The PK parameters for plasma d-amphetamine observed after oral versus intravenous administration of lisdexamfetamine (50 mg) are also summarised in Table 4. The AUC0-infinity shows that the overall drug exposure was identical irrespective of the route of administration. Importantly, intravenous injection of lisdexamfetamine did not either significantly increase the Cmax of d-amphetamine, nor did it significantly reduce its tmax. 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., 2007a,b; Lopez et al., 2008; Wigal et al., 2009) and adults (Adler et al., 2008, 2009; Wigal et al., 2010a). Amphetamine is a central nervous (CNS) system stimulant that functions by increasing the amounts of dopamine, norepinephrine, and serotonin (to a lesser extent) in the synaptic cleft through a variety of mechanisms.

Dextroamphetamine is the more potent of the two methylphenethylamine enantiomers and is sold under the brand name Dexedrine. Dextroamphetamine is the more potent form of the drug and is either used alone or in combination with levoamphetamine to prolong its effects. Inhibition of 3Hmonoamine uptake into rat brain synaptosomes by amphetamine’s enantiomers in vitro. Due to the COVID-19 pandemic, there were fewer emergency room presentations (overall and drug-related) in 2020 and 2021 when compared to the previous year’s Euro-DEN data. Therefore, any interpretation of changes in the numbers and in the proportions of amphetamine-toxicity presentations should be made with caution. Other limitations of this data relate to the fact that some hospitals reported low numbers of cases, and that the data from hospitals reflect their respective local drug-use patterns and are not necessarily representative of the regional or national situations.

• When comparing the effects of drugs on the efflux of catecholamines in the PFC it is important to take into account the highly unusual neuroanatomy of this brain region.
• Also contact your provider if you are having withdrawal symptoms that concern you.
• The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults.
• They received their optimal dose of MES-amphetamine XR, an equivalent dose of lisdexamfetamine in terms of d-amphetamine base, or placebo.
• Consistent with the findings in microdialysis experiments, d-amphetamine has greater potency than l-amphetamine to evoke stimulant-like subjective effects in rats (Schechter, 1978) and behavioural activation in primates (Scraggs and Ridley, 1978).
• Medication may be initially prescribed at a lower dose and then gradually increased.

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. It is this imperative which causes drug abusers to progress from relatively safe methods of self-administration, such as oral ingestion, onto increasingly dangerous routes, for example snorting cocaine, smoking (‘crack’ cocaine or ‘crystal meth’) or intravenous injection. Another less well-recognised factor in drug abuse is a desire of users for instant gratification. Thus, the appeal of a particular drug as a recreational substance of abuse is to a large extent determined by its ability to produce its desired effects within minutes, for example the cocaine ‘rush’.

A short history of amphetamine

As a molecule with a single chiral centre, amphetamine exists in two optically active forms, i.e. the dextro- (or d-) and levo- (or l-) isomers or enantiomers (Figure 1). Smith, Kline and French synthesised both isomers, and in 1937 commenced marketing of d-amphetamine, which was the more potent of the two isomers, under the trade name of Dexedrine®. Sales of Benzedrine and Dexedrine in chemist stores were unrestricted until 1939, when these drugs could only be obtained either on prescription from a registered medical practitioner or by signing the Poison Register (Bett, 1946). In his 1946 review, Bett commented on the widespread use of ‘energy pills’ by the allied forces in World War II, estimating that 150 million Benzedrine tablets were supplied to British and American service personnel during the course of the global conflict.

The chemical structure, particularly the 3-dimensional (3-D) structure of amphetamine, is critical in determining the pharmacological effects that underpin its considerable therapeutic benefits and also its liability for recreational abuse. 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, 2009a) and orally (Jasinski and Krishnan, 2009b). Furthermore, the time of lisdexamfetamine’s peak pharmacological effect was substantially delayed compared with IR d-amphetamine, at 3.0 h versus 1.5–2.0 h. When lisdexamfetamine was given at an increased dose of 150 mg, it significantly increased the DQRS ‘Drug liking’ score to an equivalent extent to IR d-amphetamine (40 mg oral).

When used at doses prescribed for the treatment of ADHD, the side effects of Adderall are not severe in most patients. The use of stimulants such as amphetamines and methylphenidate were shown to be effective and well-tolerated when taken over several years. However, whether long-term use affects cognitive abilities or other biological functions requires further investigation.

Administration and Dose

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., 2000; Gundlah et al., 1997; Tao et al., 2002). Donnelly et al. (1989) reported that fenfluramine was not effective in treating the disruptive and overactive Amphetamine Drug Profile behaviours in ADHD; nor did it ameliorate the conduct disorder that was present in about half of the subjects. 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. Thus, enhanced catecholaminergic signalling is the primary mediator of amphetamine’s efficacy in ADHD and narcolepsy. On the negative side, the same pharmacology is also responsible for amphetamine’s major side effects and also its liability for recreational abuse.

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, 2010). 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 D2 receptors as measured by 11C-raclopride positron emission tomography (PET) finding the stimulants aversive rather than pleasurable (Volkow et al., 1999a). 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).

Dopamine

In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive. You might be hesitant to use one because the word “amphetamine” can carry negative connotations. But your healthcare provider is there to guide you and make sure these drugs are safe and effective. They can reassure you and empower you when it comes to how these medications affect your life.

Amphetamines’ Effects on Your Brain

In October 2022, the FDA announced shortages of some amphetamine medications, especially drugs containing amphetamine, dextroamphetamine and lisdexamfetamine. Those shortages affect various dosages and formulations (immediate release vs. extended release) into 2025 and possibly beyond. That might affect the availability of some of these medications from your pharmacy.

This fact, along with the perception that d-amphetamine is much safer than the more potent and enduring stimulant methamphetamine, which is now widely abused, has resulted in a more relaxed attitude of physicians in the USA to the prescribing of d-amphetamine. Luckily, for reasons that are obscure, the recreational abuse methamphetamine has never really caught on in Europe, and almost all illegal use of the amphetamines is confined to d-amphetamine as the sulphate salt. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use.

• The optimal dose for an individual depends upon the absorption of the drug that tends to vary from person to person.
• Another factor was the use of d-amphetamine as an antidepressant in the 1950s before the discovery of the tricyclic monoamine reuptake inhibitors.
• This profile is consistent with lisdexamfetamine being pharmacologically inactive.
• It is generally accepted that the efficacy of the amphetamines is not different from that of methylphenidate (Faraone et al., 2006; James et al., 2001; Pelham et al., 2005), which is the other major stimulant used to treat ADHD.
• Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse.

Review Date 5/4/2024

Furthermore, switching to the intravenous route for lisdexamfetamine appeared to have relatively little influence on the abuse potential of the prodrug. When the in vivo pharmacological profiles of amphetamine’s isomers are compared, d-amphetamine is three to fivefold more potent than l-amphetamine (Figure 4). Moreover, an analysis of the relative effects of amphetamine’s isomers on individual catecholamines reveals d-amphetamine has greater effects on dopamine than noradrenaline, whereas l-amphetamine has a more balanced action to increase both dopaminergic than noradrenergic neurotransmission (Figure 4).

Amphetamines, i.e. racemic amphetamine, d-amphetamine and methamphetamine, were widely used to promote wakefulness in World War II, which in turn led to a large increase in production that resulted in large surpluses of these drugs after the war. Much of these stocks got into the ‘black market’, and in the 1950s d-amphetamine abuse became recognised. In a classic study of that period, Connell from the Institute of Psychiatry reported a group of heavy d-amphetamine users who had become paranoid (Connell, 1966). This flagged up the potential psychiatric dangers of this drug and may have encouraged prescribers away from d-amphetamine and on to methylphenidate.

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, 2009b). Although amphetamine has been established as an effective treatment for ADHD, as well as other central nervous system (CNS) disorders such as narcolepsy for decades, its use in the UK (and in the wider European context) has been rather limited in comparison with its widespread use in the USA. The reasons for this are complex and relate to social and medical attitudes to the condition of ADHD, pharmaceutical industry marketing policies, as well as to concerns regarding the use of drugs in paediatric indications which are perceived to have a high potential for recreational abuse and to cause addiction.

Recently, longer-lasting formulations that need to be administered only once a day were released. These delayed-release beads are enteric-coated and have a peak effect after four to seven hours after drug ingestion, with the effect of the drug lasting for about 12 hours. Such extended-release formulations of mixed salts like Adderall may be administered at a maximum dosage of 30 mg per day. Medication may be initially prescribed at a lower dose and then gradually increased.