Diazepam

Also known as

Vallies, V, blues, valley girls, pumpkin seeds, downers, candy, Vs, yellow Vs, blue Vs, benzos, dead flower powers, foofoo, howards, sleep away, tranks

Classification

Anticonvulsant, anxiolytic, sedative, muscle relaxant

Overview

A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. It is used in the treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant, and in the management of alcohol withdrawal syndrome .

Medical usage

Diazepam is used to treat anxiety disorders, alcohol withdrawal symptoms, or muscle spasms. Diazepam is sometimes used with other medications to treat seizures .

What does it look like?

Tablets, oral liquid solutions, injectable formulations, and rectal tubules .

Source

Because its synthesis is challenging, the presence of diazepam in illicit drug markets is almost always due to illegal sales or diversion of prescribed pharmaceutical stock .

Street price

According to the National Drug Intelligence Center (which closed in 2012), Valium goes for $1 - $10 per pill on black markets .

Why take it?

Sought after effects

• sedative,
• relaxant ,
• intense feelings of happiness,
• reduced stress,
• increased mental and physical relaxation,
• drowsiness .

Undesired effects

• headaches/dizziness,
• memory problems (particularly if sleep is interrupted),
• tremors/shakiness .

Dosage

Abuse

• Threshold - 1 mg - 2.5 mg,
• Light - 2.5 - 5 mg,
• Common - 5 - 15 mg,
• Strong - 15 - 30 mg,
• Heavy - 30 mg + .

What are the different forms?

• Tablets - Small, white or off-white tablets, usually 2mg when prescribed,
  • Yellow or off-white tablets are usually 5mg,
  • Blue tablets are usually 10mg,
• Oral solutions of 2mg/5ml or 5mg/5ml (with sugar free versions available) and injectable formulations of 5mg/mL exist,
• Rectal tubes also exist as 2mg/mL and 4mg/mL formulations .

How long do its effects last?

Onset of effects

• oral - 30 - 90 minutes .

Duration of effects

• oral - 12 - 24 hours .

After-effects

• oral - 24 - 36 hours .

Pharmacology

In common with other benzodiazepine drugs, diazepam elicits five principle pharmacological effects - namely: anxiolytic (anxiety-reducing)/ sedative; hypnotic (sleep-inducing); muscle relaxant and (a significant) anticonvulsant effect. These effects are a result of diazepam's action of the main inhibitory neurotransmitter GABA.

Diazepam is a long-acting benzodiazepine which appears to act on several brain regions, thus altering several functions. It acts on the 'thalamus' which is responsible for emotion, motivation, long-term memory, olfaction (sense of smell), motor function (movement), consciousness and alertness. It also acts on the hypothalamus - the regulator of body temperature, hunger, thirst, fatigue and sleep-wake cycles (circadian rhythm).

Diazepam's significant anticonvulsant properties are thought to involve regulation of sodium levels within nerve cells (neurons) and in the tiny gaps existing between neurons in the central nervous system called 'synapses'.

Its muscle-relaxant properties are thought to be caused by its inhibition of chemical pathways that ordinarily occur within the spinal cord .

Pharmacodynamics

Diazepam, a benzodiazepine, generates the same active metabolite as chlordiazepoxide and clorazepate. In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side-effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localised irritation of tissue surrounding injection sites and some thickening of veins after intravenous use .

Peak plasma levels

Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; 10 - 45 minutes for rectal, and between 1 - 5 minutes intravenously .

Bioavailability

Oral 85% - 100% . Bioavailability of 93% .

Metabolism

Hepatic via the Cytochrome P450 enzyme system. The main active metabolite is desmethyldiazepam, in addition to minor active metabolites including temazepam and oxazepam .

Half-life

Biphasic 1 - 2 days and 2 - 5 days, active metabolites with long half lives .

Elimination

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates .

Lethal dosage

2.5946 LD50 mol/kg in rats .

Tolerance

Tolerance develops with continued use of many substances like alcohol, opioids, and benzodiazepines like diazepam. Over time, as the body adapts to the medication's consistent presence, the original dose of diazepam is not able to produce the same results. This leads to the need to increase the dose taken, increase the frequency, or both .

Dependence

This is an expected and common process that is related to consistently using or abusing a substance. The body gets used to having diazepam and begins to need it to function normally. Dependence is possible even when one is taking diazepam as prescribed; however, dependence can indicate that someone is developing an addiction, as well .

Mechanism of action

Benzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarised cell membrane that prevents further excitation of the cell .

Mode of use

• Orally - swallowed as a tablet/capsule, drunk as an oral solution,
• Snorted - The tablets are sometimes crushed and taken nasally,
• Injected - injectable formulations as well as gelcaps are known to be used intravenously (injected into the limbs, groin or neck) or intramuscularly,
• Rectally - using rectal tubes .

Effects

Minor effects

• constipation,
• loss of libido,
• diarrhoea,
• swallowing difficulties,
• double vision,
• dry mouth,
• feeling of constant movement of self or surroundings,
• erectile dysfunction,
• increase in sexual ability, desire, drive, or performance,
• increased interest in sexual intercourse,
• increased salivation,
• indigestion,
• passing of wind or flatus,
• double vision,
• sensation of spinning .

Major effects

Common

• shakiness,
• unsteady walk,
• unsteadiness,
• trembling,
• problems with muscle control or coordination .

Incidence not known

• abdominal or stomach pain,
• agitation,
• anxiety,
• black, tarry stools,
• blistering, flaking, or peeling of skin,
• blurred vision,
• changes in patterns and rhythms of speech,
• chills,
• confusion,
• cough,
• dark urine,
• decrease in frequency of urination,
• decrease in urine volume,
• difficulty in passing urine (dribbling),
• discouragement,
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly,
• false beliefs that cannot be changed by facts,
• fast heartbeat,
• fast or irregular breathing,
• feeling sad or empty,
• feeling that others are watching you or controlling your behaviour,
• feeling that others can hear your thoughts,
• hallucinations,
• fever,
• headache,
• hyperexcitability,
• increased muscle spasms or tone,
• irritability,
• itching,
• lack of appetite,
• lack of memory of what takes place after a certain event,
• loss of appetite,
• loss of bladder control,
• loss of interest or pleasure,
• lower back or side pain,
• mood or other mental changes,
• nausea,
• nervousness,
• nightmares,
• outbursts of anger,
• painful or difficult urination,
• pale skin,
• rash,
• restlessness,
• seizures,
• shakiness in the legs, arms, hands, or feet,
• shortness of breath,
• sleeplessness,
• slurred speech,
• sore throat,
• sweating,
• trembling or shaking of the hands or feet,
• tremor,
• trouble concentrating,
• trouble in speaking,
• trouble sleeping,
• ulcers, sores, or white spots in the mouth,
• unable to sleep,
• unpleasant breath odour,
• unusual behaviour,
• unusual bleeding or bruising,
• unusual feeling of excitement,
• unusual tiredness or weakness,
• vomiting of blood,
• jaundice .

Physical effects

• muscle relaxation,
• motor control loss,
• respiratory depression,
• sedation,
• seizure suppression,
• dizziness .

Cognitive effects

• compulsive redosing,
• delusions,
• dream potentiation,
• amnesia,
• analysis suppression,
• anxiety suppression,
• disinhibition,
• emotion suppression,
• information processing suppression,
• thought deceleration .

Positive

• euphoria,
• relaxation,
• anti-anxiety effects .

Neutral

• drowsiness,
• appetite fluctuation .

Negative

• memory loss,
• blackout potential,
• motor skill impairment,
• dizziness,
• depression,
• irritability,
• aggression,
• rage,
• personality changes,
• emotional and social dissociation or de-realization (long term use) .

Overdose

• change in consciousness,
• difficult or troubled breathing,
• irregular, fast or slow, or shallow breathing,
• lack of coordination,
• loss of consciousness,
• loss of strength or energy,
• muscle pain or weakness,
• cyanosis,
• sleepiness,
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness .

Dangerous interactions

Dangerous

• Alcohol - Ethanol ingestion may potentiate the CNS effects of many benzodiazepines. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Blacking out and memory loss is almost certain.
• GBL / GHB - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position.
• Opioids - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Blackouts/memory loss likely.
• Tramadol - Central nervous system - and/or respiratory-depressant effects may be additively or synergistically present. Vomit aspiration a risk when passed out, lay down in recovery position if ingested .

Unsafe

• PCP - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely .

Withdrawal

• depressed or irritable mood,
• severe anxiety,
• panic,
• restlessness,
• inability to sleep,
• confusion,
• muscle cramps,
• headache,
• sweating,
• vomiting,
• extreme sensitivity to light,
• hallucinations,
• tremors,
• seizures .

Harm reduction

• Alcohol can interact negatively with diazepam, so it's not a good idea to drink while you're taking it,
• Benzodiazepines can also interact with one another, so it's not a good idea to take diazepam if you are already taking another benzo. If in doubt, check with a doctor,
• If you've been prescribed diazepam and you notice a tolerance starting to develop (you need to keep taking more to get the same effect) speak to your doctor - don't just start increasing your dose yourself,
• Don't suddenly stop taking them, or you may start to experience symptoms of withdrawal - these can range from a return of your original symptoms (possibly even worse than before) to totally new symptoms,
• If you have become addicted to diazepam, the symptoms of abruptly stopping are likely to be even worse - it's important to get proper medical advice on how to reduce your intake slowly,
• It's also possible to become psychologically dependent on the drug (feeling like you need it all the time) - if you think this is happening, see your doctor as soon as possible, but don't suddenly stop taking it .

History

Diazepam was developed in 1963 by the Polish chemist Dr. Leo Sternbach while working at the Swiss pharmaceutical company Hoffmann-La Roche. It was the second benzodiazepine drug to be developed - succeeding chlordiazepoxide (Librium). Diazepam's potency was found to be more than twice that of chlordiazepoxide, meaning lower dosages could be used to achieve desired clinical effects. It was also found to have a better safety profile than that of the barbiturates, which were previously the most widely-used class of drugs with similar properties to benzodiazepines. Such properties helped diazepam rapidly achieve popularity amongst clinicians and patients alike, resulting in the drug being both widely available and arguably, readily-prescribed.

The 1970's through to the early 1980's saw huge sales of diazepam around the world - particularly in the United States. In 1985 diazepam came 'off-patent', meaning that Hoffmann-La Roche's production exclusivity ended and many other companies were able to start producing the drug.

As the extent of both its addictive properties and inducement of drug tolerance amongst users was realised, enthusiasm from many quarters began to wane and clinicians began heeding long-standing warnings about these issues. An increasingly-cautious approach to prescribing diazepam followed although British doctors still issue close to 18 million prescriptions for it per year.

Non-prescribed (black-market) sales of diazepam have increased to meet demand from people using the drug for a variety of reasons. These include use to induce the expected clinical effects, excessive use to achieve a 'high' or by those already with a dependency, combined use with other depressant drugs or following stimulant drug use to make inevitable 'come downs' more manageable and to remove the urge to take more stimulants .

Diazepam was the second benzodiazpine (The first of which was Librium) invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility. It was released in 1963 as an improved version of Librium, it became incredibly popular. Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets .

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