Diazepam

Diazepam is the archetype, the benzodiazepine against which all others are measured, and its subjective character reflects that classical pedigree. The onset is unhurried, typically taking thirty to sixty minutes to fully establish itself, and it arrives not as a wave but as a gradual warming of the internal climate. The first sign is a loosening of the muscles -- a deep, spreading relaxation that begins in the large muscle groups of the back and thighs and works its way outward to the fingers and toes. It is as though someone had slowly turned up the thermostat inside the body while simultaneously loosening every joint.

The come-up brings with it the anxiolytic effects for which Valium became famous. Worry does not vanish so much as lose its adhesive quality: thoughts about problems and obligations still arise, but they no longer stick. They drift through consciousness like clouds, acknowledged and released. There is a warmth to this state that goes beyond the merely physical -- an emotional warmth, a sense that the world is fundamentally safe and that one's place in it is secure. Social interactions become easier, not through stimulation but through the removal of the invisible barriers that anxiety erects. The body feels heavy in the most pleasant sense, each limb weighted with a comfortable gravity that makes movement feel optional.

At the peak, diazepam reveals its signature character: a smooth, encompassing calm that extends from the physical to the emotional to the cognitive. The muscle relaxation is profound -- the body feels like warm wax, pliable and at ease. The mind is quiet, not empty but unhurried, and there is a subtle slowing of perception that makes the world feel more spacious. Time seems to expand gently, moments lingering longer than they should. There is a mild euphoria in many users, particularly those for whom anxiety is a constant companion, and it takes the form of simple, uncomplicated contentment. The world does not look different; it simply feels better. Coordination is softened, and there is a characteristic looseness to movement and speech that betrays the depth of the relaxation.

The offset is one of diazepam's great virtues: it is long, gentle, and forgiving. The effects taper over many hours, the calm gradually thinning rather than breaking. The long half-life means there is no cliff edge, no sudden return of tension. Sleep comes easily during the descent, and the following day often retains a ghost of the previous night's tranquility -- a residual softness that can last well into the afternoon, as though the body remembers the calm even after the molecule has been metabolized.

Diazepam is a long-acting "classical" benzodiazepine. Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations. Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.

Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes the binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. 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. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.

The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and, to a large degree, the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.

Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects. Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs, including diazepam increase the inhibitory processes in the cerebral cortex.

Benzodiazepines produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the neurotransmitter gamma aminobutyric acid (GABA) by acting on its receptors. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of diazepam on the nervous system. The anticonvulsant properties of benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.

Following chlordiazepoxide (Librium), which was approved for use in 1960, diazepam was the second benzodiazepine invented by Leo Sternbach of pharmaceutical company Hoffman-La Roche. Released in 1963 as an improved version of Librium, diazepam became incredibly popular and quickly surpassed it in sales, helping Roche to become a pharmaceutical industry giant. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.

The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler, Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion Valium tablets.

Diazepam is a long-acting "classical" benzodiazepine. Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations. Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.

Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes the binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. 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. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.

The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and, to a large degree, the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.

Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects. Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs, including diazepam increase the inhibitory processes in the cerebral cortex.

Benzodiazepines produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the neurotransmitter gamma aminobutyric acid (GABA) by acting on its receptors. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of diazepam on the nervous system. The anticonvulsant properties of benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.

Reports in our experience index:

hashish+(has+to+do+with+my+benzo+tollerance.+T:+4:10+11.40:+Effects+are+gradually+declining,+I%27m+feeling+more+sober+after+having+eaten+a+full+pita+with+chease+and+ham.+T:+4:50+00.20:+I%27m+coming+down,+the+sensation+is+decreasing+in+its+intensity+and+I%27m+slowly+but+steadily+going+back+to+baseline.+T:+5:10+00.40:+effects+have+vanished+complitely,+now+I+Just:

low toxicity relative to dose. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications in spite of having high concentrations of diazepam and its metabolites esmethyldiazepam, oxazepam, and temazepam (according to samples taken in the hospital and as follow-up).

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. After cessation,7-14 days. However, in certain cases this may take significantly longer in a manner which is proportional to the duration and intensity of one's long-term usage.

Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction. For more information on tapering from benzodiazepines in a controlled manner, please see this guide.

Benzodiazepine discontinuation is notoriously difficult; it is potentially life-threatening for individuals using regularly to discontinue use without tapering their dose over a period of weeks. There is an increased risk of hypertension, seizures, and death.. Benzodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly.

Symptoms of a benzodiazepine overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death. Benzodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Benzodiazepine overdoses are sometimes treated with flumazenil, a GABAA antagonist, however care is primarily supportive in nature.