as pronounced amnesia and more rarely hallucinations, especially when used in large doses. On rare occasions, these drugs can produce a fugue state, wherein the patient sleepwalks and may perform relatively complex actions, including cooking meals or driving cars, while effectively unconscious and with no recollection of the events upon awakening. While this effect is rare (and has also been reported to occur with some of the older sedative drugs such as temazepam and secobarbital), it can be potentially hazardous, and so further development of this class of drugs has continued in an effort to find new compounds with further improved profiles.
Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.
Side-effects can differ within the drug class due to differences in metabolism and pharmacology. For example, long-acting benzodiazepines have problems of drug accumulation especially in the elderly or those with liver disease, and shorter-acting benzodiazepines have a higher risk of more severe withdrawal symptoms. In the case of the nonbenzodiazepines, zaleplon may be the safest in terms of next-day sedation, and – unlike zolpidem and zopiclone – zaleplon has been found to have no association with increased motor vehicle accidents even when taken for middle-of-the-night insomnia due to its ultrashort elimination half-life.
Increased Risk of Depression
It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. In support of this claim an analysis of data of clinical trials submitted to the US Food and Drug Administration (FDA) concerning the drugs zolpidem, zaleplon, and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills. Hypnotic drugs, therefore, may be contraindicated in patients suffering from or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long-term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. Cognitive-behavioural therapy (CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.
Sleeping pills, including the Z-drugs, have been associated with an increased risk of death.
In older people this family of medications increases the risk of fractures and falls.
The Z-drug zaleplon may have fewer side effects compared to benzodiazepines.
Dependence and Withdrawal Management
Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or more preferably diazepam) can be tried followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse is manifested, an inpatient detoxification may be required, with flumazenil as a possible detoxification tool.
The Journal of Clinical Sleep Medicine published a paper that had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines, and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favourable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published papers when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry-sponsored trials on their own results showing that use of hypnotics is correlated with depression.
The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers, and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that “major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks.” The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia. Significant increases in skin cancers and tumours are found in clinical trial data of the nonbenzodiazepine hypnotics compared to trial subjects having taken placebo tablets. Other cancers of the brain, lung, bowel, breast, and bladder also occurred. An increase of infections, possibly due to decreased immune function, also occurred in the nonbenzodiazepine users. It has been hypothesised that either depressed immune function or the viral infections themselves were the cause of the increased rates of cancer.
Initially, the FDA was hesitant to approve some of the nonbenzodiazepines due to concerns regarding increases in cancers. The author reported that, due to the fact that the FDA requires reporting of both favourable and unfavourable results of clinical trials, the FDA New Drug Application data is more reliable than the peer-reviewed literature, which is subject to serious bias regarding hypnotics. In 2008, the FDA analysed their data again and confirmed an increased rate of cancers in the randomised trials compared to placebos but concluded that the rate of cancers did not warrant any regulatory action. Later studies on several common hypnotics found that receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year and that hypnotics cause mortality through the growing US overdose epidemic.
Nonbenzodiazepine hypnotic drugs, similar to benzodiazepines, cause impairments in body balance and standing steadiness upon waking; falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and lasting benefits of non-drug treatments for insomnia in adults of all age groups and that these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (e.g. anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
A review of the literature regarding hypnotics including the nonbenzodiazepine Z drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness due to tolerance. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. It is preferred that they should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.
More recently, a range of non-sedating anxiolytic drugs derived from the same structural families as the Z-drugs have been developed, such as alpidem (Ananyxl) and pagoclone, and approved for clinical prescription. Nonbenzodiazepine drugs are much more selective than the older benzodiazepine anxiolytics, producing effective relief of anxiety/panic with little or no sedation, anterograde amnesia, or anticonvulsant effects, and are thus potentially more precise than older, anti-anxiety drugs. However, anxiolytic nonbenzodiazepines are not widely prescribed and many have collapsed after initial clinical trials and consumption halted many projects, including but not limited to alpidem, indiplon, and suriclone.
Benzodiazepines (BZD, BDZ, BZs), sometimes called “benzos”, are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. As depressants – drugs which lower brain activity – they are prescribed to treat conditions such as anxiety, insomnia, seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann-La Roche, which soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.
Benzodiazepines are depressants that enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorised as short, intermediary, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.
Benzodiazepines are generally viewed as safe and effective for short-term use – about two to four weeks – although cognitive impairment and paradoxical effects such as aggression or behavioural disinhibition can occur. A minority of people have paradoxical reactions such as worsened agitation or panic when they stop taking benzodiazepines. Benzodiazepines are associated with an increased risk of suicide due to aggression, impulsivity, and negative withdrawal effects. Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, benzodiazepine withdrawal syndrome, and an increased risk of dementia and cancer. In the long-term, stopping benzodiazepines often leads to improved physical and mental health. The elderly are at an increased risk of both short- and long-term adverse effects, and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults. There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn.
Taken in overdose, benzodiazepines can cause dangerous deep unconsciousness, but they are less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken. Combined with other central nervous system (CNS) depressants such as alcohol and opioids, the potential for toxicity and fatal overdose increases. Benzodiazepines are commonly misused and taken in combination with other addictive substances.
The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann-La Roche on the development of tranquilisers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a “nicely crystalline” compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach’s focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. The compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam marketed by Hoffmann-La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.
The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the UK, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the expert witnesses (the consultant psychiatrists) had a conflict of interest. The court case fell through, at a cost of £30 million, and led to more cautious funding through legal aid for future cases. This made future class action lawsuits less likely to succeed, due to the high cost from financing a smaller number of cases, and increasing charges for losing the case for each person involved.
Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped. For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone. Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.
Benzodiazepines have been detected in plant specimens and brain samples of animals not exposed to synthetic sources, including a human brain from the 1940s. However, it is unclear whether these compounds are biosynthesized by microbes or by plants and animals themselves. A microbial biosynthetic pathway has been proposed.
Benzodiazepines possess psycholeptic, sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions, which are useful in a variety of indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly, or rectally. In general, benzodiazepines are well tolerated and are safe and effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is also a risk of dependence, and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability. The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression, and anxiety. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term. Benzodiazepines can have serious adverse health outcomes, and these findings support clinical and regulatory efforts to reduce usage, especially in combination with non-benzodiazepine receptor agonists.
Because of their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those holding benzodiazepines are not effective long-term and should be reserved for treatment-resistant cases to those holding they are as effective in the long term as selective serotonin reuptake inhibitors (SSRIs).
The American Psychiatric Association (APA) guidelines note that, in general, benzodiazepines are well tolerated, and their use for the initial treatment for panic disorder is strongly supported by numerous controlled trials. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and psychotherapy should be based on the patient’s history, preference, and other individual characteristics. SSRIs are likely to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also often used, and some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing benzodiazepine dependence. The APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of substance use disorder. The APA guidelines state that, in general, pharmacotherapy of panic disorder should be continued for at least a year, and that clinical experience supports continuing benzodiazepine treatment to prevent recurrence. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients using benzodiazepines long-term. For many such patients, stable doses of benzodiazepines retain their efficacy over several years.
Guidelines issued by the UK-based National Institute for Health and Clinical Excellence (NICE), carried out a systematic review using different methodology and came to a different conclusion. They questioned the accuracy of studies that were not placebo-controlled. And, based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use. Nevertheless, benzodiazepines are still prescribed for long-term treatment of anxiety disorders, although specific antidepressants and psychological therapies are recommended as the first-line treatment options with the anticonvulsant drug pregabalin indicated as a second- or third-line treatment and suitable for long-term use. NICE stated that long-term use of benzodiazepines for panic disorder with or without agoraphobia is an unlicensed indication, does not have long-term efficacy, and is, therefore, not recommended by clinical guidelines. Psychological therapies such as cognitive behavioural therapy (CBT) are recommended as a first-line therapy for panic disorder; benzodiazepine use has been found to interfere with therapeutic gains from these therapies.
Benzodiazepines are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.
Generalised Anxiety Disorder
Benzodiazepines have robust efficacy in the short-term management of generalised anxiety disorder (GAD), but were not shown effective in producing long-term improvement overall. According to NICE, benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2-4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.
Likewise, Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4-6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.
A 2015 review found a larger effect with medications than talk therapy. Medications with benefit include serotonin-noradrenaline reuptake inhibitors (SNRIs), benzodiazepines, and selective serotonin reuptake inhibitors.
Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. The Committee on Safety of Medicines report recommended that where long-term use of benzodiazepines for insomnia is indicated then treatment should be intermittent wherever possible. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness. However, they worsen sleep quality by increasing light sleep and decreasing deep sleep. Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation.
The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia varies between countries. Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.
Since the release of non benzodiazepines in 1992 in response to safety concerns, individuals with insomnia and other sleep disorders have increasingly been prescribed nonbenzodiazepines (2.3% in 1993 to 13.7% of Americans in 2010), less often prescribed benzodiazepines (23.5% in 1993 to 10.8% in 2010). It is not clear as to whether the new non benzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar. According to the US Agency for Healthcare Research and Quality, indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. However, NICE did not find any convincing evidence in favour of Z-drugs. NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient’s preference.
Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed. When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence that shows twice the incidence of traffic collisions among driving patients, and falls and hip fracture for older patients.
Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenous clonazepam, lorazepam, and diazepam are first-line choices. In the community, intravenous administration is not practical and so rectal diazepam or buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.
When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy. Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France. Clobazam was approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy. Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy. Discontinuation after long-term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.
Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam may be used as an alternative. Both are used in the detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risks of developing tolerance and dependence to the benzodiazepine medication itself. The benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous (and potentially lethal) alcohol withdrawal effects are less likely to occur. On the other hand, short-acting benzodiazepines may lead to breakthrough seizures, and are, therefore, not recommended for detoxification in an outpatient setting. Oxazepam and lorazepam are often used in patients at risk of drug accumulation, in particular, the elderly and those with cirrhosis, because they are metabolised differently from other benzodiazepines, through conjugation.
Benzodiazepines are the preferred choice in the management of alcohol withdrawal syndrome, in particular, for the prevention and treatment of the dangerous complication of seizures and in subduing severe delirium. Lorazepam is the only benzodiazepine with predictable intramuscular absorption and it is the most effective in preventing and controlling acute seizures.
Benzodiazepines are sometimes used in the treatment of acute anxiety, as they bring about rapid and marked relief of symptoms in most individuals; however, they are not recommended beyond 2-4 weeks of use due to risks of tolerance and dependence and a lack of long-term effectiveness. As for insomnia, they may also be used on an irregular/”as-needed” basis, such as in cases where said anxiety is at its worst. Compared to other pharmacological treatments, benzodiazepines are twice as likely to lead to a relapse of the underlying condition upon discontinuation. Psychological therapies and other pharmacological therapies are recommended for the long-term treatment of GAD. Antidepressants have higher remission rates and are, in general, safe and effective in the short and long term.
Benzodiazepines are often prescribed for a wide range of conditions:
They can sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the risk of respiratory depression, and it is recommended that benzodiazepine overdose treatment facilities should be available. They have also been found to increase the likelihood of later PTSD after people have been removed from ventilators.
Benzodiazepines are indicated in the management of breathlessness (shortness of breath) in advanced diseases, in particular where other treatments have failed to adequately control symptoms.
Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be useful, as patients may not remember unpleasantness from the procedure. They are also used in patients with dental phobia as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious. Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect.
Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects. Baclofen or tizanidine are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.
Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication. Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection. They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, bringing about rapid tranquillisation and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania; their long-term use is not recommended due to risks of dependence. Further research investigating the use of benzodiazepines alone and in combination with antipsychotic medications for treating acute psychosis is warranted.
Clonazepam, a benzodiazepine is used to treat many forms of parasomnia. Rapid eye movement behaviour disorder responds well to low doses of clonazepam. Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.
Benzodiazepines are sometimes used for obsessive-compulsive disorder (OCD), although they are generally believed ineffective for this indication. Effectiveness was, however, found in one small study. Benzodiazepines can be considered as a treatment option in treatment resistant cases.
Antipsychotics are generally a first-line treatment for delirium; however, when delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are a first-line treatment.
There is some evidence that low doses of benzodiazepines reduce adverse effects of electroconvulsive therapy.
Because of their muscle relaxant action, benzodiazepines may cause respiratory depression in susceptible individuals. For that reason, they are contraindicated in people with myasthenia gravis, sleep apnoea, bronchitis, and COPD. Caution is required when benzodiazepines are used in people with personality disorders or intellectual disability because of frequent paradoxical reactions. In major depression, they may precipitate suicidal tendencies and are sometimes used for suicidal overdoses. Individuals with a history of excessive alcohol use or non-medical use of opioids or barbiturates should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs.
In the United States, the Food and Drug Administration (FDA) has categorised benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.
Exposure to benzodiazepines during pregnancy has been associated with a slightly increased (from 0.06 to 0.07%) risk of cleft palate in newborns, a controversial conclusion as some studies find no association between benzodiazepines and cleft palate. Their use by expectant mothers shortly before the delivery may result in a floppy infant syndrome, with the newborns suffering from hypotonia, hypothermia, lethargy, and breathing and feeding difficulties. Cases of neonatal withdrawal syndrome have been described in infants chronically exposed to benzodiazepines in utero. This syndrome may be hard to recognise, as it starts several days after delivery, for example, as late as 21 days for chlordiazepoxide. The symptoms include tremors, hypertonia, hyperreflexia, hyperactivity, and vomiting and may last for up to three to six months. Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as diazepam or chlordiazepoxide, are recommended over potentially more harmful benzodiazepines, such as temazepam or triazolam. Using the lowest effective dose for the shortest period of time minimises the risks to the unborn child.
The benefits of benzodiazepines are least and the risks are greatest in the elderly. They are listed as a potentially inappropriate medication for older adults by the American Geriatrics Society. The elderly are at an increased risk of dependence and are more sensitive to the adverse effects such as memory problems, daytime sedation, impaired motor coordination, and increased risk of motor vehicle accidents and falls, and an increased risk of hip fractures. The long-term effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression, or anxiety syndromes, and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinence, and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses. Short to intermediate-acting benzodiazepines are preferred in the elderly such as oxazepam and temazepam. The high potency benzodiazepines alprazolam and triazolam and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects. Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines.
Long-term use of benzodiazepines is associated with increased risk of cognitive impairment and dementia, and reduction in prescribing levels is likely to reduce dementia risk. The association of a past history of benzodiazepine use and cognitive decline is unclear, with some studies reporting a lower risk of cognitive decline in former users, some finding no association and some indicating an increased risk of cognitive decline.
Benzodiazepines are sometimes prescribed to treat behavioural symptoms of dementia. However, like antidepressants, they have little evidence of effectiveness, although antipsychotics have shown some benefit. Cognitive impairing effects of benzodiazepines that occur frequently in the elderly can also worsen dementia.
The most common side-effects of benzodiazepines are related to their sedating and muscle-relaxing action. They include drowsiness, dizziness, and decreased alertness and concentration. Lack of coordination may result in falls and injuries, in particular, in the elderly. Another result is impairment of driving skills and increased likelihood of road traffic accidents. Decreased libido and erection problems are a common side effect. Depression and disinhibition may emerge. Hypotension and suppressed breathing (hypoventilation) may be encountered with intravenous use. Less common side effects include nausea and changes in appetite, blurred vision, confusion, euphoria, depersonalisation and nightmares. Cases of liver toxicity have been described but are very rare.
The long-term effects of benzodiazepine use can include cognitive impairment as well as affective and behavioural problems. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur. Not everyone, however, experiences problems with long-term use. Additionally, an altered perception of self, environment and relationships may occur.
Compared to other sedative-hypnotics, visits to the hospital involving benzodiazepines had a 66% greater odds of a serious adverse health outcome. This included hospitalisation, patient transfer, or death, and visits involving a combination of benzodiazepines and non-benzodiapine receptor agonists had almost four-times increased odds of a serious health outcome.
In September 2020, the FDA required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
The short-term use of benzodiazepines adversely affects multiple areas of cognition, the most notable one being that it interferes with the formation and consolidation of memories of new material and may induce complete anterograde amnesia. However, researchers hold contrary opinions regarding the effects of long-term administration. One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after stopping benzodiazepine usage. Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorder is the cause of these deficits.
While the definitive studies are lacking, the former view received support from a 2004 meta-analysis of 13 small studies. This meta-analysis found that long-term use of benzodiazepines was associated with moderate to large adverse effects on all areas of cognition, with visuospatial memory being the most commonly detected impairment. Some of the other impairments reported were decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The authors of the meta-analysis and a later reviewer noted that the applicability of this meta-analysis is limited because the subjects were taken mostly from withdrawal clinics; the coexisting drug, alcohol use, and psychiatric disorders were not defined; and several of the included studies conducted the cognitive measurements during the withdrawal period.
Paradoxical reactions, such as increased seizures in epileptics, aggression, violence, impulsivity, irritability and suicidal behaviour sometimes occur. These reactions have been explained as consequences of disinhibition and the subsequent loss of control over socially unacceptable behaviour. Paradoxical reactions are rare in the general population, with an incidence rate below 1% and similar to placebo. However, they occur with greater frequency in recreational abusers, individuals with borderline personality disorder, children, and patients on high-dosage regimes. In these groups, impulse control problems are perhaps the most important risk factor for disinhibition; learning disabilities and neurological disorders are also significant risks. Most reports of disinhibition involve high doses of high-potency benzodiazepines. Paradoxical effects may also appear after chronic use of benzodiazepines.
Long-Term Worsening of Psychiatric Symptoms
While benzodiazepines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e. greater than 2-4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat. Potential explanations include exacerbating cognitive problems that are already common in anxiety disorders, causing or worsening depression and suicidality, disrupting sleep architecture by inhibiting deep stage sleep, withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction, and reducing coping with trauma/stress and increasing vulnerability to future stress. Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines. Functioning significantly improves within 1 year of discontinuation.
Physical Dependence, Withdrawal and Post-Withdrawal Syndromes
The main problem of the chronic use of benzodiazepines is the development of tolerance and dependence. Tolerance manifests itself as diminished pharmacological effect and develops relatively quickly to the sedative, hypnotic, anticonvulsant, and muscle relaxant actions of benzodiazepines. Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use. In general, tolerance to the amnesic effects does not occur. However, controversy exists as to tolerance to the anxiolytic effects with some evidence that benzodiazepines retain efficacy and opposing evidence from a systematic review of the literature that tolerance frequently occurs and some evidence that anxiety may worsen with long-term use. The question of tolerance to the amnesic effects of benzodiazepines is, likewise, unclear. Some evidence suggests that partial tolerance does develop, and that, “memory impairment is limited to a narrow window within 90 minutes after each dose”.
A major disadvantage of benzodiazepines that tolerance to therapeutic effects develops relatively quickly while many adverse effects persist. Tolerance develops to hypnotic and myorelexant effects within days to weeks, and to anticonvulsant and anxiolytic effects within weeks to months. Therefore, benzodiazepines are unlikely to be effective long-term treatments for sleep and anxiety. While BZD therapeutic effects disappear with tolerance, depression and impulsivity with high suicidal risk commonly persist. Several studies have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep or anxiety. This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness. Additionally, because tolerance to benzodiazepine sedating effects develops more quickly than does tolerance to brainstem depressant effects, those taking more benzodiazepines to achieve desired effects may suffer sudden respiratory depression, hypotension or death. Most patients with anxiety disorders and PTSD have symptoms that persist for at least several months, making tolerance to therapeutic effects a distinct problem for them and necessitating the need for more effective long-term treatment (e.g. psychotherapy, serotonergic antidepressants).
Withdrawal Symptoms and Management
Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (two to four weeks), may result in two groups of symptoms – rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of physical dependence.
The most frequent symptoms of withdrawal from benzodiazepines are insomnia, gastric problems, tremors, agitation, fearfulness, and muscle spasms. The less frequent effects are irritability, sweating, depersonalisation, derealisation, hypersensitivity to stimuli, depression, suicidal behaviour, psychosis, seizures, and delirium tremens. Severe symptoms usually occur as a result of abrupt or over-rapid withdrawal. Abrupt withdrawal can be dangerous, therefore a gradual reduction regimen is recommended.
Symptoms may also occur during a gradual dosage reduction, but are typically less severe and may persist as part of a protracted withdrawal syndrome for months after cessation of benzodiazepines. Approximately 10% of patients experience a notable protracted withdrawal syndrome, which can persist for many months or in some cases a year or longer. Protracted symptoms tend to resemble those seen during the first couple of months of withdrawal but usually are of a sub-acute level of severity. Such symptoms do gradually lessen over time, eventually disappearing altogether.
Benzodiazepines have a reputation with patients and doctors for causing a severe and traumatic withdrawal; however, this is in large part due to the withdrawal process being poorly managed. Over-rapid withdrawal from benzodiazepines increases the severity of the withdrawal syndrome and increases the failure rate. A slow and gradual withdrawal customised to the individual and, if indicated, psychological support is the most effective way of managing the withdrawal. Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested, but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses, and amount of available support, a year or more may be needed to withdraw.
Withdrawal is best managed by transferring the physically dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines, is metabolised into long-acting active metabolites and is available in low-potency tablets, which can be quartered for smaller doses. A further benefit is that it is available in liquid form, which allows for even smaller reductions. Chlordiazepoxide, which also has a long half-life and long-acting active metabolites, can be used as an alternative.
Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence. Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another. During withdrawal, fluoroquinolone-based antibiotics are best avoided if possible; they displace benzodiazepines from their binding site and reduce GABA function and, thus, may aggravate withdrawal symptoms. Antipsychotics are not recommended for benzodiazepine 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.
Withdrawal from long term benzodiazepines is beneficial for most individuals. Withdrawal of benzodiazepines from long-term users, in general, leads to improved physical and mental health particularly in the elderly; although some long term users report continued benefit from taking benzodiazepines, this may be the result of suppression of withdrawal effects.
Beyond the well established link between benzodiazepines and psychomotor impairment resulting in motor vehicle accidents and falls leading to fracture; research in the 2000s and 2010s has raised the association between benzodiazepines (and Z-drugs) and other, as of yet unproven, adverse effects including dementia, cancer, infections, pancreatitis and respiratory disease exacerbations.
A number of studies have drawn an association between long-term benzodiazepine use and neuro-degenerative disease, particularly Alzheimer’s disease. It has been determined that long-term use of benzodiazepines is associated with increased dementia risk, even after controlling for protopathic bias.
Some observational studies have detected significant associations between benzodiazepines and respiratory infections such as pneumonia where others have not. A large meta-analysis of pre-marketing randomized controlled trials on the pharmacologically related Z-Drugs suggest a small increase in infection risk as well. An immunodeficiency effect from the action of benzodiazepines on GABA-A receptors has been postulated from animal studies.
A Meta-analysis of observational studies has determined an association between benzodiazepine use and cancer, though the risk across different agents and different cancers varied significantly. In terms of experimental basic science evidence, an analysis of carcinogenetic and genotoxicity data for various benzodiazepines has suggested a small possibility of carcinogenesis for a small number of benzodiazepines.
The evidence suggesting a link between benzodiazepines (and Z-Drugs) and pancreatic inflammation is very sparse and limited to a few observational studies from Taiwan. A criticism of confounding can be applied to these findings as with the other controversial associations above. Further well-designed research from other populations as well as a biologically plausible mechanism is required to confirm this association.
Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose. Taken alone, they rarely cause severe complications in overdose; statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug. However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity. The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use. The various benzodiazepines differ in their toxicity; temazepam appears most toxic in overdose and when used with other drugs. The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.
A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote is not routinely recommended because of the high risk of resedation and seizures. In a double-blind, placebo-controlled trial of 326 people, 4 people had serious adverse events and 61% became resedated following the use of flumazenil. Numerous contraindications to its use exist. It is contraindicated in people with a history of long-term use of benzodiazepines, those having ingested a substance that lowers the seizure threshold or may cause an arrhythmia, and in those with abnormal vital signs. One study found that only 10% of the people presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.
Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be divided roughly into two groups. The largest group consists of those that are metabolised by cytochrome P450 (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolised through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have few drug interactions.
Many drugs, including oral contraceptives, some antibiotics, antidepressants, and antifungal agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side-effects. In contrast, drugs that induce cytochrome P450 enzymes, such as St John’s wort, the antibiotic rifampicin, and the anticonvulsants carbamazepine and phenytoin, accelerate elimination of many benzodiazepines and decrease their action. Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing, and other adverse effects that have potential to be lethal. Antacids can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.
Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.
GABA controls the excitability of neurons by binding to the GABAA receptor. The GABAA receptor is a protein complex located in the synapses between neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter gamma-aminobutyric acid (GABA), while a subset of GABAA receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex does not alter binding of GABA. Unlike other positive allosteric modulators that increase ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. This increased chloride ion influx hyperpolarizes the neuron’s membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. Different GABAA receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct neuronal circuits. Hence, activation of different GABAA receptor subtypes by benzodiazepines may result in distinct pharmacological actions. In terms of the mechanism of action of benzodiazepines, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug at higher doses induces sleep.
The subset of GABAA receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ1). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects. Benzodiazepines bind at the interface of the α and γ subunits on the GABAA receptor. Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3, and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. For instance, those ligands with high activity at the α1 are associated with stronger hypnotic effects, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.
The benzodiazepine class of drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are present in peripheral nervous system tissues, glial cells, and to a lesser extent the central nervous system. These peripheral receptors are not structurally related or coupled to GABAA receptors. They modulate the immune system and are involved in the body response to injury. Benzodiazepines also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action. Benzodiazepines have binding sites in the periphery, however their effects on muscle tone is not mediated through these peripheral receptors. The peripheral binding sites for benzodiazepines are present in immune cells and gastrointestinal tract.
A benzodiazepine can be placed into one of three groups by its elimination half-life, or time it takes for the body to eliminate half of the dose. Some benzodiazepines have long-acting active metabolites, such as diazepam and chlordiazepoxide, which are metabolised into desmethyldiazepam. Desmethyldiazepam has a half-life of 36-200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40-250 hours. These long-acting metabolites are partial agonists.
Short-acting compounds have a median half-life of 1-12 hours. They have few residual effects if taken before bedtime, rebound insomnia may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day rebound anxiety with prolonged usage. Examples are brotizolam, midazolam, and triazolam.
Intermediate-acting compounds have a median half-life of 12-40 hours. They may have some residual effects in the first half of the day if used as a hypnotic. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer-acting benzodiazepines. Examples are alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam, lorazepam, nitrazepam, and temazepam.
Long-acting compounds have a half-life of 40-250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of rebound effects and withdrawal. Examples are diazepam, clorazepate, chlordiazepoxide, and flurazepam.
Benzodiazepines share a similar chemical structure, and their effects in humans are mainly produced by the allosteric modification of a specific kind of neurotransmitter receptor, the GABAA receptor, which increases the overall conductance of these inhibitory channels; this results in the various therapeutic effects as well as adverse effects of benzodiazepines. Other less important modes of action are also known.
The term benzodiazepine is the chemical name for the heterocyclic ring system (see figure to the right), which is a fusion between the benzene and diazepine ring systems. Under Hantzsch-Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom and the maximum possible number of cumulative double bonds. The “benzo” prefix indicates the benzene ring fused onto the diazepine ring.
Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds that do not have useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABAA receptor and so modulate the pharmacological properties. Many of the pharmacologically active “classical” benzodiazepine drugs contain the 5-phenyl-1H-benzo diazepin-2(3H)-one substructure. Benzodiazepines have been found to mimic protein reverse turns structurally, which enable them with their biological activity in many cases.
Nonbenzodiazepines also bind to the benzodiazepine binding site on the GABAA receptor and possess similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs possess a common pharmacophore, which explains their binding to a common receptor site.
Clorazepate, diazepam, flurazepam, halazepam, prazepam, and others.
In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain states and temazepam prescriptions require specially coded pads in certain states.
In Canada, possession of benzodiazepines is legal for personal use. All benzodiazepines are categorised as Schedule IV substances under the Controlled Drugs and Substances Act. Since 2000, benzodiazepines have been classed as targeted substances, meaning that additional regulations exist especially affecting pharmacists’ records. Since approximately 2014, Health Canada, the Canadian Medical Association and provincial Colleges of Physicians and Surgeons have been issuing progressively stricter guidelines for the prescription of benzodiazepines, especially for the elderly (e.g. College of Physicians and Surgeons of British Columbia). Many of these guidelines are not readily available to the public.
In the United Kingdom, the benzodiazepines are Class C controlled drugs, carrying the maximum penalty of 7 years imprisonment, an unlimited fine or both for possession and a maximum penalty of 14 years imprisonment an unlimited fine or both for supplying benzodiazepines to others.
In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20 mg of temazepam, are all placed on List 2 of the Opium Law. A prescription is needed for possession of all benzodiazepines. Temazepam formulations containing 20 mg or greater of the drug are placed on List 1, thus requiring doctors to write prescriptions in the List 1 format.
In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance. Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.
Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam, which is a Schedule III drug under the Convention on Psychotropic Substances.
Benzodiazepines are considered major addictive substances. Non-medical benzodiazepine use is mostly limited to individuals who use other substances, i.e. people who engage in polysubstance use. On the international scene, benzodiazepines are categorized as Schedule IV controlled drugs by the INCB, apart from flunitrazepam, which is a Schedule III drug under the Convention on Psychotropic Substances. Some variation in drug scheduling exists in individual countries; for example, in the UK, midazolam and temazepam are Schedule III controlled drugs.
British law requires that temazepam (but not midazolam) be stored in safe custody. Safe custody requirements ensures that pharmacists and doctors holding stock of temazepam must store it in securely fixed double-locked steel safety cabinets and maintain a written register, which must be bound and contain separate entries for temazepam and must be written in ink with no use of correction fluid (although a written register is not required for temazepam in the UK). Disposal of expired stock must be witnessed by a designated inspector (either a local drug-enforcement police officer or official from health authority). Benzodiazepine use ranges from occasional binges on large doses, to chronic and compulsive drug use of high doses.
Benzodiazepines are commonly used recreationally by poly-drug users. Mortality is higher among poly-drug users that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users. Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among drug misusers; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms such as depression, anxiety (often to the point of panic attacks), and agoraphobia. Benzodiazepines and, in particular, temazepam are sometimes used intravenously, which, if done incorrectly or in an unsterile manner, can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, and gangrene. Sharing syringes and needles for this purpose also brings up the possibility of transmission of hepatitis, HIV, and other diseases. Benzodiazepines are also misused intranasally, which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.
A 1999-2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin, and be arrested or imprisoned. Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.
Overall, anecdotal evidence suggests that temazepam may be the most psychologically habit-forming (addictive) benzodiazepine. Non-medical temazepam use reached epidemic proportions in some parts of the world, in particular, in Europe and Australia, and is a major addictive substance in many Southeast Asian countries. This led authorities of various countries to place temazepam under a more restrictive legal status. Some countries, such as Sweden, banned the drug outright. Temazepam also has certain pharmacokinetic properties of absorption, distribution, elimination, and clearance that make it more apt to non-medical use compared to many other benzodiazepines.
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of seizures, status epilepticus, and tetanus, and as maintenance therapy in epilepsy (in particular, in cats). They are widely used in small and large animals (including horses, swine, cattle and exotic and wild animals) for their anxiolytic and sedative effects, as pre-medication before surgery, for induction of anaesthesia and as adjuncts to anaesthesia.
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