Amphetamines should not be stimulants of first choice
Amphetamines in DEA Schedule 2 (AdderallR, DexedrineR, VyvanseR) are the most commonly prescribed stimulants in the USA. These amphetamines should not be the stimulants of first choice. However, amphetamine use increased 2.5 fold from 2006 to 2016. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261411/)
Stimulant medicines (amphetamines, methylphenidate, modafinil, armodafinil, solriamfetol) are generally dopamine and norepinephrine reuptake inhibitors. They increase the amount of dopamine and norepinephrine in the brain, especially in the front of the brain. As a result, they improve attention and wakefulness. They significantly improve quality of life in patients with attention deficit, narcolepsy, or idiopathic hypersomnia.
Amphetamines are unusual stimulants. They are the only stimulants that actually cause release of dopamine from nerve cells. This causes pleasure and makes amphetamines rather addicting. They are widely abused. The pills can also be crushed and the powder then inhaled or injected. Amphetamines are now the second largest cause of overdose deaths in the USA. Amphetamines cause more overdose deaths than cocaine, heroin, and common prescription opioids, but not as many as synthetic opioids. Illegal use of amphetamines continues to rise in young adults. Amphetamines are the most abused prescription medicines.
Adult baboons and squirrel monkeys were treated with a 3:1 mixture of dextro- and levo- amphetamines (similar to Adderall) in doses similar to human clinical treatment for 3 to 6 weeks. They developed evidence of toxicity to nerve cells. High levels of dopamine in cytoplasm causes severe oxidative stress injury. Methylphenidate does not cause similar toxicity to nerve cells, since it does not cause dopamine release. Only amphetamines cause dopamine release.
Methylphenidate (and bupropion) seem actually to decrease the risk of amphetamine abuse. They may be useful in treating amphetamine abuse. Methylphenidate and d-methylphenidate (ConcertaR, RitalinR, MetadateR, FocalinR) are safer stimulants, and we prefer them to amphetamines. They work just as well as amphetamines for the average person. A major drug company tried to prove that amphetamines work better than methylphenidate, but the data apparently showed otherwise and was never published. Of course, there will be patients who will not respond to methylphenidate, and amphetamines may be necessary is such patients. In that case, extended release amphetamines cause less dopamine release than regular amphetamines. We do not prescribe regular amphetamines at all, prescribing only extended release amphetamines.
There is another amphetamine (benzphetamine, DidrexR) which is inactive. It is slowly converted in the body to active amphetamines. This gives a much smoother response with less release of dopamine. It is considered less addicting and is the only amphetamine that is not in DEA Schedule 2. However, it is only approved for treating obesity, and is typically not covered by insurance companies.
Unfortunately, we are running into more patients coming in demanding AdderallR (an amphetamine). They get very upset when we tell them we will not prescribe it just because they want it. We tell them we will carefully evaluate their attention deficit symptoms, and treat any underlying causes (especially sleep disorders). If we determine they need stimulant treatment, we prefer other stimulant medicines to DEA Schedule 2 amphetamines such as AdderallR. They only become more upset. Perhaps they would even benefit from treatment for stimulant drug abuse.
To summarize, stimulant medicines are wonderful treatment for attention deficit, narcolepsy, and idiopathic hypersomnia. Non-amphetamine stimulants should be preferred to amphetamines. Amphetamines are more abused, and more likely to cause nerve cell toxicity. When it is appropriate to use amphetamines, only extended-release amphetamines should be used.