When was amphetamine discovered

Data taken from Jackson et al and Rowley et al Earlier in the review, we described the formulation of MES-amphetamine. In vivo experiments have also been performed to explore the interaction between the ratio of d- and l- isomers in this formulation Glaser et al. The experiments were performed in anaesthetised rats using in vivo voltammetry to determine the extracellular concentration of dopamine in the striatum and nucleus accumbens.

Using this technique, Joyce et al. The authors hypothesised that l- amphetamine in MES-amphetamine modulates the activity of DAT so that the actions of the d -isomer are prolonged Joyce et al.

An alternative explanation for the observed prolongation of pharmacological effect is that the ratio of d- to l- isomers in the MES-amphetamine formulation is serendipitously optimised so that entry of the d -isomer into catecholaminergic nerve terminals is modulated by competition for DAT by the l- isomer, thereby prolonging the neurotransmitter-releasing action of the more potent d -isomer. The primary action of amphetamine is to increase synaptic concentrations of monoamine neurotransmitters, thereby indirectly enhancing noradrenergic, dopaminergic neurotransmission in the CNS.

This opinion is based on clinical experience with fenfluramine, which is a chemical analogue of amphetamine and a powerful releasing agent with a preferential action on 5-HT Baumann et al. Donnelly et al. However, it is possible that the actions of amphetamine to increase serotonergic drive may have a beneficial effect on anxiety or depression that is often comorbid with ADHD. Therefore, optimising therapeutic efficacy whilst simultaneously maintaining side effects at an acceptable level is a difficult balance requiring careful dose titration in the patient.

It has long been accepted that in ADHD there is dysregulation of the brain catecholaminergic systems in the PFC and its connections to subcortical regions including the striatum Arnsten and Dudley, ; Durston, ; Russell et al.

Neuroimaging studies in subjects with ADHD have revealed anatomical alterations and functional changes consistent with reduced dopaminergic function in various dopamine-rich areas of the brain including the frontal cortex, striatum and globus pallidus Castellanos, ; Castellanos et al.

Based on observations that the isomers of amphetamine evoke very large and rapid increases in the efflux of dopamine and noradrenaline in the PFC and dopamine in the striatum, it was predicted that these drugs would be highly effective in the treatment of ADHD.

It is generally accepted that the efficacy of the amphetamines is not different from that of methylphenidate Faraone et al.

However, a meta-analysis by Faraone and Buitelaar did show moderately greater efficacy for amphetamine medications. This agrees with preclinical findings that methylphenidate also markedly enhances catecholaminergic drive in the PFC and striatum see Heal et al. This finding fits well with results from in vivo microdialysis experiments that have shown atomoxetine can produce moderate increases in extracellular noradrenaline and dopamine in the PFC as a result of blocking the entry of both catecholamine neurotransmitters into noradrenergic neurones via NET sites, but as a selective noradrenaline reuptake inhibitor it is without effect in other brain regions, such as striatum and nucleus accumbens, where synaptic dopamine concentrations are regulated by DAT sites Swanson et al.

With clinical applications of amphetamine as a drug to combat fatigue, an appetite suppressant and a treatment of narcolepsy, adverse effects such as anorexia, weight loss and insomnia are predictable and frequent adverse events associated with the use of amphetamine-based medications in the management of ADHD.

These side effects have been reported for d -amphetamine James et al. Other adverse events evoked by the amphetamines include nausea, vomiting, abdominal cramps, increases in blood pressure and heart rate and possibly also the exacerbation of motor tics Adler et al. Stimulants have a tendency to be liked by a certain proportion of the population, though not by everyone by any means.

There is some evidence that basal dopamine tone determines this, with people who have a higher number of dopamine D 2 receptors as measured by [ 11 C]-raclopride positron emission tomography PET finding the stimulants aversive rather than pleasurable Volkow et al.

However, a pleasurable experience from d- amphetamine can lead to excessive use of it as a prescribed drug by the patient and the mis use of the prescription by others diversion. For these reasons, all current amphetamine-type stimulant treatments are Controlled Drugs under the UK Misuse of Drugs Act , with all members of being placed in Class B except methamphetamine, which was recently placed into Class A because of fears of an explosion of recreational abuse similar to that seen in the USA and Thailand.

In reality, there is little abuse of these drugs by patients with ADHD Merkel and Kuchibhatla, , and in most cases the challenge for the prescribing doctor is to keep the patients taking their medication rather than limiting its use.

Many teenage patients stop using despite the drugs having clear benefits for their school performance; they cite reasons such as feeling too controlled, wanting empowerment from medication, etc. For these reasons, observations of dependence and abuse of prescription d- amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place Jasinski and Krishnan, b.

It is well known that recreational drug abusers and dependent users generally administer psychostimulants at doses several-fold higher than those stipulated for therapeutic use. Furthermore, to achieve its greatest pharmacological effect, the maximum quantity of drug must be delivered into the CNS in the shortest possible time.

Another less well-recognised factor in drug abuse is a desire of users for instant gratification. The kinetics of d- amphetamine when taken orally make it less rewarding pleasurable than cocaine or methamphetamine. Methamphetamine enters more slowly and its peak effects are delayed by 10—15 min compared with cocaine Fowler et al. Although d- amphetamine sulphate has not been studied in an exactly comparable way, we can predict from its physico-chemical properties that after oral ingestion d- amphetamine would have even slower rate of uptake into the brain than methamphetamine.

Having said that, the abuse of d- amphetamine is not a cause for complacency. Although amphetamine abuse peaked in the s Rasmussen, , the misuse of amphetamine is a persistent social, legal and medical problem Das-Douglas et al.

The intravenous use of d -amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice Charnaud and Griffiths, ; Das-Douglas et al. Some of this intravenous abuse is derived from the diversion of ampoules of d- amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation.

However, most intravenous d- amphetamine use is from local illicit production. Some abusers will use solvents to extract the active ingredient from tablets or capsules, which can then be concentrated and injected intravenously. The development of tamper-deterrent d- amphetamine formulations has been a major objective of the pharmaceutical industry to prevent this type of abuse. Several new once-daily d- amphetamine-containing prescription drugs have emerged that have a high degree of tamper deterrence, for example Adderall XR.

In addition, lisdexamfetamine as a prodrug of d- amphetamine, is a further advance in reducing diversion risk since it provides a more gradual increase in brain drug concentration, thereby further reducing the pleasurable effects of the d- amphetamine. These topics will be revisited later in this review. Volkow and colleagues have performed an enormous body of research using PET and other brain imaging techniques to explore the relationship between DAT occupancy, synaptic dopamine concentration and dopamine D 2 receptor occupancy for psychostimulant drugs of abuse.

Although the dopamine release hypothesis of drug reinforcement proposed by Di Chiara and Imperato based on experiments performed in rats and then extended in humans by Volkow and colleagues , a has its limitations, it is now well accepted that euphoria, psychostimulation and reinforcement produced by stimulant drugs occur when there are rapid and substantial increases in the synaptic concentrations of dopamine in the basal striatum and mesolimbic system of the human brain.

Although d -amphetamine is a competitive substrate for DAT rather than a classical reuptake inhibitor, these same principles apply to its pharmacological action. Thus, the rate and magnitude of neuronal dopamine release produced by amphetamine is absolutely dependent on the rate and concentration of drug that reaches DAT sites in the brain Heal et al.

There has been little research conducted in humans on this kinetic course using brain imaging, but it seems likely that the same rules apply. Consistent with the findings in microdialysis experiments, d -amphetamine has greater potency than l- amphetamine to evoke stimulant-like subjective effects in rats Schechter, and behavioural activation in primates Scraggs and Ridley, Both amphetamine isomers have been shown to serve as positive reinforcers in animals i.

The same is true for human subjects Smith and Davis, ; Van Kammen and Murphy, , with the d -isomer once again being two to threefold more potent than the l -isomer Risner, ; Smith and Davis, ; Van Kammen and Murphy, ; Yokel and Pickens, As indicated above, it is the combination of the rapid rate of increase and magnitude of effect that accounts for the powerful stimulant effects of amphetamine.

Although l- amphetamine is the less potent of the two isomers, its pharmacological efficacy should not be underestimated. Cheetham et al. In contrast, the maximum increases in dopamine efflux achieved by classical dopamine reuptake inhibitors e.

The importance of the rate of increase of synaptic dopamine concentrations to the induction of stimulation and euphoria is exemplified by the observation that bupropion and GBR were not experienced as stimulant or euphoriant by normal volunteers Hamilton et al.

In those bupropion and GBR trials where d -amphetamine was employed as the positive control, its stimulant, energising and reinforcing effects were unequivocally recognised by normal subjects and recreational drug users Hamilton et al.

In previous reviews, we have extensively described the efficacy and safety of stimulant and non-stimulant drugs used in the management of ADHD and compared the relative merits of each Heal et al. This analysis has revealed that the stimulants, including amphetamine, are still accepted to be the most efficacious drugs available.

On the other hand, the innovations in formulation technology and drug delivery systems have made significant strides forward in improving the clinical management of ADHD.

All of the stimulants have biological half-lives that require at least twice-daily dosing to deliver efficacy over 12—14 h. ADHD is characterised by inattention, distractibility, working memory deficits and impulsivity, and as such, subjects with this disorder are particularly unsuited to compliance with rigid dosing schedules.

Examples of once-daily amphetamine medications include MES-amphetamine XR and the d- amphetamine prodrug, lisdexamfetamine. As briefly discussed earlier in the review, lisdexamfetamine is the first amphetamine prodrug to have been approved for use in treating ADHD.

This profile is consistent with lisdexamfetamine being pharmacologically inactive. Although there is no definitive information on the subject, the large molecular size and polar characteristics of lisdexamfetamine predict that the parent molecule is unlikely to cross the blood—brain barrier.

In vitro experiments revealed that the metabolism of lisdexamfetamine to d -amphetamine occurs in red blood cells by rate-limited enzymatic hydrolysis Pennick, Lack of affinity of lisdexamfetamine for a portfolio of abuse-related molecular targets. The locomotor activity of the rats was also simultaneously monitored. After administration of equivalent doses of lisdexamfetamine and IR d- amphetamine 1.

These observations are entirely consistent with the postulated rate-limited enzymatic conversion of lisdexamfetamine to d- amphetamine. This difference in PK characteristics had a profound impact on the pharmacological effects of these two compounds in rats Figure 5. Lisdexamfetamine produced a gradual and sustained increase in striatal dopamine efflux, whereas the increase produced by IR d- amphetamine was faster in onset, reaching a peak at 30 min, and it subsequently declined more rapidly Figure 5.

In the case of lisdexamfetamine, the more gradual and sustained increase in dopamine efflux was associated with a much smaller and visibly delayed locomotor response. Using the hysteresis analysis in a more conventional way to explore the relationship between the plasma concentration of d- amphetamine and the functional response, there was a clear difference between the two compounds with an anticlockwise hysteresis for lisdexamfetamine and no hysteresis for IR d- amphetamine Rowley et al.

The anticlockwise hysteresis shows that the functional effect of lisdexamfetamine was greater as the plasma concentration of d- amphetamine was falling, whilst the lack of hysteresis with IR d- amphetamine demonstrates that as soon as the plasma concentration of the drug starts to decline, so does its pharmacological effect.

The clinical importance of these findings will be discussed in the following section. The efficacy of lisdexamfetamine has been demonstrated in a number of randomised, double-blind, placebo-controlled clinical trials in ADHD in children, adolescents Biederman et al. Since lisdexamfetamine has been the subject of several reviews Dew and Kollins, ; Heal et al. Biederman et al. Following a 3-week, open-label run-in period where the dose of MES-amphetamine XR was optimised to 10, 20 or 30 mg once a day, subjects were then randomised into a 3-way double-blind, placebo-controlled crossover trial.

They received their optimal dose of MES-amphetamine XR, an equivalent dose of lisdexamfetamine in terms of d- amphetamine base, or placebo.

On the primary and secondary efficacy variables of behaviour, attention and problem solving, lisdexamfetamine delivered equivalent or better efficacy than MES-amphetamine XR with both drugs being maximally effective at 2 h post-dose Biederman et al. However, on the problem-solving endpoints, it was also evident that lisdexamfetamine maintained its maximum effect for at least 12 h, whereas the effect of MES-amphetamine XR showed a clear decline after 6—8 h Biederman et al.

An exceptionally long duration of effect of lisdexamfetamine was observed by Wigal et al. A post-hoc analysis of the data also showed that the sex and age of the subjects had no significant influence on the efficacy of lisdexamfetamine Wigal et al. These observations fit well with the PD profile of lisdexamfetamine in the microdialysis experiments. Another way to produce a more gentle increase of brain dopamine is to bind d -amphetamine to a support.

Another factor that almost certainly contributes to the consistently high level of therapeutic efficacy observed with lisdexamfetamine treatment is the very low inter- and intra-subject variability in the plasma concentration of d -amphetamine observed after administration of the prodrug compared with traditionally formulated stimulants, including beaded and osmotic-release formulations.

Once again, the reproducible pharmacokinetics of its active metabolite, d -amphetamine, are probably due to the rate-limited, enzymatic cleavage of the precursor molecule that occurs primarily in red blood cells Ermer et al.

In two earlier published studies, Jasinski and Krishnan compared the subjective effects of lisdexamfetamine and IR d -amphetamine in drug-experienced human volunteers when these compounds were administered intravenously Jasinski and Krishnan, a and orally Jasinski and Krishnan, b. In the trial where they compared these compounds after oral administration, IR d -amphetamine 40 mg However, the peak effect of the higher dose of lisdexamfetamine was even more delayed, at 4.

Both compounds yielded equivalent AUC h values, but compared with the equivalent dose of IR d -amphetamine, the C max for plasma d- amphetamine was threefold smaller for lisdexamfetamine and the t max was threefold greater Jasinski and Krishnan, b.

From these results, it can be concluded that although in terms of d- amphetamine base equivalents lisdexamfetamine is clearly less potent than IR d -amphetamine, it does nonetheless produce d -amphetamine-like subjective effects in man.

Although increasing the dose of lisdexamfetamine enhanced its efficacy, it also progressively delayed its time of peak effect.

Furthermore, switching to the intravenous route for lisdexamfetamine appeared to have relatively little influence on the abuse potential of the prodrug. To explore this possibility further, we performed a post-hoc analysis on the data in the original clinical study reports Jasinski, , NRP A02; Jasinski, , NRP A03 to compare pharmacodynamics and pharmacokinetics of lisdexamfetamine when given by the clinical route oral versus one of those favoured by recreational abusers intravenous.

This topic is of particular importance because lisdexamfetamine has very high aqueous solubility, making the prodrug very easy to extract. This result shows that the subjective effects of lisdexamfetamine were not enhanced when the drug was given intravenously. Blood pressure measurements are useful objective measures of the PD effects of sympathomimetic drugs. It was in Japan that the first MA epidemic occurred.

In the U. Nevertheless, by the s, the prevalence of amphetamine use was on the rise among civilians, including groups such as college students, truck drivers, athletes, housewives, and individuals performing monotonous jobs.

In the s, administering amphetamines, including MA, by intravenous injection gained popularity, especially among individuals already using illicit drugs.

It was this group that may have first used amphetamines solely for their euphoric effects. Most of the amphetamines available at that time were diverted from pharmaceutical companies.

A Japanese chemist first synthesized methamphetamine—also called meth, crank, crystal meth or speed—from another stimulant in Methamphetamine was used early on as a medical treatment for narcolepsy, asthma and as a weight-loss drug. After the war, meth use increased dramatically, even after it was outlawed by the United States in Scientists first developed amphetamine-type stimulants—including methamphetamine—as a manmade alternative to the ephedra plant.

Ephedra is a type of shrub whose extract has been used in traditional Chinese medicine for over 5, years. In , Nagai Nagayoshi—a Japanese chemist studying in Germany—identified the active chemical in ephedra, a stimulant called ephedrine. Methamphetamine was difficult to make until , when another Japanese chemist—Akira Ogata—streamlined the process. Methamphetamine is a stimulant drug.

A form of the drug known as methamphetamine hydrochloride, marketed as Desoxyn, is a Food and Drug Administration FDA -controlled substance used to treat attention deficit hyperactivity disorder ADHD and obesity. Other, illegal forms of methamphetamine—usually in the form of a white powder—can be recreationally snorted or dissolved in water and injected. Crystal meth is a solid, crystalline form of the drug.

It may look like shards of glass or clear-white rocks. Users often smoke or snort crystal meth. Smoking the drug can quickly elevate levels of methamphetamine in the brain. This gives users a rapid, intense high, making crystal meth both more addictive and potentially more harmful than other forms of methamphetamine. American pharmaceutical company Smith, Kline, and French began marketing the amphetamine inhaler for use in asthma and nasal congestion in Their inhaler medication, called Benzedrine, was initially available without a prescription.

People soon discovered its euphoric, energizing side effects. Because of these stimulant-type effects, pharmaceutical companies began to manufacture Benzedrine in pill form for narcolepsy a sleep disorder. During World War II , German pharmaceutical company Temmler marketed methamphetamine tablets as a nonprescription drug under the brand name Pervitin. Japanese, U. Kamikaze pilots received high doses of Pervitin before suicide flight missions.

Japanese factory workers also used methamphetamine to work longer hours. The German army ordered front-line soldiers and fighter pilots to take military-issued stimulants that contained a combination of methamphetamine and cocaine.

Recreational use of Benzedrine—or bennies—became a popular part of Beatnik culture in the s. Auden , reportedly used artificial stimulants, including bennies.