Methamphetamines are a more lethal and ersatz version of amphetamines. There is a structural difference between the two substances that allows methamphetamine to more rapidly enter the brain producing additional detrimental and addictive effects. A large quantity of middle-class American society received prescriptions for low-dose amphetamines from their private doctors to alleviate the stress of their daily routines.
Members of the lower class and people from marginalized groups relied mostly on homemade methamphetamine, broadly known as crack, because of its widespread availability. Nevertheless, high profile public figures, such as President John F. Kennedy, were no exception to the stimulant compulsion. Taking the drug intravenously proved to be more effective in inducing amplified euphoria. The overprescription and illegal use of the medication raised an alarm for national concern, leading to the drastic shift in public opinion.
Studies conducted worldwide displayed its negative effects, garnering a great deal of attention from individuals using or already addicted to the drug. Newly Discovered side effects like psychosis, addiction, malnutrition, major mood shifts, hallucinations and irregular heartbeats turned away many users. But while the stigmatization of the stimulant had begun, the abuse did not stop there. Its new branding: Adderall. There is a general consensus amongst psychiatrists that individuals diagnosed with the condition should either be therapeutically or medically treated in order to alleviate their symptoms.
Nowadays, Adderall is a mainstream drug for students looking to cope with the stress of school and maintaining grades. Studies show that 60 percent of individuals who abuse Adderall are between the ages of 18 and There is a widespread misconception among college students that Adderall makes you smarter or that they are entirely harmless with no harmful effects.
Ramin Mojtabai, MD, Ph. 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. On top of this, on the rare occasions when the disorder was identified, the preferred treatment option was psychotherapy because it fitted with the background of the child psychiatrists and psychologists who were responsible for managing these patients.
It was left to certain paediatricians to develop the requisite expertise in the use of stimulants for treating children with ADHD, which many did quite successfully. In recent years, child psychiatrists have begun to assume a prescribing role as well, largely using methylphenidate preparations. Amphetamines, i. 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, This flagged up the potential psychiatric dangers of this drug and may have encouraged prescribers away from d- amphetamine and on to methylphenidate.
Another factor was the use of d- amphetamine as an antidepressant in the s before the discovery of the tricyclic monoamine reuptake inhibitors. In later years, local outbreaks of d- amphetamine abuse have occurred in various parts of the UK, often using locally synthesised d- amphetamine; again, this will have made doctors shy away from prescribing d- amphetamine lest it contributes to its misuse.
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.
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. Although it was synthesised many decades before the discovery that the monoamines, i. As shown in Figure 1 , the similarity between the chemical structures of the catecholamine neurotransmitters, noradrenaline and dopamine, and the isomers of amphetamine is abundantly clear.
The 3-D structures of the catecholamines and amphetamine molecules reveal the long planar conformation that is common to all of these compounds. Figure 2 illustrates the mechanism responsible for the uptake transport of monoamines and amphetamine into presynaptic nerve terminals. There are two pools of monoamine neurotransmitter within each type of nerve terminal: the cytosolic pool that holds newly synthesised monoamines, and the vesicular pool that stores the monoamines and from which they are released when neurones fire action potentials.
Although the concentration of a monoamine neurotransmitter in the cytosol of the presynaptic nerve terminal is regulated, controlled by its rates of synthesis, release, reuptake and catabolism, it is now recognised that transport of the monoamine into the vesicular storage granules has a critically important role to play in this process.
Translocation of monoamines from the cytosolic pool into the storage pool is performed by a similar active transporter system, the vesicular monoamine transporter 2 VMAT2 Fei et al. Since amphetamine competes with the endogenous monoamines for transport into the nerve terminals via NET, DAT or SERT, the higher the concentration of amphetamine present in the synapse, the greater the number of amphetamine molecules transported relative to every molecule of monoamine see Figure 3.
Once inside the presynaptic terminal, amphetamine displaces monoamines from the cytosolic pool. The outcome of these actions is that the direction of the reuptake transporter reverses, so that instead of pumping neurotransmitter from the synapse into the nerve terminal, it pumps neurotransmitter out of neurones into the synapse.
There are experimental reports stating that d- amphetamine releases [ 3 H] noradrenaline, dopamine and 5-HT from synaptosomes Holmes and Rutledge, ; Rothman et al.
Comparing the relative potencies of d- and l- amphetamine, Heikkila et al. In contrast, l- amphetamine was either as potent, or more so, than d- amphetamine as a releaser of [ 3 H]noradrenaline Easton et al. The monoamine transporters are not particularly selective in terms of which monoamines they transport, and this lack of selectivity is explained by the close structural similarity between them Figure 1. Furthermore, this structural similarity between the monoamine neurotransmitters and amphetamine explains why the latter has promiscuous actions to release the important CNS monoamines noradrenaline, dopamine and 5-HT.
Amphetamine also releases adrenaline from the peripheral sympathetic nervous system, an action linked to its cardiovascular side effects. Although most of these experiments have looked at the effects of amphetamine isomers on basal [ 3 H]monoamine release from synaptosomes or slices, amphetamine also augments electrically stimulated efflux Easton et al. This action indicates that its retro-transport mechanism can act both co-operatively with, and independently of, neuronal firing.
Although the pharmacological effect of amphetamine is predominantly mediated by monoamine release, this mechanism is complemented by reuptake inhibition and probably also inhibition of monoamine oxidase MAO that combine additively or synergistically to augment synaptic monoamine concentrations.
Comparisons of the isomers of amphetamine reveal that l- amphetamine is 3. Its potency is so low that l- amphetamine would not be considered to be a 5-HT reuptake inhibitor. Finally, excess monoamines within the nerve terminal are catabolised by the mitochondrial-bound enzyme, MAO. Inhibition of MAO would further augment the quantity of neurotransmitter that is available for retro-transport into the synapse. Although this mechanism is often discounted because amphetamine is a relatively weak inhibitor of MAO, in the situation where amphetamine is concentrated in presynaptic nerve terminals, shown in Figure 3 , it is probable that some inhibition of this enzyme would occur.
Although in vitro experiments provide a good insight into individual mechanisms, the efficacy of amphetamine relative to other indirect monoamine agonists, for example classical reuptake inhibitors, can only be estimated from in vivo experiments. We have used dual-probe intracerebral microdialysis to explore the in vivo effects of d- and l- amphetamine in the spontaneously hypertensive rat SHR , which has been proposed as a rodent model of ADHD Heal et al.
Both isomers of amphetamine dose-dependently increased the extracellular concentrations of noradrenaline in the prefrontal cortex PFC and dopamine in the striatum. The pharmacodynamics of their effects are typical of those reported for monoamine releasing agents, i. 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.
In spite of the fact that there are few DAT sites on PFC dopaminergic neurones, their reuptake capacity is sufficient for amphetamine to evoke substantial dopamine release from them Maisonneuve et al. A comparison of the effects of the d- and l- isomers of amphetamine on noradrenaline and dopamine efflux in the brains of freely moving rats.
The vertical arrow indicates the time of administration of drug or saline. Data taken from Cheetham et al. Note the different doses of the two drugs. Kuczenski et al. The effect was considerably smaller than found for dopamine and there was a smaller potency separation between the two isomers.
The effects of administration of d -amphetamine and lisdexamfetamine on the extracellular concentration of dopamine in the striatum and locomotor activity of freely moving rats. Drug doses are expressed in terms of d- amphetamine free base for both d- amphetamine sulphate and lisdexamfetamine. The vertical arrow indicates time of drug administration. Significantly different from the vehicle-treated control group: Extracellular dopamine: d- Amphetamine 1.
Activity: d- Amphetamine 1. 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, That's where the college kids come in.
By the end of the s, the Adderall of its day had taken over the academic world. Students from all backgrounds were using Benzedrine to stay awake late into the night to finish their school work and probably to have a good time. Both the allied forces and the Nazis used amphetamine and it's relative, methamphetamine, during World War II to stimulate the troops. It has been recorded that more than million methamphetamine pills were distributed to German troops between and The Nazis were known for marching for extreme distances, which was often fueled by drugs.
Amphetamine-based drugs, like Benzedrine Sulfate, became popular among mothers in the s. It was also used to treat Parkinson's Disease. Benzedrine was later a drug of choice for many of the beatniks of the s and 60s. Writers Jack Kerouac and William S. Burroughs often used the drug for fun or to help them write.
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