Phentermine is an anorectic medication utilized principally for the short-term treatment of obesity as an adjunct to caloric restriction, dietary modifications, and physical exercise. It is formally classified as a psychostimulant due to the fact that it increases mental and physical arousal [via sympathomimetic mechanisms]. Specifically, phentermine facilitates central and peripheral catecholamine release (primarily of norepinephrine), thereby upregulating activation of the sympathetic nervous system.
Analogous to amphetamine-related compounds, phentermine interacts with TAAR1 (Trace amine-associated receptor 1), and to a lesser extent, VMAT2 (Vesicular monoamine transporter 2). Its agonism of TAAR1 (Trace amine-associated receptor 1) generates substantial increases in intraneuronal norepinephrine concentrations, as well as modest increases in intrasynaptic dopamine and serotonin. Its modest effect upon VMAT2 is thought to promote additional monoaminergic release.
As a result of its notable psychostimulatory mechanism, many hypothesize that phentermine could be useful as a pharmacological intervention for ADHD (attention-deficit/hyperactivity disorder). When considering that phentermine is an amphetamine-derivative, as well as that variants of amphetamine (e.g. dextroamphetamine) are FDA approved as ADHD medications – it is reasonable to question why phentermine hasn’t already undergone extensive evaluation for the treatment of ADHD. Furthermore, compelling anecdotal accounts from phentermine users have suggested that the drug effectively attenuates symptoms of ADHD.
How Phentermine May Treat ADHD (Mechanisms)
Assuming that phentermine may be an effective pharmacological intervention for ADHD, it is necessary to highlight the neurobiological and/or physiological mechanisms by which it may alleviate symptoms. The primary mechanism by which phentermine is likely to reduce ADHD symptoms is via triggering the release of norepinephrine, thereby bolstering noradrenergic signaling. Since many individuals with ADHD exhibit abnormalities in the neurotransmission of norepinephrine, enhancement of noradrenergic signaling may be a critical mechanism by which phentermine improves attention and reduces impulsivity.
In addition to its facilitation of norepinephrine release, phentermine is known to induce the dopamine release, as well as serotonin release at high doses. As a comparative reference, researchers have discovered that phentermine triggers the release of approximately one-tenth the amount of dopamine compared to norepinephrine – and one-hundredth the amount of serotonin compared to norepinephrine. Though negligible increases in serotonin are unlikely to have any impact upon symptoms of ADHD, the modest increases in dopamine may contribute to the drug’s therapeutic effect.
Furthermore, phentermine is understood to increase activation of the sympathetic nervous system. Based on the finding that individuals with ADHD often to exhibit overactivity of the parasympathetic nervous system, an increase in sympathetic nervous system function induced by phentermine may decrease ADHD symptoms. Moreover, perhaps other effects exerted by phentermine such as modulation of: hormones, neural activation, neuroelectrical patterns (brain waves), and peripheral catecholamines – may be complementary therapeutic mechanisms by which reduces symptoms of ADHD.
Norepinephrine signaling: A myriad of studies suggest that abnormalities in norepinephrine transporter function, signaling, and/or binding can cause ADHD. Genetic polymorphisms may be a major reason as to why individuals with ADHD often exhibit noradrenergic abnormalities. A study published in 2008 by Kim et al. noted that variations in the norepinephrine transporter (NET) gene increased risk of attention-deficit/hyperactivity disorder.
Specifically, individuals with ADHD often carry a -3081(T) allele, which represses transcription of SLC6A2 and alters norepinephrine transporter activity. Abnormalities in norepinephrine transporter function affect norepinephrine reuptake to presynaptic neurons, and ultimately noradrenergic signaling. A plausible downstream effect of abnormal noradrenergic activity is hypoactivity of the prefrontal cortex.
Prefrontal hypoactivity can deleteriously affect attention, working memory, organization, planning and self-control. A mechanism by which many medications are thought to provide therapeutic benefit is through increasing concentrations of norepinephrine via reuptake inhibition and/or release. A notable example of a norepinephrine reuptake inhibitor that effectively treats ADHD is Strattera (Atomoxetine).
By increasing norepinephrine concentrations, prefrontal activity is enhanced and attention improves. Although phentermine acts differently than Strattera (Atomoxetine), its principal mechanism of action involves stimulating the release of norepinephrine. It is logical to speculate that increasing norepinephrine concentrations in the brain could improve functioning and symptoms of those with ADHD – especially among patients for whom noradrenergic dysfunction is a likely cause of symptoms.
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Dopamine signaling: It is known that psychostimulants (e.g. dextroamphetamine) act as dopamine reuptake inhibitors and releasers. The dopaminergic modulation provided by psychostimulants is often capable of reducing prominent symptoms of ADHD such as: inattentiveness, hyperactivity, and impulsivity. Individuals with ADHD often exhibit dopaminergic dysfunction that detrimentally affects prefrontal cortex and reward pathway activity.
Specifically, this dopaminergic dysfunction is thought to cause downstream hypoactivity within the prefrontal cortex, and abnormal processing in reward pathways. As a result, individuals with ADHD induced by dopaminergic dysfunction often experience attentional deficits, impulsivity, and lack of motivation to accomplish tasks. Upon administration of a psychostimulant, hypoactivity within the prefrontal cortex is reversed and activity within reward processing pathways (such as the nucleus accumbens) is modulated.
Reversal of ADHD-related prefrontal hypoactivity is important in that it normalizes executive functions such as: attentional control, working memory, cognitive flexibility, reasoning, problem solving, and planning. Modulation of reward processing pathway activity is important in that it likely improves motivation among those with ADHD. Although phentermine initiates approximately 10-fold greater release of norepinephrine compared to dopamine, it still triggers release of dopamine.
Even a modest release of dopamine as a result of taking phentermine may be enough to upregulate prefrontal function and/or combat abnormalities in the nucleus accumbens. This may explain why some phentermine users report improvements in attentiveness, working memory, and motivation during treatment.
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Sympathetic tone: There’s some evidence to suggest that individuals with ADHD may exhibit imbalances in autonomic nervous system (ANS) function, particularly an overactive parasympathetic nervous system. A study by Musser et al. (2011) noted that children with ADHD often struggle with emotional regulation and speculated that difficulty with emotional regulation may be related to abnormalities in activation of the autonomic nervous system (ANS).
To test this hypothesis, a total of 32 children with ADHD and 34 healthy controls were recruited for participation. All were presented with emotion tasks and researchers measured autonomic nervous system activity. Evaluation of results suggested that the chief difference between those with ADHD and healthy controls was related to parasympathetic nervous system activity.
Specifically, individuals diagnosed with ADHD exhibited a stable pattern of heightened parasympathetic nervous system activity across all emotion tasks, whereas the healthy controls did not. It is difficult to know whether similar findings would occur among adults with ADHD or in a follow-up study. However, based on this study we can speculate that elevated parasympathetic tone and deficient sympathetic tone may account for some ADHD symptoms such as inability to regulate emotion.
Phentermine is known to increase sympathetic nervous system function by acting as a sympathomimetic. Its sympathomimetic effect may upregulate sympathetic tone among individuals with ADHD in which sympathetic function is inadequate. For this reason, improving sympathetic tone may be a critical mechanism by which phentermine treats a subset of individuals with ADHD.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21394506
Hormonal modulation: Some studies have discovered hormonal abnormalities among individuals diagnosed with ADHD. A study by West et al. (1996) examined thyroid function among adolescents with bipolar disorder plus ADHD and compared thyroid function to individuals with standalone bipolar disorder. It was discovered that concentrations of T4 (thyroxine) were significantly lower among those diagnosed with bipolar disorder plus ADHD – compared to standalone bipolar disorder.
Additional research conducted by Alvarez-Pedrerol et al. (2007) evaluated the relationship between thyroid hormone, cognitive function, and ADHD symptoms in pediatrics. Researchers discovered that pediatrics with ADHD symptoms exhibited abnormally low free T4 (thyroxine) concentrations compared to healthy, non-ADHD pediatrics. While findings of low T4 levels among pediatrics do not automatically confirm that all children with ADHD exhibit insufficient T4, it is plausible to hypothesize that for some individuals, low T4 may be a biomarker implicated in ADHD.
Administration of phentermine in conjunction with dietary modifications and exercise is documented to increase T4 levels. A study by Sonka et al. (1980) discovered that after 12 days of phentermine administration, T4 concentrations increased by 14%. Researchers speculated that the increases in T4 levels may have been a byproduct of the sympathomimetic mechanism of phentermine.
Though it’s likely a stretch to assume that increasing concentrations of T4 is the sole mechanism by which ADHD symptoms are attenuated, it is a plausible mechanism by which the drug may improve symptomatic severity – especially among individuals with ADHD exhibiting low T4. It is also necessary to consider that phentermine-induced modulation of other hormones (besides T4) such as cortisol and epinephrine contribute to improvements in symptomatic severity of ADHD.
A study by Isaksson et al. (2012) suggested that ADHD is associated with deficits in cortisol, likely stemming from dysregulation of the HPA (hypothalamic-pituitary-adrenal axis). Though it is unclear as to whether phentermine modulates the HPA axis or cortisol release, most would speculate that as a sympathomimetic, it is likely to stimulate production of extra cortisol and/or prolong cortisol degradation. Facilitating additional cortisol production may be necessary for combatting low physiological arousal associated with ADHD.
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Catecholaminergic modulation: While it is possible that a subset of those diagnosed with ADHD exhibit dysfunction within a single neurotransmitter system (e.g. low dopamine), many exhibit simultaneous dysfunction across multiple neurotransmitter systems. ADHD is understood to be caused by dysfunction of norepinephrine, dopamine, and epinephrine – collectively referred to as catecholamines. A study from by Hanna, Ornitz, and Hariharan (1996) documented differences in catecholamine excretion among pediatrics with ADHD compared to non-ADHD controls.
The catecholamine levels were determined using high-pressure liquid chromatography. Results indicated that those with ADHD excreted lower levels of the norepinephrine metabolite “DOPEG,” and exhibited a trend for decreased urinary epinephrine (EPI). Researchers concluded that the differences in central and/or peripheral catecholamine levels may account for symptoms of ADHD.
In previous research, an inverse relationship was discovered between epinephrine and inattentiveness and restlessness. Another study by Pliszka, McCracken, and Maas (1996) noted that dysfunction within catecholaminergic systems influence symptoms of ADHD. They suggested that central norepinephrine may fail to activate the cortical posterior attention system to external stimuli, resulting in the symptom of inattentiveness.
Additionally, dopaminergic input appears to influence mental processing of information within anterior attention networks and when dysfunctional, attention suffers. Peripheral epinephrine is also thought to affect various aspects of cognitive function. A report by Prince (2008) highlighted various genetic polymorphisms such as of DRD4 and DRD5 that are implicated in ADHD, and explained that these polymorphisms affect catecholaminergic processing in the prefrontal cortex and subcortical circuitry.
Specifically, these genetic polymorphisms affect function of catecholaminergic transporters, whereby dopamine and norepinephrine concentrations appear abnormally low and ADHD symptoms result. It is possible that administration of phentermine counteracts a lack of central and peripheral catecholaminergic signaling among those with ADHD. At high enough doses, phentermine is known to bolster norepinephrine, dopamine, and epinephrine (centrally and peripherally).
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Neural activation: A means by which phentermine could mitigate symptoms of ADHD is through modulation of neural activation. Individuals with ADHD are understood to exhibit underactivity and/or dysfunction in various regions of the brain compared to those without the condition. Examples of some regions in which individuals with ADHD exhibit dysfunction include the: prefrontal cortex, HPA (hypothalamic-adrenal-pituitary) axis, and nucleus accumbens.
Upon administration of phentermine, concentrations of norepinephrine and dopamine are released within the brain, and in response to these catecholaminergic alterations – neural activity is altered. Increasing central catecholamine concentrations tends to enhance activation of the prefrontal cortex, an area of the brain associated with executive functions such as attention and self-control. This is helpful for those with ADHD due to the fact that the condition is generally improved via pharmacological enhancement of prefrontal activity.
In addition to enhancing prefrontal activation to improve ADHD symptoms, phentermine may also increase HPA axis reactivity. A study by Ma et al. (2011) discovered that children diagnosed with ADHD exhibited significantly lower concentrations of cortisol compared to those without the condition. Researchers speculated that abnormally low cortisol may be related to under-reactivity of the HPA axis.
Low plasma cortisol is thought to induce symptoms of attentional deficits, hyperactivity, and impulsivity – all of which are signs of ADHD. The sympathomimetic effect exerted by phentermine may increase reactivity of the HPA axis, leading to normalization of cortisol levels and thus, a reversal of unwanted symptoms. Activity in a region of the brain known as the nucleus accumbens may also undergo modulation by phentermine to improve symptoms of ADHD.
A study by Volkow et al. (2011) discovered that motivational deficits among those with ADHD stem from dysfunction in the reward circuitry of the brain, particularly the nucleus accumbens. The nucleus accumbens plays a critical role in reward processing and it relies upon the neurotransmission of dopamine (for desire) and serotonin (for satiety and inhibition). In their study, researchers utilized PET (positron emission tomography) neuroimaging to analyze the brains of individuals with ADHD.
They discovered that motivation was significantly correlated with D2/D3 receptor and dopamine transporter densities in the nucleus accumbens. Those with lower densities of dopamine receptors and transporters were less motivated to attain rewards, possibly explaining the comorbid occurrence of reward deficiency syndrome among individuals with ADHD. Although not confirmed in humans, testing in animal models reveals that phentermine enhances activity within the nucleus accumbens for increased motivation.
A study by Hong et al. (2016) reported that phentermine specifically acts upon the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway within the nucleus accumbens of mice to generate conditioned rewarding effects. When phentermine (1 and 3 mg/kg, i.p.) was administered to mice, it significantly increased conditioned place preference and climbing behavior on tests. Phentermine also increased expression of the dopamine transporter (DAT) in the nucleus accumbens.
Despite the lack of human research assessing the effect of phentermine upon human motivation, it is reasonable to hypothesize that it would increase it via altering neural activity in the nucleus accumbens. Since the nucleus accumbens is affected by dopaminergic release, those taking higher doses of phentermine may be more likely to attain a substantial motivation boost than low-dose users. The cumulative modulation of activity within the prefrontal cortex, HPA axis, and nucleus accumbens may provide benefit to those with ADHD.
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Neuroelectrical activity: Psychostimulant drugs are known to modulate neuroelectrical activity (brain waves), and this modulation may be a mechanism by which phentermine improves symptoms of ADHD. It is likely that individuals with ADHD who respond well to phentermine treatment may exhibit specific neuroelectrical patters that differ from non-responders. Though it is unclear exactly how phentermine modulates brain wave activity, its modulation is likely similar to that of its parent drug (amphetamine) and related stimulatory agents (e.g. methylphenidate).
A study by Clarke et al. (2002) reported differences in QEEGs of “good” and “poor” responders to dextroamphetamine and methylphenidate among children with ADHD. Those who responded well to methylphenidate exhibited hypoarousal prior to treatment, and those who responded well to dextroamphetamine were classified as exhibiting “maturational lag.” Since phentermine is closely related to dextroamphetamine, it may be that individuals with “maturational lag” would respond best to its administration.
Research by Song et al. (2005) documented the effect of methylphenidate on QEEG activity among boys with ADHD during task performance. It was noted that, during task performance, methylphenidate significantly increased frontal and occipital alpha waves, as well as beta waves in nearly every other region. Moreover, theta waves and delta waves were decreased in other areas of the brain such as temporo-parietal and occipito-parietal regions.
Another study by Bresnahan et al. (2006) analyzed the effect of dextroamphetamine on QEEG activity among adults with ADHD. Researchers collected QEEG measures before and after dextroamphetamine administration. Among responders to dextroamphetamine, there was a significant decrease in slow wave activity (e.g. theta/delta bands) compared to a control group.
Some researchers believe that the effect of drugs upon brain wave activity can directly improve behavior among those with ADHD. Though there aren’t many studies assessing the effect of phentermine upon brain waves of ADHD patients, its effect may be similar to that of dextroamphetamine (the right-isomer of its parent drug). In other words, phentermine’s sympathomimetic effect may suppress slow wave activity throughout the brain to attenuate attentional deficits.
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Decreased sugar consumption: A subset of researchers believe that ADHD could be caused directly via dietary intake. It is known that sugar consumption has accelerated significantly over the past hundred years, and today accounts for approximately 15% to 20% of an average adult’s daily caloric intake. Among children in the United States and the United Kingdom, sugar consumption is thought to account for around 25% of average caloric intake.
As sugar consumption continues to rise, ADHD diagnoses have become more prevalent. While it is certainly unscientific to assume that, since increased sugar consumption is correlated with a greater number of ADHD diagnoses – eating sugar causes ADHD. However, it may be a mistake to automatically rule out the possibility that chronically high sugar consumption doesn’t have deleterious effects upon the neurobiology – some of which may cause ADHD in some individuals.
There is evidence that among pediatrics consuming diets comprised mostly of “junk food,” hyperactivity is more likely to occur by the age of 7 compared to pediatrics who eat less junk food. So how would sugar consumption potentially cause and/or exacerbate symptoms of ADHD? By modifying dopaminergic systems within the brain, particularly receptor sites and extracellular concentrations.
Some researchers believe that sugar consumption stimulates the acute release of dopamine in the brain. Though an occasional release of dopamine isn’t problematic, a chronic ongoing dopaminergic release can detrimentally affect the brain. Assuming an individual consumes copious amounts of sugar over an extended duration, dopamine receptor sites will downregulate as an adaptation.
The decrease in dopamine receptor sites is thought to be accompanied by a simultaneous decrease in extracellular dopamine levels. The combination of reduced receptor sites and extracellular dopamine concentrations desensitizes signaling axes, and ultimately, may cause symptoms of ADHD. Sugar consumption then becomes a vicious circle in that more sugar is consumed by those with ADHD to reverse sugar-induced dopaminergic deficiencies.
Based on this information, we can conclude that heightened sugar consumption may be a significant problem for those with ADHD. Abstaining from sugar consumption for an extended duration may help upregulate dopamine receptors and alleviate symptoms. Since phentermine is known to help individuals abstain from excessive food consumption by regulating appetite, it may be easier to cut back on sugar – or even avoid it altogether.
If the appetite reduction effect of phentermine allows individuals to abstain from sugar consumption, the result may be an upregulation of dopamine receptors and extracellular dopamine. Upregulated dopamine receptor densities may improve attentional abilities and reduce hyperactivity. Keep in mind that this may only be a useful mechanism among those that previously consumed large amounts of sugar and found phentermine helpful for decreasing sugar intake.
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Caloric restriction: Restricting caloric intake is understood to affect neurobiology and physiology by altering concentrations of neurotransmitters, peptides, and hormones. Phentermine releases catecholamines within the CNS that act upon the hypothalamus and make it easier for an individual to restrict his/her calories. Though weight loss that occurs from phentermine is slightly related to mobilization of fat stores, other weight loss occurs simply because the drug makes it easier for users to restrict calories.
Perhaps an indirect means by which ADHD symptoms are treated with phentermine is related to ongoing caloric restriction that occurs during treatment. A report by Gillette-Guyonnet and Vellas (2008) noted that caloric restriction affects brain functioning. Caloric restriction has been suggested to decrease inflammation, reduce oxidative stress, enhance plasticity of synapses, alter neurotrophic factors, and promote neurogenesis.
Though caloric restriction is not guaranteed to occur in all phentermine users, it is likely to occur in many. Since individuals with ADHD often exhibit abnormalities in oxidative stress and neurotrophic factors, ongoing caloric restriction resulting from phentermine treatment may reverse these abnormalities and improve ADHD symptoms. Drug-related caloric restriction may also enhance the catecholaminergic effect of phentermine to synergistically decrease symptoms of ADHD.
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Benefits of Phentermine for ADHD (Possibilities)
There are numerous hypothetical benefits that may be attained from using phentermine for the treatment of ADHD. Perhaps the most significant benefit associated with phentermine is that the drug is closely related to amphetamine and appears to stimulate the release of norepinephrine and dopamine. Stimulating the release of catecholaminergic neurotransmitters within the brain is understood to combat inattentiveness, hyperactivity, and impulsivity.
Other advantages associated with using phentermine for ADHD include: its low addiction potential [compared to other psychostimulants] and its ability to treat comorbid obesity. What’s more, there’s evidence to suggest that phentermine may motivation among those with ADHD and low motivation and/or deficient reward processing. Moreover, phentermine may serve as an alternative off-label medication for those who fail to derive benefit from first-line pharmacological therapies.
Addiction potential: Phentermine is classified as a Schedule IV controlled substance, suggesting it has a low potential for abuse and dependence relative to other psychostimulants approved to treat ADHD. Other psychostimulant drugs for ADHD such as mixed amphetamine salts and methylphenidate, are classified as Schedule II controlled substances, indicating that they are addictive drugs (with high potential for abuse and dependence). Since the potential for abuse and/or dependence should be concerns for medical professionals and psychostimulant users, less addictive psychostimulants such as phentermine may be advantageous – provided they still treat symptoms.
It is possible that phentermine may deliver sufficient therapeutic benefit to some individuals with ADHD, without fostering addiction. Interestingly, a report by An, Sohn, and Chung (2013) documented that the effect of phentermine at the dopamine transporter was similar to both methamphetamine and MDMA, yet surprisingly, it wasn’t associated with abuse or addiction. The lack of abuse and addiction potential is largely due to its lack of stimulation upon CNS neurons to release dopamine.
Nevertheless, phentermine may release central norepinephrine and alter peripheral catecholamine concentrations enough to combat some symptoms of ADHD. It may even release a very minuscule amount of central dopamine at high doses – making it slightly addictive and rightfully classified as a Schedule IV drug. That said, since its effect upon the CNS is less substantial than other psychostimulants, users are less likely to become addicted [by comparison]. (Source: http://www.ncbi.nlm.nih.gov/pubmed/23678348).
ADHD subtypes: Though all individuals diagnosed with ADHD tend to exhibit symptoms such as inattentiveness, impulsivity, and hyperactivity – these symptoms typically vary in severity on a case-by-case basis. Variation in the severity of ADHD symptoms has lead experts to discover that different types of ADHD exist. Some individuals may struggle with mostly inattentiveness, whereas others tend to have a more difficult time with hyperactivity and impulsivity.
Each of these variations in symptomatic severity is often associated with differences in neurobiological underpinnings. Clearly not everyone with ADHD will benefit from phentermine, however, it is possible that individuals with a particular ADHD subtype may respond better to phentermine than other interventions. Since phentermine primarily acts upon norepinephrine, those with ADHD symptoms resulting from dysfunctional noradrenergic signaling may be most likely to benefit from its administration.
Alternative intervention: Not everyone responds well to first-line pharmacological interventions for ADHD. Some individuals with ADHD may end up testing a barrage of medications and find that none are able to combat their particular symptoms, or that certain treatments are only partially effective. Anyone with debilitating refractory ADHD that responds inadequately to conventional pharmacology may resort to pursuing off-label alternatives.
Since phentermine is similar to dextroamphetamine, it is reasonable to speculate that it could be a useful off-label alternative treatment in some individuals. Assuming the central dopaminergic modulation elicited by mixed amphetamine salts and/or methylphenidate is overpowering and/or unnecessary, phentermine may be a viable intervention. Compared to other psychostimulants phentermine barely modulates central dopamine, however, if only slight dopaminergic modulation is necessary to treat ADHD – phentermine may be useful.
Appetite & dietary effects: Phentermine improves appetite control by modulating activity in the hypothalamus. Some individuals with ADHD are highly impulsive when it comes to food consumption, possibly to the extent of binge eating. This appetite reduction may be helpful for those who previously struggled with impulsive purchasing of food and/or consumption.
Additionally, appetite reduction often leads to weight loss – a side effect often preferred by patients compared to weight gain. Decreased appetite from phentermine may also help those with ADHD cut back on consumption of hyperpalatable foods (e.g. high-sugar/high-fat) that are known to deleteriously affect brain function. Assuming a person’s reduced appetite helps them significantly reduce sugar over a period of months, this could upregulate dopamine receptor densities, as well as extracellular dopamine levels – leading to improved attention.
Furthermore, a lower appetite may result in reduced caloric intake over an extended duration. This caloric restriction is known to benefit the brain by upregulating neurotrophic factors, brain cell growth, and neuroprotective mechanisms – all of which may reduce symptoms of ADHD. It is also reasonable to assume that a lower appetite could result in phentermine users making better dietary choices when they are hungry [by eating nutrient-dense foods].
Consumption of nutrient-dense foods may be easier for a person who feels as if they are in control of his/her hunger. Ramping up consumption of nutrient-dense foods may correct previous micronutrient deficiencies that caused or exacerbated ADHD-related symptoms. While appetite reduction may not be therapeutic for all phentermine users, it may significantly help those who previously were unable to control appetite.
Cognitive enhancement: Those with ADHD often exhibit cognitive impairment as measured by deficits in attention, memory, organization of thoughts, planning, and more. Some studies have even gone as far as to report that the IQ of pediatrics with ADHD is lower than that of their non-ADHD counterparts. There are numerous neurobiological underpinnings that may help explain cognitive impairment in ADHD including suboptimal catecholaminergic activity and low cortisol.
Phentermine measurably increases catecholamine activity and its sympathomimetic effect may bolster cortisol production. The combination of heightened catecholamine activity and sympathomimetic effects should offset ADHD-related cognitive impairment and enhance cognitive function. It is possible that when administered at optimal doses, users attain the effect of cognitive enhancement – such as that their cognitive function becomes better-than-usual.
Efficacy: Phentermine hasn’t ever been subject to formal evaluation for the treatment of ADHD, therefore, we cannot know whether it’s legitimately effective. Nor can we deduce its efficacy compared to other FDA approved treatments. That said, numerous anecdotal reports from phentermine users suggest that the drug is highly effective for ADHD.
Some of these anecdotal reports have noted that the drug works as well as conventional therapies. Other anecdotal accounts suggest that phentermine is even more effective (for their ADHD) than first-line treatments. While anecdotal reports certainly do not indicate that phentermine is effective for a majority of individuals with ADHD, they suggest that it may – at the very least – be effective in a subset of users.
Energy increase: Although some individuals with ADHD exhibit hyperactive behavior, they may also report having extremely low energy. While many would suspect that hyperactivity is associated with higher-than-average energy, this isn’t always the case. Furthermore, not all individuals with ADHD exhibit severe hyperactivity – some may complain of inattentiveness, spaciness, and excessive fatigue.
If you have ADHD and low energy levels, it is reasonable to suspect that the low energy may impair with your ability to accomplish occupational tasks stay socially engaged. Feeling lethargic may also make it difficult to stay physically active, and this lack of physical activity may perpetuate the underlying lethargy in a vicious circle. There are numerous possible causes of low energy among those with ADHD including: lack of catecholaminergic signaling, hormonal deficits, overactive parasympathetic nervous system, and more.
Regardless of the reason for low energy, phentermine is understood to exert a sympathomimetic effect, which should significantly increase energy. The heightened energy level may combat the ADHD-related fatigue and help you stay more productive throughout the day without feeling sleepy. Moreover, energy increases may help you stay physically active and reap the benefits of exercise on the brain.
Lower potency: The potency of phentermine’s action upon CNS neurons is thought to be lesser than that of mixed amphetamine salts and methylphenidate. While many individuals with severe forms of ADHD may benefit from highly potent CNS psychostimulants, others may derive more benefit from a less pronounced CNS effect. It appears as though phentermine is still capable of stimulating catecholamine release in the CNS – but its effect isn’t as strong as other ADHD medications.
Some may believe that a lower potency CNS psychostimulant such as phentermine may be favorable in that it is less likely to cause addiction. Additionally, it may be easy for individuals with milder forms of ADHD to become overstimulated from potent CNS activators, thereby impairing cognitive performance of certain tasks. Phentermine may provide a slight amount of stimulation to alleviate ADHD in milder cases, without causing overstimulation.
Mechanism of action: The mechanism of action associated with phentermine may be helpful for some individuals with ADHD, especially those that fail to derive benefit from conventional treatments. Although it is classified as a psychostimulant, phentermine’s mechanism of action differs from agents such as dextroamphetamine and methylphenidate in that it exerts a less significant central effect. Furthermore, it tends to primarily stimulate the release of norepinephrine, with a less significant effect upon dopamine.
Some researchers have gone as far as to compare phentermine’s mechanism of action to that of the atypical antidepressant Wellbutrin (Bupropion). This comparison is warranted for the fact that both phentermine and bupropion tend to increase concentrations of synaptic norepinephrine and dopamine (plus Bupropion is sometimes used for ADHD). Knowing that some practitioners may prescribe Bupropion for ADHD on an off-label basis suggests that phentermine could be equally as therapeutic – or perhaps even more useful due to its similarity to amphetamine.
Motivation increase: As is known, many individuals with ADHD struggle with a lack of motivation or “drive” to complete tasks. A lack of motivation may be perceived as laziness, but may have an underlying neurobiological link to under-expression of the dopamine transporter (DAT) within the nucleus accumbens. Lack of dopamine transporter expression is thought to impair reward processing ability and motivation to attain rewards.
Studies in animal models have shown that phentermine increases expression of the dopamine transporter in the nucleus accumbens. Upon increasing expression of the dopamine transporter, behavioral motivation tends to significantly increase. For this reason, it is possible that phentermine ameliorates motivational deficits associated with ADHD.
Weight loss: Individuals with ADHD often struggle with comorbid obesity and/or being overweight. If you’re clinically obese and/or overweight, phentermine may be prescribed by a medical professional as an adjunct weight loss intervention. The drug is FDA approved for the short-term management of obesity due to the fact that it suppresses appetite and mobilizes fat stores.
In the event that you’re taking phentermine for weight loss, you may find that the drug successfully manages your ADHD. Rather than worrying about treating either your obesity or ADHD, phentermine may be an ideal intervention for targeting both conditions simultaneously. While it generally has a more substantial effect in reducing body weight than symptoms of ADHD, many users report reductions in both.
Drawbacks of Phentermine for ADHD (Possibilities)
There are some clear drawbacks associated with utilizing phentermine for the treatment of ADHD. Perhaps the most notable drawback is that it has never undergone testing in humans for the treatment of ADHD. This means that the drug could be completely useless for reducing inattentiveness, hyperactivity, and/or impulsivity.
What’s more, in order for phentermine to reverse symptoms of ADHD, it may need to be administered at high dosages. The problem with administering high doses is that it increases likelihood of serious adverse events (e.g. myocardial infarction). Moreover, there appear to be an array of safe and effective medications for ADHD – making phentermine a relatively risky intervention.
Adverse reactions: A prominent drawback associated with taking phentermine for ADHD is the risk of adverse reactions. Since treating ADHD may require a relatively high dose of phentermine for increased central action, likelihood of serious adverse reactions may be increased. Examples of serious adverse reactions associated with phentermine usage include: hypertension, ischemic attack, and myocardial infarction.
Other adverse events reported to occur among a subset of phentermine users include: allergic reactions, drug-induced psychosis, hair loss, and tachycardia. As a result of these adverse events, a subset of those taking phentermine for ADHD may end up hospitalized. Although extremely uncommon, individuals taking phentermine at too high of a dose and/or administering it despite a contraindication may end up dying.
Contraindications: Many individuals with ADHD have been diagnosed with neuropsychiatric comorbidities such as anxiety disorder, bipolar disorder, or major depression. A notable problem for these individuals is that even if phentermine works well for the ADHD, it may exacerbate psychiatric comorbidities. For example, its sympathomimetic effect may worsen anxiety, trigger bipolar mania, or exacerbate suicidality among those with depression.
In addition to being contraindicated among those with various psychiatric diagnoses, phentermine is also contraindicated for usage with general medical conditions such as: cardiac disease, cerebrovascular disease, epilepsy, glaucoma, hyperthyroidism, prostatic hypertrophy, and ulcer – as its usage may worsen each condition. Furthermore, it is recommended to abstain from phentermine while pregnant and/or breast feeding due to the fact that it may cause birth defects.
Dependence: Phentermine is classified as a Schedule IV controlled substance, suggesting that its usage may lead to dependence. Although phentermine’s potential for dependence is lower than that of other psychostimulants such as mixed amphetamine salts and methylphenidate (each of which are Schedule II controlled substances), its potential for dependence shouldn’t be entirely discounted. The catecholaminergic boost provided by phentermine is known to enhance cognitive function, energy levels, and in some cases – mood.
These effects may lead some users to report improved productivity at work, better social relationships, weight loss, and a positive outlook on life. The problem is that individuals may become reliant upon phentermine to help them function in all facets of life. Without the daily release of norepinephrine and dopamine provided by phentermine, a person may struggle to function – becoming dependent on a drug.
Though some may not care if they become dependent on phentermine as long as it treats their ADHD, it may be problematic to continue using phentermine for an extended duration. Using phentermine for an extended duration as a result of dependence may provoke deleterious health problems that wouldn’t have otherwise occurred. Moreover, there are drugs on the market without any potential for dependence, that are approved to treat ADHD (e.g. atomoxetine); these options should be considered long before phentermine.
Depression: Some phentermine users may find that the drug helps reduce symptoms of ADHD, but cannot tolerate treatment due to the fact that it causes depression. Researchers have reported that phentermine may have: a pro-depressive effect in a subset of patients and/or a dose-dependent depressive effect. This means that if your particular neurochemistry isn’t a good fit for the noradrenergic and dopaminergic release provided by phentermine, you may end up seriously depressed.
The depression may even become so severe that you end up experiencing suicidal thoughts and/or feel as though you want to die. This could occur even if you never had a prior history of depression and may take awhile to recover from upon cessation of phentermine. The potential of worsening depression while taking phentermine may be reason enough to avoid it for the management of ADHD.
High dose: Another possible drawback associated with using phentermine for ADHD is related to the dosage. When taking phentermine for weight loss, it may be possible to take the drug at a relatively low dose and still reap significant therapeutic benefit. However, when taking phentermine for ADHD, high and/or supratherapeutic dosages may be required to manage attentional deficits.
At low doses, the central dopaminergic effects of phentermine are considered modest. In fact, when administered at a dose under 20 mg, dopaminergic modulation is insignificant. Since some individuals with ADHD may require greater release of dopamine for symptomatic relief, high or supratherapeutic dosages of phentermine (e.g. exceeding 37.5 mg) may be necessary.
The biggest problem with high-dose phentermine usage is that it increases likelihood of serious adverse effects. Another problematic outcome associated with high dose usage is that it may yield intoxicating effects (e.g. euphoria), thereby increasing odds of future abuse/misuse. Moreover, the higher the dose of phentermine, the greater the number of side effects users can expect to deal with (e.g. anxiety, palpitations, frequent urination, etc.) –making the drug difficult to tolerate.
Ineffective: The most significant drawback associated with phentermine is that it may turn out to be completely useless for the treatment of ADHD – or may even worsen underlying ADHD symptoms. Zero randomized controlled trials have been conducted to test the efficacy of phentermine for ADHD in humans (or even animal models). Due to lack of RCTs, there’s no proof of the concept that phentermine may be useful for reducing attentional deficits.
Due to its lack of central effect, some experts believe that testing phentermine for ADHD could be nothing more than a waste of time and money. As a result of its strong peripheral effect, dosages of phentermine required to manage symptoms of ADHD may turn out to be unsafe (as a result of adverse reactions). Moreover, even if phentermine turned out to be therapeutic for a subset of those with ADHD, it is unknown as to whether its safety and efficacy is on par with FDA-approved interventions.
Interactions: In addition to being contraindicated for use among individuals with various medical conditions, phentermine capable of interacting with pharmaceutical drugs, dietary supplements, and even alcohol. These interactions could be dangerous such as by provoking myocardial infarction, ischemic attacks, or death. What’s more, if phentermine is used with certain drugs and/or supplements, the efficacy of each may be diminished as a result of a pharmacokinetic interaction.
Medical literature suggests that phentermine cannot be taken along with antidepressants (SSRIs, SNRIs, TCAs, MAOIs) as it may trigger a condition known as “serotonin syndrome” in which abnormally high serotonin causes serious complications. Additionally, phentermine cannot be administered with any form of psychostimulant such as amphetamine or methylphenidate – nor can it be taken with drugs that increase catecholamine levels (e.g. NRIs, NDRIs, DRIs). It is also documented that phentermine cannot be used with drugs that increase blood pressure – as this may cause a hypertensive crisis.
Minimal effect upon CNS: Research suggests that phentermine’s effect upon neurons in the CNS is minimal. A study by Alexander et al. (2005) assessed the effect of phentermine, amphetamine, and ephedrine on baboons – by using PET scans. It was discovered that only amphetamine facilitated the release of dopamine from CNS neurons, whereas phentermine had no such effect.
While results from a baboon study do not automatically apply to humans, it does give reason to believe that effect of phentermine on CNS neurons is minimal. Although its minimal effect upon CNS may make phentermine favorable to amphetamine in terms of addiction potential, it may also make phentermine less efficacious for the treatment of ADHD. Individuals with ADHD are understood to exhibit deficits in noradrenergic and dopaminergic signaling, primarily within the CNS.
If the central effect of phentermine is only modest, those taking it for the treatment of ADHD may attain only partial or insignificant symptomatic relief. To ramp up its central effect, large doses of phentermine may be required. As was already discussed, the problem with large doses is that the peripheral sympathomimetic effect may lead to serious adverse events and/or medical complications (e.g. hypertensive crises). For this reason, using phentermine to treat ADHD may be highly inefficient.
Long-term effects: The long-term effects of phentermine may be more serious than some users suspect. Over time, a phentermine user’s neurochemistry adapts to treatment by downregulating norepinephrine and dopamine receptor sites, as well as by decreasing endogenous catecholamine production. In addition to substantially altering neurochemistry, long-term phentermine usage is understood to take a toll on the physical body, organ function, and other endogenous processes.
For this reason, most medical professionals limit its usage to a maximum of 3 months. Limiting phentermine usage to 3-month span may be problematic for those with ADHD who need ongoing, long-term treatment. Assuming an individual were to use phentermine consistently without any drug vacations (or breaks in the treatment), one long-term effect that may occur is pulmonary hypertension.
Pulmonary hypertension occurs when blood vessels within the lungs are narrowed, blocked, and/or destroyed – making it difficult for blood to flow through the lungs. Phentermine’s vasoconstrictive effect keeps blood vessels within the lungs narrowed for an extended duration, which in turn increases pressure on the right ventricle of the heart. Increased ventricular pressure may lead to irreversible heart weakening and/or failure.
Furthermore, long-term effects associated with using phentermine plus a stimulatory adjunct may be more serious. As an example, administration of fenfluramine with phentermine in the form of “fen-phen” is understood to cause heart valve damage, resulting in a leakage of blood. This damage may lead to serious complications and may require surgery. It is reasonable to assume that using other sympathomimetic agents with phentermine may cause similar long-term complications.
Side effects: Some individuals may struggle to deal with the side effects of phentermine, reporting that the drug is difficult to tolerate. Examples of common phentermine side effects include: anxiety, appetite reduction, dizziness, gastrointestinal distress, headache, insomnia, and weight loss. Although phentermine may improve your attentional deficits and hyperactivity, if the side effects are severe, you’ll probably end up discontinuing treatment.
Additionally, since the effective dose of phentermine for ADHD may be higher than its effective dose for weight loss, side effects may be even more severe. If you are a person that’s already in good shape and/or skinny, the weight loss experienced on phentermine may be unhealthy. Moreover, there are FDA approved interventions for ADHD that have fewer side effects and are easier to tolerate than phentermine.
Superior options: Since phentermine hasn’t been formally approved by the FDA for the treatment of ADHD, it should be regarded as inferior to already-approved interventions in terms of safety and efficacy. Drugs that have been granted FDA approval for ADHD have been subject to rigorous scientific evaluation – specifically among populations with attentional deficits. Phentermine hasn’t even undergone a single proof of concept trial in humans with ADHD.
For this reason, phentermine should be considered a last-line, off-label intervention without any evidence to support its usage for ADHD. FDA-approved drugs for ADHD can be safely administered over a long-term and maintain efficacy when used under medical supervision – the same cannot be said for phentermine. Until there’s at least one well-designed randomized controlled trial with some data to support usage of phentermine for ADHD, most experts should rightfully consider it a suboptimal treatment option.
Tolerance: Using phentermine on a daily basis over an extended duration will lead to the inevitable onset of tolerance. Once tolerance is established, it may feel as though the drug has completely stopped working for the treatment of ADHD. Tolerance occurs as a result of the brain adapting to daily administration of the phentermine, particularly by decreasing receptor sites and downregulating endogenous catecholamine production.
When tolerance is established, individuals may end up increasing their phentermine dosage to cope. An increase in dosage may help temporarily by alleviating symptoms of ADHD, but is not a sustainable long-term solution. This is due to the fact that the individual will eventually become tolerant to the highest possible dose of phentermine.
Upon tolerance development to the highest possible dose, an individual may continue taking that same dose to avoid withdrawal. However, if the individual increases his/her phentermine dose to a supratherapeutic level, serious adverse events may occur; high doses are associated with serious adverse reactions. Based on the inevitability of tolerance onset, and the fact that phentermine is a psychostimulant without formal approval for ADHD – it is not recommended.
Unknown long-term efficacy: The efficacy of phentermine in general isn’t well understood for ADHD. It is thought that phentermine is less effective than other psychostimulants for reducing attentional deficits due to the fact that it has a weaker central effect than peripheral effect. Even if phentermine was effective over a short-term for the treatment of ADHD, it is unknown as to whether this therapeutic effect could be sustained over a long-term.
Knowing that many individuals with ADHD require pharmacological treatment on a daily basis for years at a time, phentermine may be a poor treatment choice. Medical documentation cautions against using phentermine for a duration exceeding 3 months – primarily due to risk of adverse effects (e.g. pulmonary hypertension). Nonetheless, there’s not much reason to believe that phentermine’s effect can be sustained over an extended term without tolerance-related dosage increases.
Withdrawal symptoms: Many people use phentermine for awhile and think they can stop taking it and immediately revert back to their pre-phentermine selves. In most cases, individuals that discontinue phentermine are hit hard with phentermine withdrawal symptoms. These symptoms may include: anxiety, brain fog, dizziness, fatigue, lack of motivation, and tiredness.
What’s more, the withdrawal duration may interfere with your ability to function at work, at school, or in relationships. Withdrawal symptoms are a result of training your brain and nervous system to expect phentermine, and then suddenly stripping the drug away (with discontinuation). Your neurophysiology will still expect the phentermine, but since the drug isn’t delivered, a backlash of discontinuation effects ensue.
Even more problematic may be the fact that these discontinuation effects overlap with the resurgence of your underlying ADHD – resulting in ADHD symptoms that are more severe than pre-treatment. While experiencing these withdrawal symptoms, you may regret your initial decision to take phentermine. Moreover, some users may experience PAWS (post acute withdrawal syndrome) in which symptoms linger for months after cessation.
Phentermine for ADHD (Review of Evidence)
As of 2016, there is zero research that has examined the safety and efficacy of phentermine for the treatment of ADHD. Based on the absence of research, it is impossible to know whether phentermine may be an efficacious intervention for ADHD. Nevertheless, it may be useful to analyze some studies documenting the effects of phentermine on cognitive function, as well as understand how it compares to already-approved ADHD medications.
2009: Evolution of stimulants to treat ADHD: transdermal methylphenidate.
A report by Patrick et al. (2009) discussed the transdermally-administered psychostimulant dl-methylphenidate, marketed under the brand name “Daytrana.” In this report, researchers noted the fact that transdermal patches are a convenient modality by which a drug can be delivered. Additionally, they also discussed a study in which the pharmaceutical company Shire examined the abuse potential of Daytrana.
To determine its abuse potential, Shire administered the Daytrana patch, as well as oral phentermine – to adults with a history of stimulant abuse. It was discovered that both the Daytrana patch, as well as phentermine (oral) induced a mild state of euphoria among the adult [with a history of stimulant abuse]. Although this study doesn’t reveal much about the efficacy of phentermine for ADHD, it suggests that its abuse potential is similar to Daytrana, an agent approved for the treatment of ADHD.
It could be hypothesized that since each substance: exhibits analogous abuse potential, appears safe at clinical doses, and functions as a psychostimulant – therapeutic uses may be similar. In other words, like the Daytrana patch, phentermine may be effective for the treatment of ADHD. Moreover, some may even argue that phentermine’s classification as a Schedule IV substance indicates that its abuse potential is lower than that of methylphenidate, a Schedule II substance.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19051222
2008: Abuse liability assessment of atomoxetine in a drug-abusing population.
A study by Jasinski et al. (2008) examined the abuse potential of atomoxetine, sold under the brand name Strattera. Atomoxetine is a non-amphetamine drug utilized primarily to treat symptoms of ADHD in children and adolescents. Prior to this study by Jasinski et al., other research suggested that atomoxetine has a low potential for abuse among recreational drug users.
However, researchers sought to elucidate the abuse potential of atomoxetine among drug abusers with a preference for psychostimulants. A total of 40 individuals (drug abusers with a preference for stimulants) were recruited to participate in a placebo-controlled, double-blinded, randomized study. Participants were assigned to receive either: a placebo, desipramine (100 mg or 200 mg), methylphenidate (90 mg), phentermine (60 mg), or atomoxetine (45 mg, 90 mg, 180 mg).
It was noted that the placebo and desipramine served as negative controls, whereas the methylphenidate and phentermine served as positive controls. For a 24-hour period after each treatment, subjective and physiological effects were documented with a 49-item Addiction Research Center Inventory (ARCI) questionnaire. Results suggested that phentermine and methylphenidate were preferred significantly more than the atomoxetine, placebo, and desipramine.
Researchers concluded that atomoxetine has significantly less abuse potential than psychostimulants such as methylphenidate and phentermine. The ARCI questionnaire results suggested that phentermine and methylphenidate yielded greater: amphetamine-like stimulant effects, euphoria, and intellectual efficacy plus energy – compared to the other groups. Due to the overt parallels between methylphenidate and phentermine, and knowing that methylphenidate is an approved ADHD medication – it could be surmised that phentermine may treat ADHD.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18328639/
2003: A comparison of tyrosine against placebo, phentermine, caffeine, and D-amphetamine during sleep deprivation.
A study by Waters et al. (2003) compared the effects of various substances including: tyrosine (an amino acid precursor), caffeine, and dextroamphetamine – among individuals who were sleep deprived. The goal of this study was to determine whether any of these substances could reverse cognitive and/or motor deficits associated with sleep deprivation. A total of 76 adult males were recruited for the 4-day double-blind, randomized, placebo-controlled study.
Participants were assigned randomly to receive either: phentermine (37.5 mg), tyrosine (150 mg/kg), caffeine (300 mg/70 kg), dextroamphetamine (20 mg), or a placebo. Results indicated that dextroamphetamine decreased sleep drive, but was detrimental to recovery sleep. Those receiving dextroamphetamine exhibited heightened alertness on the very first day of recovery.
Interestingly, both phentermine (37.5 mg) and caffeine decreased sleep drive, and phentermine impaired recovery sleep by interfering with REM (rapid-eye-movement). Due to the fact that dextroamphetamine is simply the right-handed isomer of amphetamine, and phentermine is a derivative of amphetamine – it makes sense that they exhibited similar effects in this study. Both drugs decreased sleep drive following deprivation and interfered with recovery sleep efforts.
That said, since the drugs were not tested on individuals with ADHD, nor were they tested for treating ADHD symptoms – this study isn’t of help for determining phentermine’s value as an intervention for ADHD. The study does reveal that there are some similarities between dextroamphetamine and phentermine among those who are sleep deprived. However, based upon the observed stimulatory effect of phentermine, some may speculate that it would be useful among those with ADHD caused by insufficient arousal.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12887139
2000: Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.
Research by Baumann et al. (2000) published in Synapse analyzed the effect of phentermine and fenfluramine on rats. Specifically, researchers sought to determine how phentermine and fenfluramine would affect monoaminergic neurotransmission within a region of the brain known as the nucleus accumbens. High-performance liquid chromatography (HPLC) revealed that phentermine infusions elevated extracellular dopamine concentrations and fenfluramine infusions elevated extracellular serotonin concentrations.
Even when both agents were injected systemically, similar results were observed. It was reported that phentermine increased locomotor activity in the mice, whereas fenfluramine didn’t. Though the combination of fenfluramine plus phentermine (“Fen-Phen”) has been discontinued from pharmaceutical sale as a result of serious adverse events associated with the combination, authors of this report suggested that it may be useful for treating substance abuse disorders and obesity. Those with substance abuse disorders often exhibit simultaneous deficits in concentrations of dopamine and serotonin.
It is understood that individuals with ADHD exhibit abnormalities in D2/D3 receptor densities, as well as DATs (dopamine transporters) within the nucleus accumbens. Assuming phentermine manages to increase dopamine concentrations in the nucleus accumbens of humans similar as it does in rats, it may prove therapeutically useful in managing symptoms of ADHD. Symptomatic improvement may occur upon normalizing dopaminergic transmission throughout the nucleus accumbens – as well as via complementary mechanisms.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10767057
1984: Comparison of the acute physical and mental effects of ephedrine, fenfluramine, phentermine and prolintane.
A study by Kuitunen, Kärkkäinen, and Ylitalo (1984) compared the single-dose effects of various drugs including: phentermine (7.5 mg or 11.25 mg), ephedrine (30 mg or 40 mg), fenfluramine (15 mg or 20 mg), and prolitane (10 mg or 20 mg). Researchers organized a double-blinded, placebo-controlled study with healthy volunteers (in the form of medical students). Physiological and mental measures were collected before receiving a sympathomimetic, as well as at 1.5-hour and 2.5-hour intervals post-administration.
All volunteers fasted for at least 3 hours prior to sympathomimetic administration. Results indicated that ephedrine significantly increased measures of systolic blood pressure and heart rate, whereas the other sympathomimetic agents had no significant effect upon these measures. Mental measures were collected with a self-rating checklist, and based on the results, it appeared that none significantly altered mental activity.
In addition, aspects of cognitive function including memory, concentration and learning were measured with a sign recording test and digit span test. Though none of the sympathomimetic agents improved results on the digit span test, phentermine and prolintane significantly improved scores on the sign recording test, respectively. These improvements were significant at both the 1.5-hour and 2.5-hour measures post-administration.
Since single-doses of phentermine tend to enhance aspects of cognitive function in healthy volunteers, and single-doses of ADHD medications also bolster cognition when given to healthy adults – we could speculate that phentermine may be useful in treating ADHD. Furthermore, it is widely documented that individuals diagnosed with ADHD tend to exhibit cognitive deficits. Perhaps phentermine would be useful in reversing various ADHD-related cognitive deficits and attenuate symptomatic severity.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/6471970
Why research of phentermine for ADHD may be warranted…
Phentermine has been on the market since 1959 and is clinically effective for promoting weight loss among those with obesity, primarily by suppressing appetite. That said, many anecdotes from phentermine users report that the drug attenuates ADHD symptoms, allowing them to finally focus without distraction. What’s more, a subset of anecdotal reports go as far as to claim that phentermine is more effective for their ADHD than conventional pharmacological treatments such as mixed amphetamine salts, methylphenidate, and atomoxetine.
Often it is anecdotal reports that lead researchers to investigate repurposing a particular drug for an unapproved condition. Although anecdotal reports cannot verify the clinical efficacy of phentermine for ADHD, they are helpful in forming the hypothesis that phentermine could be useful for the treatment of ADHD. This hypothesis now warrants testing in human participants in a small-scale, randomized controlled trial (RCT) to evaluate proof of concept.
For some researchers, anecdotal reports of phentermine’s efficacy for the treatment of ADHD may be insufficient to warrant even a small proof of concept trial. Another reason phentermine warrants investigation for ADHD is that it is a derivative of amphetamine, an already-approved intervention for ADHD. Amphetamine is approved for ADHD and sold as mixed amphetamine salts (under the brand name Adderall) consisting of 75% dextroamphetamine plus 25% levoamphetamine.
Like phentermine, many patients have reported success using Adderall for weight loss, likely due to the fact that it suppresses appetite and mobilizes energy stores. This is direct evidence to suggest that the mechanism of the already-approved amphetamine for ADHD is similar to that of phentermine. While the lack of central dopaminergic effect associated with phentermine (especially at low doses) may lead some to speculate that it would be ineffective for ADHD, it does facilitate central release of norepinephrine.
The neurotransmission of norepinephrine is often dysfunctional among those with ADHD, and some FDA approved treatments exert no direct effects upon central dopamine. As long as a drug exerts a central noradrenergic effect, it is reasonable to believe that it could improve symptoms of ADHD. Additionally, at higher doses phentermine appears to increase central dopamine concentrations – thereby bolstering its therapeutic effect.
Researchers should reflect upon the fact that the noradrenergic effect exerted by phentermine may make it less addictive than traditional psychostimulants, yet still capable of treating ADHD. It appears to have a greater addition potential than atomoxetine (a non-stimulant drug), but less addiction potential than mixed amphetamine salts. This may be related to the fact that it acts centrally upon norepinephrine as well as dopamine, but the dopaminergic action is modest compared to that of amphetamine.
Another point to be made is that individuals with ADHD tend to exhibit functional abnormalities of the peripheral nervous system. Abnormal functioning of the peripheral nervous system such as inadequate sympathetic tone and low arousal – may contribute more to ADHD than some suspect. Phentermine alters peripheral activity via catecholaminergic release to increase sympathetic tone, possibly a mechanism by which ADHD symptoms decrease.
It should also be mentioned that the peripheral nervous system and central nervous system communicate in a bidirectional manner, meaning significant drug-induced changes to one will affect the other. Even if phentermine only exerts a modest direct effect upon the central nervous system, its potent effect upon the peripheral nervous system will signal back to the central nervous system to alter neural activity. Clearly the drug is altering a user’s neurobiology and neural activity – possibly in such ways as to decrease ADHD.
The knowledge that phentermine is a psychostimulant closely related to amphetamine [with a lower addiction potential] should justify its investigation in humans for the treatment of ADHD. Furthermore, it appears to increase catecholamine concentrations that are often deficient among those with attentional deficits, and anecdotal reports testify for its efficacy in treating ADHD. While there is some risk of adverse long-term effects associated with phentermine use, it is unclear as to whether these are more substantial than other psychostimulants.
Since phentermine is FDA approved for the short-term management of obesity, perhaps a study testing its efficacy among those with obesity and comorbid ADHD is warranted. Thereafter, researchers could determine whether phentermine alleviates ADHD symptoms in non-obese individuals. Overall, the fact that there hasn’t been a single published human trial testing the safety and efficacy of phentermine for ADHD remains surprising.
Why isn’t phentermine currently used to treat ADHD?
It’s relatively simple to understand why phentermine isn’t currently used to treat ADHD. Phentermine is NOT approved by the FDA for the treatment of ADHD and has zero evidence from randomized controlled trials to support its usage for this indication. Without FDA approval nor proof of concept trials to support its efficacy in treating ADHD, it would be unacceptable for a medical professional to even consider prescribing phentermine as a first-line intervention for the treatment of attention-deficit/hyperactivity disorder.
Another glaringly obvious reason phentermine isn’t used for ADHD is that safe and proven treatments already exist. Why prescribe a drug like phentermine off-label without any evidence supporting its usage when safe and effective interventions exist? Anyone with legitimate ADHD should want to receive a pharmacological treatment that’s been rigorously tested – not one that they think might work based on anecdotal reports and/or hypotheses.
We also aren’t sure as to whether phentermine usage for ADHD would result in deleterious long-term effects. Its significant peripheral vasoconstrictive properties increase risk of pulmonary hypertension as well as cardiac events. For this reason, it may be a wise idea to utilize agents with more of a central effect as to avoid ongoing vasoconstriction and the ensuing cardiac burden.
Medical professionals understand that current evidence indicates that phentermine’s effect may be isolated to the hypothalamus, which is helpful in regulating appetite – but not treating ADHD. Medications successful in treating ADHD tend to significantly alter activity within an area of the brain known as the striatal-prefrontal cortex. At this time, it remains unclear as to whether phentermine affects striatal-prefrontal pathways.
Additionally, the combination of minimal central effects with heightened peripheral effects may mean that phentermine has all of the drawbacks associated with psychostimulants, but poorer therapeutic efficacy. Even among patients with ADHD caused primarily by noradrenergic dysfunction, phentermine is not preferred over agents such as Strattera (atomoxetine) that centrally inhibit the reuptake of norepinephrine. Unless data emerges to support the usage of phentermine for ADHD, there’s no reason it should be prescribed off-label for this condition.
What dosage of phentermine is best for ADHD?
Due to the fact that phentermine hasn’t been formally evaluated for the treatment of ADHD, it is unknown as to what dosage would be optimal for this indication. Based on the fact that lower doses of phentermine (e.g. 20 mg) exert a modest central effect and don’t really alter dopaminergic transmission, it may be that a high dose is necessary for ADHD. In other words, if phentermine were to be used for ADHD, it is likely that a high dose such as 37.5 mg (or even greater) would be necessary to combat symptoms.
Compared to lower doses, administering phentermine at high doses should exert a more significant central effect, as well as noticeably modulate dopamine. In theory, this should help alleviate symptoms of ADHD caused by deficits in catecholaminergic signaling. The only problem with using a high dose (e.g. 37.5+) is that the peripheral effect will be potent enough to cause serious adverse effects.
Using a high dose of phentermine over an extended duration may significantly increase risk of a cardiac events, ischemic attack, and mortality. There are no formal dosing guidelines of phentermine for ADHD, and if the drug were to be utilized for ADHD, dosage optimization via guidance of a psychopharmacologist should be required. That said, extremely low doses are unlikely to have a significant effect upon ADHD symptoms unless peripheral dysfunction is heavily implicated as a causal underpinning.
Have you tried Phentermine for ADHD?
If you’ve been diagnosed with ADHD and have used phentermine, share your experience in the comments section below. How would you rate phentermine’s efficacy in terms of reducing your particular ADHD symptoms? Assuming you’ve tried other FDA approved medications for ADHD, how does phentermine compare?
In your experience, would you say phentermine is more or less effective and/or tolerable than mixed amphetamine salts, methylphenidate, and atomoxetine? Would you consider phentermine to be very effective, marginally effective, or completely useless as an intervention for ADHD? To help others get a better understanding of your situation, provide some additional details such as: the phentermine dosage you used (e.g. 37.5 mg), how long it took after starting treatment for you to notice any therapeutic effect, and whether any adjunct pharmaceuticals and/or supplements were used along with it.
Also share your specific type of ADHD such as: solely inattentive, hyperactive-impulsive, inattentive-impulsive, etc. Did you find the phentermine to be more effective for certain ADHD symptoms than others? In other words, did phentermine work better for inattentiveness compared to hyperactivity and impulsivity, vice-versa, or was it equally efficacious in reducing all symptoms?
What is the longest duration that you’ve used phentermine to manage your ADHD? For those that used phentermine for an extended duration (e.g. 3 months), did it maintain its effectiveness the entire duration OR did its efficacy fade over time? Also feel free to mention how you attained phentermine in the first place (e.g. from a medical professional, illicitly, etc.).
If you were prescribed phentermine, note the condition for which it was prescribed. Realize that while phentermine may be helpful in combatting certain symptoms of ADHD, particularly those related to noradrenergic abnormalities – it cannot be considered universally effective. At this time, using phentermine as an off-label drug solely for the treatment of ADHD isn’t a good idea, however, among those looking to treat obesity plus ADHD – it may be a viable short-term intervention.