The Quest for the Adderall Killer
Looking for a safe, effective Adderall alternative with more tolerable side effects? That would be the holy grail of smart drugs. But in all seriousness, it exists. It's called modafinil.
My personal experience with Adderall has been that it is highly effective at controlling the symptoms of ADHD, but the side effect are just not worth it.
I always crashed at the end of the day, and was left feeling "tired and wired" after the drug wore off. Adderall also gave me headaches, insomnia, low-grade hypertension and made my extremities feel very cold (peripheral vasoconstriction).
There are many drugs and nutraceuticals that mimic some of the effects of Adderall. Having tried different Adderall alternatives, I've found that ultimately the best options are modafinil, deprenyl and possibly nicotine. (Not tobacco, obviously. Nicotine in the form of Nicorette or a nicotine patch.)
Why Adderall Use is on the Rise
America has been engaged in an ongoing love affair with Adderall for decades now. Healthy adults are continuing to use Adderall to bolster productivity in college and at work in a kind of intellectual arms race.
Adderall is a pretty effective prescription ADHD medication, but it can be difficult to obtain legitimately.
Some physicians are leery about prescribing Adderall even when the patient in question is not a drug-seeker and legitimately needs the medication to function. This reluctance may reflect Adderall's addictive potential.
Adderall is comprised of mixed amphetamine salts. It "works" by hijacking endogenous reward circuitry, i.e., the dopaminergic system. So it makes some sense that Adderall has a fairly high abuse potential.
There are a number of substances that can be legally purchased online (without a prescription) that elicit effects analogous to Adderall. Many of them are not technically psychostimulants, but exhibit psychostimulant-like effects. Some are classified as nootropics ("smart drugs"), nutraceuticals or dietary supplements that enhance concentration and dispel fatigue.
Modafinil is a prescription wakefulness enhancer that's becoming very popular in silicon valley. It's a smart drug - it increases productivity and cognitive function - with more manageable side effects. You can read more about the mechanism of action of modafinil here.
The drug is very expensive, and so I resorted to buying modafinil online. Buying prescription drugs online sounds pretty shady, doesn't it? But in all seriousness, there are quite a few reliable modafinil vendors that have emerged to meet demand.
Comparison of Adderall Alternatives
Finding the right over-the-counter Adderall substitute really depends on your individual neurophysiology and how you respond to drugs. Some people are non-responders to modafinil, for genetic reasons.
Finding the right Adderall alternative is therefore very much a trial-and-error process.
|Strattera (Atomoxetine)||Norepinephrine reuptake inhibitor (Prescription drug)||↑ norepinephrine, dopamine (indirect)||Likely effective|
|Nicotine||Sympathomimetic (OTC drug)||↑ acetylcholine (nicotinic acetylcholine receptor agonist), ↑ dopamine||Likely effective, but safety concerns exist|
|Modafinil||Wakefulness-enhancer (prescription)||↑ Dopamine, glutamate/GABA, histamine/orexin||Likely effective|
|Adrafinil||Adrafinil is a prodrug for the popular wakefulness enhancer modafinil. Like modafinil, adrafinil decreases the subjective perception of fatigue and improves concentration||↑ Dopamine, glutamate/GABA, histamine/orexin||Likely effective|
|Desipramine||Tricyclic antidepressant (prescription)||↑ Norepinephrine (norepinephrine reuptake inhibitor)||Likely effective|
|Deprenyl (selegeline)||Selective MAO-B inhibitor (prescription)||↑ Dopamine, norepinephrine||Likely effective|
|Rasagiline||Rasagiline is technically a prescription drug (though it can be purchased online quasi-legally). It is a selective MAO-B inhibitor that enhances dopaminergic neurotransmission. Users report stimulant-like effects.||↑ Dopamine, norepinephrine||Likely effective|
|Phenylpiracetam||Phenylpiracetam is a piracetam-phenylethylamine hybrid with psychostimulant like effects. For some, phenylpiracetam has a "speedy" feel that is reminiscent of Adderall||Poorly understood||Insufficient evidence|
|Bromantane||Bromantane is serotonin-dopamine reuptakine inhibitor with dual stimulant and anxiolytic properties. Bromantane would be a good Adderall substitute due to its ability to increase synaptic dopamine concentrations.||↑ Dopamine, ↑ serotonin||Insufficient evidence|
Other Supplements Noted to Help with ADHD
|Zinc||Nutritional supplement||Zinc is a cofactor for the metabolism of neurotransmitters, affects dopamine metabolism, is a necessary for 100 different enzymes||Possibly effective|
|Fish oil (DHA/EPA)||Nutritional supplement||Critical to brain development and function; patients with ADHD may be deficient||Possibly effective|
|Melatonin||Sleep-promoting neurohormone (Nutritional supplement)||Promotes sleep and may treat ADHD-associated insomnia, but little effect on core symptoms||Likely ineffective|
|S-adenosyl L-methionine (SAMe)||Trimonoamine modulator (Nutritional supplement)||↑ monoamines (serotonin, dopamine, norepinephrine)||Insufficient evidence|
|Piracetam||Allosteric glutamate modulator (Nutraceutical/prescription drug)||↑ glutamatergic signaling||Insufficient evidence|
Modafinil vs Adderall
Strictly speaking, comparing Modafinil to Adderall does not make a lot of sense. Adderall is a psychostimulant that enhances how rewarding you perceive tasks to be (task salience), whereas Modafinil reduces fatigue and increases arousal. In other words, Modafinil will make you feel more alert; it's like a souped up version of caffeine.
So while the modafinil vs adderall comparison isn't really valid from a pharmacological standpoint - I do think that Modafinil is one of the best Adderall alternatives available. (Though it's not OTC, access is much less restricted compared to Adderall).
How Adderall Works in the Brain
Adderall is a potent prescription psychostimulant (and a controlled substance in the US) that treats ADHD and narcolepsy. Adderall can also be used off-label for depression. It's a very effective drug at treating the inattentive symptoms of ADHD. But Adderall carries significant risks which must be weighed carefully. These include addiction or dependence, insomnia, and personality changes.
Adderall is a mixture of four amphetamine salts. Amphetamines are "catecholamine releasing agents." This means that amphetamine elicits the release of dopamine and norepinephrine in the brain. Dopamine, and to a lesser extent norepinephrine, are neurotransmitters that play important roles in regulating motivation, concentration, executive function, planning, organization, reward and task salience.
"Task salience" refers to how important you perceive a task to be or how engaging you find an activity. It is thought that patients with ADHD either (a) synthesize or release less of these catecholamines, (b) metabolize and clear them especially quickly, or (3) have receptors that are less sensitive to them.
Potential Nootropic or Cognitive Enhancing Effects of Adderall
Adderall is increasingly being used by college students as a "smart drug" to enhance concentration and facilitate studying. The jury is still out on whether Adderall really improves cognition in healthy subjects. Some studies suggest that Adderall makes individuals feel smarter without really improving performance. If Adderall does improve cognitive performance in individuals without ADHD, it is likely it only has an effect in individuals with lower baseline cognitive function to begin.
The (mis)use of Adderall as a study drug is cause for concern because Adderall use may negatively affect brain development, has many unwanted side-effects like insomnia and hypertension, and carries significant long-term risks. There is the issue of psychological dependence, since Adderall use to facilitate studying may make it more difficult to study without the drug.
General Safety of Adderall
At prescribed doses, Adderall is generally regarded as safe and the benefits probably outweigh the risks for patients who are functionally impaired without proper treatment for their ADHD. For example, a neuroimaging study showed that Adderall prevented brain abnormalities in patients with ADHD compared to unmedicated controls. This result suggests that Adderall may have a beneficial effect on brain development for suffers of ADHD. An interesting anecdote is that Paul Erdos, an extremely prolific mathematician, famously took amphetamines well into old age and remained very sharp with no obvious ill health effects.
Risks of Adderall Neurotoxicity
However, the theoretical risk of injury to the brain (Adderall neurotoxicity) still exists, even at prescribed doses. We still don't know the whole story. In animal models, Adderall likely damages dopaminergic neurons, though this deleterious effect remains unconfirmed in human patients at prescribed dosages. At high, abuse doses, Adderall has been shown to predispose one to get Parkinson's disease, which is highly suggestive of neurotoxicity to the dopaminergic system.
Adderall likely causes oxidative stress in the brain and depletes endogenous antioxidant defense. Recall that Adderall enhances dopamine release in the central nervous system (CNS). This can be harmful because excessive (synaptic) dopamine can promote the formation of a neurotoxic, oxidized derivative of dopamine called 6-hydroxydopamine. This is one of many proposed mechanism by which Adderall might cause harm. Another mechanism is related to the fact that amphetamine disrupts electrochemical gradients (or the membrane potential) in serotonergic neurons.
The Best Adderall Alternative
Based on my experiences, Modafinil is the best Adderall alternative available. There's some evidence that Modafinil is an effective treatment for ADHD, which supports the notion Modafinil does have some psychostimulant-like effects that aid concentration. Modafinil is also arguably a lot gentler on your brain compared to Adderall, and may even be neuroprotective (see this abstract. By neuroprotective, I mean that it protects the brain from insult and injury (e.g., concussions).
Modafinil also weakly inhibits dopamine reuptake, increasing dopamine concentrations at synapses (brain connections). This aspect of Modafinil's mechanism of action overlaps with Adderall and may partially explain some similiarities (though Modafinil does a lot more mechanistically - it also enhances the connectivity of gap junctions between neurons, for example).
Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial (2009)
This randomized, double-blind, placebo-controlled, 6-month trial examined the efficacy and safety of once-daily morning-dosed atomoxetine in adult patients with attention-deficit/hyperactivity disorder (ADHD) and the efficacy of atomoxetine in ameliorating symptoms through the evening hours. Patients received once-daily atomoxetine (n = 250) or placebo (n = 251) in the morning for approximately 6 months. The efficacy measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version, Clinical Global Impressions-ADHD-Severity of Illness, and Adult ADHD Quality of Life Scale. Overall, 94 patients randomized to atomoxetine and 112 patients randomized to placebo completed the study. On the AISRS total score, Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version evening index total score, Clinical Global Impressions-ADHD-Severity of Illness score, and Adult ADHD Quality of Life Scale total score, atomoxetine was statistically superior to placebo at the 10-week and 6-month time points. From the visitwise analysis, the mean (SD) AISRS total scores for atomoxetine decreased from 38.2 (7.5) at baseline to 21.4 (12.3) at the 6-month end point compared with 38.6 (7.0) to 25.8 (13.2) for placebo (P = 0.035). Nausea, dry mouth, fatigue, decreased appetite, urinary hesitation, and erectile dysfunction were the treatment-emergent adverse events reported significantly more often with atomoxetine. Discontinuations due to adverse events were 17.2% and 5.6% for atomoxetine and placebo, respectively (P < 0.001). Once-daily morning-dosed atomoxetine is efficacious for treating ADHD in adults when measured 10 weeks and 6 months after initiating treatment. Atomoxetine demonstrated significant efficacy that continued into the evening. Adverse events were similar to previous trials.
Nicotine effects on adults with attention-deficit/hyperactivity disorder (1996)
Several lines of evidence suggest that nicotine may be useful in treating the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). The current study was an acute, placebo-controlled double-blind experiment to determine whether nicotine might be useful as an alternative treatment of adults with ADHD symptomatology. Six smokers and 11 nonsmokers who were outpatient referrals for ADHD were diagnosed by DSM-IV criteria. Measures of treatment effect included the Clinical Global Impressions (CGI) scale, Hopkins' symptom check list (SCL-90-R), the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT), the Stroop test, and an interval-timing task. The smokers underwent overnight deprivation from smoking and were given a 21 mg/day nicotine skin patch for 4.5 h during a morning session. The nonsmokers were given a 7 mg/day nicotine skin patch for 4.5 h during a morning session. Active and placebo patches were given in a counter-balanced order approximately 1 week apart. Nicotine caused a significant overall nicotine-induced improvement on the CGI. This effect was significant when only the nonsmokers were considered, which indicated that it was not due merely to withdrawal relief. Nicotine caused significantly increased vigor as measured by the POMS test. Nicotine caused an overall significant reduction in reaction time (RT) on the CPT, as well as, with the smokers, a significant reduction in another index of inattention, variability in reaction time over trial blocks. Nicotine improved accuracy of time estimation and lowered variability of time-estimation response curves. Because improvements occurred among nonsmokers, the nicotine effect appears not to be merely a relief of withdrawal symptoms. It is concluded that nicotine deserves further clinical trials with ADHD.
Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults (2000)
Our objective was to compare the efficacy of the new wake-promoting drug modafinil to that of dextroamphetamine for the treatment of attention deficit hyperactivity disorder (ADHD) in adults. Twenty-two adults who met DSM-IV criteria for ADHD participated in a randomized, double-blind, placebo-controlled, three-phase crossover study comparing placebo, modafinil, and dextroamphetamine for the treatment of ADHD. The twice-daily study medications were titrated to doses of optimum efficacy over 4-7 days and then held constant during the rest of each 2-week treatment phase. Measures of improvement included the DSM-IV ADHD Behavior Checklist for Adults, the Controlled Oral Word Association Test (COWAT, using the letters C, F, and L version), Stroop, and Digit Span (Wechsler Adult Intelligence Scale version). For the 21 (96%) completers, the mean (+/- SD) optimum doses of modafinil and dextroamphetamine were 206.8 mg/day +/- 84.9 and 21.8 mg/day +/- 8.9, respectively. Scores on the DSM-IV ADHD Checklist (p < 0.001) were significantly improved over the placebo condition following treatment with both active medications. Performance on the COWAT (p < 0.05) reached trend levels of significance. Both medications were generally well tolerated. This preliminary study suggests that modafinil may be a viable alternative to conventional stimulants for the treatment of adults with ADHD.
Desipramine treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette's syndrome (1993)
OBJECTIVE: As many as 50% of patients with Tourette's syndrome (TS) also meet diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Since antipsychotics are of limited value in controlling the symptoms of ADHD and stimulants can exacerbate tics, alternative treatments are directly needed. The purpose of this study was the examination of the efficacy of desipramine (DMI) in the treatment of pediatric patients with chronic tic disorder (CTD; TS or chronic motor tics) + attention-deficit hyperactivity disorder (ADHD). METHOD: All pediatric patients with the diagnosis of CTD that were treated with DMI were ascertained from retrospective systematic chart reviews of a psychopharmacology clinic and a neurology service specialized in movement disorders. RESULTS: Of the 33 identified patients, 30 had comorbid CTD + ADHD and three had CTD alone. In all, 82% had significant improvement in CTD symptomatology and 80% significantly improved ADHD symptoms without major adverse effects over an average follow-up period of 16 months. CONCLUSIONS: Although the conclusions from this retrospective report can be seen as preliminary only until replicated in a controlled investigation, the magnitude and persistence of the response is encouraging and suggest a therapeutic role for DMI in the treatment of CTD + ADHD patients.[/expand]
Selegiline in ADHD adults: plasma monoamines and monoamine metabolites (1997)
Plasma monoamines and monoamine metabolites were assessed before and during selegiline treatment in adults with attention deficit/hyperactivity disorder (ADHD). Selegiline, at low dose, is a selective monoamine oxidase inhibitor type B (MAOI-B). After 2-week placebo baseline, 36 ADHD adults were randomized to 6-week placebo or 20 mg/day or 60 mg/day selegiline, followed by 2-week posttreatment placebo. Twenty-seven subjects continued into a 6-week 20-mg/day or 60-mg/day selegiline period. Behavioral variables included self-rated scores on the Conners' Abbreviated Teacher Rating Scale (Conners-ATRS) and performance on a Continuous Performance Task (CPT). Plasma samples were assayed for amines (dopamine, norepinephrine, epinephrine), precursor (DOPA), and metabolites (HVA, DOPAC, DHPG, normetanephrine, metanephrine, 5-HIAA). Selegiline produced dose-dependent changes in monoamine metabolites and DOPA plasma levels. Dopaminergic indices were associated with ADHD symptom severity (Conners-ATRS) and noradrenergic indices with CPT performance. Serotonergic metabolism, challenged by selegiline, correlated with clinical changes. These findings support a multisystem dysfunction underlying ADHD pathophysiology.
Zinc in Attention-Deficit/Hyperactivity Disorder (2005)
Objective: The aim of this study was to review the published evidence for a role of zinc nutrition in attention-deficit/hyperactivity disorder (ADHD).Method: A computer literature search was supplemented by the authors’ knowledge.Results:Numerous controlled studies report cross-sectional evidence of lower zinc tissue levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal controls and population norms. A few studies show correlations of zinc level with either clinical severity or a change thereof in response to stimulant or chemical challenge. Two placebo-controlled trials—one of zinc monotherapy, the other of zinc supplementation of methylphenidate—reported significant benefit. However, diagnostic procedures and sample representativeness were often not clear, and most such reports have come from countries and cultures with different diets and/or socioeconomic realities than are found in the United States (only one American sample in nine published reports). In particular, both positive clinical trials of zinc supplementation came from the Mid-East (Turkey and Iran), an area with suspected endemic zinc deficiency. The largest of these trials used zinc doses above the recommended upper tolerable limit and had a 2 in 3 dropout rate.
Conclusion: It is not clear how well the accumulating evidence for a possible role of zinc in ADHD applies to middle-class American children. However, the evidence appears strong enough to warrant further controlled study in well-diagnosed samples representative of the socioeconomic spectrum. Hypothesis-testing clinical trials are needed of this potential treatment that, if found effective, might become a relatively safe, cheap substitute for, or adjunct to, current treatments in some patients. At present, it should remain an investigational treatment.
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders (2006)
Omega-3 fatty acids are dietary essentials, and are critical to brain development and function. Increasing evidence suggests that a relative lack of omega-3 may contribute to many psychiatric and neurodevelopmental disorders. This review focuses on the possible role of omega-3 in attention-deficit/hyperactivity disorder (ADHD) and related childhood developmental disorders, evaluating the existing evidence from both research and clinical perspectives. Theory and experimental evidence support a role for omega-3 in ADHD, dyslexia, developmental coordination disorder (DCD) and autism. Results from controlled treatment trials are mixed, but the few studies in this area have involved different populations and treatment formulations. Dietary supplementation with fish oils (providing EPA and DHA) appears to alleviate ADHD-related symptoms in at least some children, and one study of DCD children also found benefits for academic achievement. Larger trials are now needed to confirm these findings, and to establish the specificity and durability of any treatment effects as well as optimal formulations and dosages. Omega-3 is not supported by current evidence as a primary treatment for ADHD or related conditions, but further research in this area is clearly warranted. Given their relative safety and general health benefits, omega-3 fatty acids offer a promising complementary approach to standard treatments.
Disturbed sleep in children with ADHD: is there a place for melatonin as a treatment option? (2013)
BACKGROUND: Sleep disorders are common in children with ADHD and they are aggravated by treatment with stimulantia. We focus on treatment with melatonin and weigh up its efficacy and safety.
AIM: To consider the evidence supporting the use of melatonin in the treatment of children with ADHD and to assess the efficacy and safety of such treatment. METHOD: We studied the literature using databases Embase, PubMed, PsycINFO and the Cochrane Library and the search terms 'ADHD', ‘melatonin', ‘insomnia', ‘methylphenidate', ‘side-effects', ‘endocrinology'.
RESULTS: 25-50% of children with ADHD reported disturbed sleep patterns particularly in the form of (chronic) sleep onset insomnia ((C)SOI). Currently available research results indicate that melatonin can be effective in the treatment of (C)SOI and, on the whole, is well tolerated. However, there is a lack of pharmaceutical preparations of melatonin that give details about their use for children and that give evidence-based guidelines about the dosage and timing of intake. Very little systematic research has been done into the possible impact of melatonin intake on puberty and the endocrine system. Therefore, treatment with melatonin in children with ADHD and (C)SOI is best reserved for children with persistent insomnia which is having a severe impact on daily functioning, particularly in cases where is an obvious phase-shift of the endogenous circadian rhythm.
CONCLUSION: If indications are particularly strong there may be good reason to use melatonin to treat sleep disorders in children with ADHD. However, further research into the safety of melatonin is needed.
S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: preliminary results from an open trial (1990)
The psychostimulants d-amphetamine and methylphenidate are thought to be the most effective treatment in children, adolescents, and adults with attention deficit-hyperactivity disorder (ADHD) because they potentiate both dopamine (DA) and norepinephrine (NE) at the synaptic cleft. These medications are not free from side effects and controversy. Newer effective and safe treatments are needed. S-Adenosyl-L-methionine (SAM), the active form of methionine, acts as a methyl donor and is involved in many metabolic pathways. It has beta adrenergic and DA receptor agonist activity. We have been using oral SAM in a sample of well-diagnosed adults with ADHD, residual state (RS) in a 4-week open trial to establish SAM effectiveness and safety and in a 9-week, double-blind, placebo-controlled crossover trial. Preliminary data from the open trial reveal that 75 percent (6 out of 8 male) patients improve on it. The 2 who did not improve had not improved on methylphenidate trial. Improvement ranged from moderate to marked, with minimal and transient side effects that did not interfere with functioning.
Atomoxetine and piracetam in the treatment of attention deficit hyperactivity disorder in children (2008)
Therapeutic effect of atomoxetine and piracetam has been assessed in the open controlled study included 42 patients with attention deficit hyperactivity disorder (ADHD), aged from 6 to 13 years. Group 1 (16 patients) received atomoxetine (strattera) in daily dosage 0,8-1,2 mg/kg as a monotherapy for 6 weeks. Patients of group 2 (14 children) received piracetam as a monotherapy in daily dosage 50-70 mg/kg for 6 weeks. No pharmacological therapy was conducted in group 3 (a control one) which included 12 patients with ADHD. The high effectiveness of both atomoxetine and piracetam has been shown. However, comparing to piracetam, the therapeutic effect of atomoxetine was reached earlier (two weeks after the beginning of therapy) and was more pronounced for all components of syndromes.