Phentermine is a sympathomimetic amine [derived from amphetamine] initially approved by the FDA in 1959 for the treatment of obesity. Its usage in the treatment of obesity was considered ideal due to the fact that phentermine suppressed appetite through central modulation of norepinephrine, and peripherally mobilized fat stores through catecholaminergic upregulation. That said, in the late 1990s phentermine was discontinued from pharmaceutical sale primarily based on findings that “Fen-Phen” (a combination drug of Fenfluramine plus Phentermine) damaged heart valves, increasing risk of serious cardiac events.
When administered as a standalone agent without the presence of another stimulant, phentermine is considered reasonably safe. For this reason, it was reintroduced to the pharmaceutical market under the brand names Adipex-P, Ionamin, as well as generic phentermine. The drug remains commonly used for the short-term treatment of obesity, but some speculate that it could serve as a useful intervention for neuropsychiatric conditions, including major depressive disorder (MDD).
Administration of phentermine is hypothesized to combat low arousal and fatigue commonly implicated in depression. Phentermine may alleviate depressive symptoms by increasing concentrations of norepinephrine and dopamine similar to that of Bupropion (Wellbutrin), an already approved antidepressant. Since around 1 in 3 patients with major depression fail to derive sufficient symptomatic relief from conventional pharmacology, phentermine may warrant investigation as an antidepressant.
How Phentermine May Treat Depression (Mechanisms)
There are numerous ways by which phentermine may prove helpful for individuals with depression. Phentermine functions as a TAAR1 agonist, meaning that it binds to, and stimulates TAAR1 sites. The stimulation of TAAR1 sites by phentermine generates an intrasynaptic release of monoamines including: norepinephrine, dopamine, and serotonin.
Since monoaminergic activity is hypothesized as dysfunctional among a subset of those with depression, phentermine may ameliorate some of this dysfunction and enhance mood. Another possible means by which phentermine may improve mood is through its action upon VMAT2, resulting in bolstered monoaminergic release and signaling. It is also reasonable to consider that individuals with depression may benefit from phentermine’s strong peripheral sympathomimetic effect.
The potent effect of phentermine on the peripheral nervous system is understood to: enhance energy (for exercise), burn body fat (for weight loss), and augment centrally-mediated appetite suppression. A person with depression may find that increased energy leads to more exercise, weight loss improves self-esteem, and appetite suppression leads to caloric restriction [and modulation of neurotrophic factors] – each of which may have a positive effect upon mood. Moreover, it is possible that a unique combination of phentermine’s central and peripheral effects act synergistically to attenuate depression.
Arousal increase: Administration of phentermine may be beneficial to those with depression due to the fact that it increases neurophysiological arousal. In a subset of individuals with major depression, abnormally low neurophysiological arousal may be a contributing or causative factor. Low neurophysiological arousal could be a result of numerous factors including: toxic exposures, illicit drug discontinuation, genetics/epigenetics, nutritional deficiencies, and more.
Since the underlying cause(s) of abnormally low arousal cannot always be pinpointed and corrected, it is often helpful for depressed patients to increase neurophysiological arousal with pharmacology such as phentermine. Pharmacological increases in neurophysiological arousal often attenuate unwanted depressive symptoms such as psychomotor slowing and lethargy. Phentermine upregulates peripheral arousal by upregulating catecholamine concentrations such as those of: norepinephrine, epinephrine, and dopamine.
The peripheral arousal should give individuals more energy to get out of bed and remain physically active. Though the central effect of phentermine may be less significant than its peripheral effect, it is known to also increase catecholaminergic signaling in the CNS. This could reduce symptoms such as brain fog and cognitive dysfunction, making it easier for someone with depression to think clearly.
Brain wave modulation: Analysis of QEEG patterns among healthy individuals and those with certain types of depression reveals differences in neuroelectrical activity. Those with certain types of depression exhibit excessive amounts of slow-wave activity (e.g. theta waves) and insufficient amounts of fast-wave activity (e.g. beta waves) during waking consciousness. It is the phentermine-induced modulation of neuroelectrical activity that may facilitate a therapeutic effect among those with depression.
While exact data regarding how phentermine affects neuroelectrical activity isn’t available, it is thought to alter brain waves similar to that of its parent drug (amphetamine) and other psychostimulants such as methylphenidate. A study by Bresnahan et al. (2006) conducted on adults with ADHD discovered that dextroamphetamine (the dextrorotary isomer of phentermine’s parent drug, amphetamine) suppressed slow wave activity, resulting in upregulation of fast waves. Though it is unclear as to whether similar effects would be observed in a population of individuals with depression, it is known that ADHD is a common comorbidity among those with depressive disorders.
Furthermore, the neuroelectrical patterns of those with depression often exhibit overlapping commonalities to individuals diagnosed with ADHD. Perhaps a phentermine-induced upregulation in beta waves and coinciding downregulation of theta waves may be highly therapeutic for a subset of depressive patients.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/16343642
Catecholamine release: Although at high doses phentermine is capable of modulating serotonergic signaling, a majority of its therapeutic antidepressant effect results from its ability to facilitate catecholamine release – peripherally and centrally. In a subset of individuals with depression, suboptimal catecholaminergic signaling may be the chief neurobiological culprit. Specifically, those with depression could exhibit low norepinephrine, low dopamine, and possibly even abnormal epinephrine levels and/or signaling.
Among individuals, treatment with a serotonergic modulator may prove ineffective, whereas treatment with phentermine may yield therapeutic benefit due its enhancement of catecholaminergic signaling. Deficient signaling from norepinephrine and dopamine are associated with: attentional deficits, cognitive impairment, fatigue, poor motivation, and weight gain – each of which are common symptoms of depression. Administration of phentermine may reverse catecholaminergic dysfunction and improve mood.
In addition, phentermine may improve a person’s outlook and/or quality of life by enhancing attention, cognitive function, energy levels, and motivation. Users of phentermine may feel more alert and as though all previous mental fogginess associated with major depression has lifted. Though not everyone with depression derives benefit from upregulation of catecholamines, it is likely that some patients will.
Dietary intake: Another interesting mechanism by which phentermine may improve mood is through its indirect effect on dietary intake. Phentermine is understood to function as an effective appetite suppressant, making it useful for weight reduction among those with obesity. It is theorized to suppress appetite by stimulating the release of norepinephrine from neurons within the hypothalamus.
As a result, those taking phentermine find it easy to resist the temptation to consume excessive amounts of food. It is possible that ongoing treatment with phentermine leads to: caloric restriction, decreased intake of anti-nutrients (e.g. sugar), and increased intake of nutrient-dense foods. Ongoing caloric restriction is known to alter the brain by increasing concentrations of antioxidants, neurotrophic factors (e.g. BDNF), and enhancing neurogenesis (growth of new brain cells) – possibly enhancing mood.
Decreased intake of anti-nutrients may reverse dietary-induced neurobiological underpinnings of depression. Finally, it may be easier to increase consumption of nutrient-dense foods while taking phentermine as a result of feeling consciously in control over hunger. Should a person increase consumption of nutrient-dense foods during treatment, this may mitigate preexisting micronutrient deficiencies that were causing depression. (For more information read: “Best Diet for Depression“).
Hormonal modulation: Another possible mechanism by which phentermine may be useful in the treatment of depression is via hormonal modulation. Individuals with depression often exhibit abnormalities in concentrations of hormones including: thyroid, epinephrine, and cortisol – to name a few. Subtypes of depression characterized by abnormally low levels of neurophysiological arousal may benefit from increasing the aforestated stimulatory hormones with phentermine.
A study by Hage and Azar (2012) specifically investigated thyroid levels among those with depression and discovered commonalities including: elevated T4, low T3, elevated reverse T3, and poor reactivity to thyroid stimulating hormone (TSH). Evidence suggests that phentermine may elevate T4 – which could potentially worsen depression in a subset of individuals. That said, increasing T4 may improve mood among those with low T4 and/or hypothyroidism causing their depression.
Deficiencies in peripheral levels of epinephrine and norepinephrine could also contribute to depression, provoking symptoms such as chronic fatigue and drowsiness. Phentermine is understood to increase concentrations of peripheral epinephrine (adrenaline) and norepinephrine (noradrenaline), likely increasing energy level and combatting depression-induced lethargy. It is also reasonable to hypothesize that phentermine may alter cortisol levels to improve mood.
Since phentermine is a sympathomimetic agent, it should be suspected that it would increase secretion of cortisol and/or prolong its degradation. Although 50% of individuals with major depression secrete excessive amounts of cortisol (making phentermine a poor choice of treatment), others may secrete insufficient amounts of cortisol. Research by Maripuu et al. (2014) documents that individuals with low cortisol secretion experience depression and poorer mood than those with optimized levels of cortisol.
Assuming someone with low cortisol secretion administers phentermine for depression, it is possible that increasing his/her cortisol levels within a healthier range may improve mood. Though phentermine may not correct the underlying root cause of the low cortisol (e.g. HPA axis dysfunction), the increase in cortisol may ameliorate depressive symptoms resulting from suboptimal cortisol production such as cognitive deficits and tiredness. If phentermine is capable of modulating cortisol, this modulation could indirectly impact CNS function.
The relationship between the peripheral nervous system and central nervous system is bidirectional, meaning that altering activity in the PNS should affect activity within the CNS; and vice-versa. Upon modulation of peripheral hormones, signal transmission from the peripheral nervous system to the central nervous system is altered – resulting in neurobiological changes. Although phentermine exerts a strong peripheral effect, it would be myopic to assume that its peripheral effect wouldn’t indirectly alter brain activity to improve mood.
- Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246784/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24932586
Neural activation: Though detailed neuroimaging studies assessing the effects of phentermine upon brain function haven’t been conducted, it is thought that phentermine affects activity in multiple regions of the brain. Alterations in neural activation such as by increasing activity in certain regions and/or decreasing activity in other regions – may yield therapeutic effects for those with depression. Some areas of the brain that may be affected by phentermine administration include the: prefrontal cortex, HPA axis, and nucleus accumbens.
A subset of individuals with depression exhibit hypofrontality or deficient function of the frontal lobes and prefrontal cortex. Hypofrontality results in impaired executive abilities such as: abstract thinking, attention, complex analysis, emotional regulation, and organization of thoughts. With a suboptimally functioning prefrontal cortex, it’s difficult to think logically about feasible ways to treat and/or cope with depression.
Administration of phentermine may enhance noradrenergic and dopaminergic signaling within the CNS, which could ameliorate hypofrontality. Reversal of hypofrontality should improve cognitive function, increase ability to cope with a depressed emotional state, as well as dilute the severity of depression. Another region of the brain that’s affected by phentermine is the hypothalamus.
The effect of phentermine upon the hypothalamus is associated with improved appetite regulation, but may also improve mood. A myriad of studies have discovered HPA (hypothalamic-pituitary-adrenal) axis dysfunction to be implicated in major depression. Since phentermine modulates hypothalamus activity, it is possible that it ameliorates HPA dysfunction and promotes normalization of mood.
Arguably the most significant means by which phentermine-induced neural modulation improves depressive symptoms is by targeting the nucleus accumbens. The nucleus accumbens is a region of the brain responsible for mediation of motivation and reward. Dysfunction within this particular region may be dictate the severity of depressive symptoms such as motivation, cognitive impairment, and lethargy.
A study by Hong et al. (2016) reported that phentermine administration activates the PI3K/Akt pathway within the nucleus accumbens of mice, motivating them to attain rewards. Though these findings haven’t been replicated in humans, it is reasonable to hypothesize that similar modulation of activity within the nucleus accumbens occurs. Research by Bewernick et al. (2012) discovered that deep brain stimulation targeting the nucleus accumbens of individuals with depression is a highly effective treatment with a sustained antidepressant effect.
Assuming phentermine is able to activate pathways within the nucleus accumbens of humans, mood may be enhanced. It should also be considered that simultaneous modulation of activity within the prefrontal cortex, hypothalamus and/or HPA axis, as well as the nucleus accumbens generates an antidepressant response.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26887589
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22473055
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15014598
Physical exercise: A significant problem among those with major depression is that they find it difficult to engage in physical activity as a result of fatigue, motivational deficits, and sleepiness. Remaining sedentary due to low energy associated with depression may exacerbate depression and create a vicious circle of reinforcement in which: the depression promotes inactivity AND inactivity promotes depression. Breaking the vicious circle by forcing oneself to exercise frequently may be what’s necessary to attenuate depression.
Phentermine may help an individual with depression by increasing energy levels and motivation, making it easier to engage in physical activity. Assuming phentermine enables a person with depression to exercise regularly, this will: alter brain activity, neurotransmitters, hormones, and even neurotrophic factors. For example, it is known that aerobic exercise increases BNDF levels and promotes hippocampal neurogenesis – each of which are associated with mood enhancement.
Other psychological benefits of exercise include: boosted confidence and self-esteem. A person’s appearance and physical health may also improve as a result of weight loss from physical activity – which could also decrease depression. Moreover, the instillation and adherence to an exercise habit may be associated with positive momentum – ultimately reducing depression.
Weight loss: There’s often an association between depression and obesity, as well as being overweight. A systematic review and meta-analysis by Luppino et al. (2010) reported a reciprocal link between depression and obesity. It may be subject to individual variation in regards to whether: depression causes obesity, obesity causes depression, or both conditions emerge simultaneously.
Nevertheless, depression makes it difficult to resist unhealthy foods and being overweight makes it difficult to avoid feeling depressed. One reason those with obesity may struggle with depression is a result of poor self-image, as well as inability to find a suitable mate. Another is that obesity alters gut bacteria, hormone production, and neurotransmitter levels in the brain – all of which likely reinforce depression.
Phentermine is understood to be an efficacious agent for weight loss. It helps individuals lose weight by decreasing appetite and burning excess body fat. Assuming someone ends up losing a significant amount of weight during treatment, it is likely that this weight loss may reverse depressive symptoms.
Weight loss may shift gut bacteria, alter hormone production (e.g. testosterone), and neurotransmitter production to boost mood. Losing weight may also help an individual attract a mate and/or social relationships as a result of improved appearance – resulting in an antidepressant effect. Moreover, weight loss usually improves self-esteem and confidence, each of which may be useful in attenuation of depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20194822
Benefits of Phentermine for Depression (Possibilities)
Phentermine hasn’t been investigated for the treatment of depression, but there may be some benefits to be attained from its usage – even if the usage is only short-term. The most substantial benefit associated with using phentermine for depression is that it functions atypically compared to conventional antidepressants and is faster-acting. Furthermore, it may be more effective than serotonergic agents for enhancing motivation and cognitive function. Other benefits of using phentermine include: its side effect profile (compared to SSRIs) and its ability to promote weight loss.
- Atypical intervention: When treating major depression, not everyone responds to medications that target the serotonin system. Individuals diagnosed with atypical depression in which serotonergic dysfunction isn’t implicated may benefit more from unconventional pharmacology. Phentermine may serve as a unique intervention in that it chiefly releases norepinephrine, modestly releases dopamine, and negligibly releases serotonin. This unique central mechanism, as well as a strong peripheral catecholaminergic effect, may alleviate depressive symptoms among non-responders to conventional psychopharmacology.
- Cognitive enhancement: A debilitating symptom often associated with major depression is cognitive impairment. Those experiencing cognitive impairment as a result of depression often have a difficult time with cognitively-demanding occupational and/or academic tasks. Difficulty with cognitively-demanding tasks may lead to increased stress and exacerbate underlying low mood as a result of ineffectiveness. Phentermine may ameliorate cognitive dysfunction by upregulating catecholamine signaling, possibly also reversing hypofrontality (as is seen in some cases of depression). If phentermine enhances cognitive function to reverse deficits, this may increase confidence, competence, and ultimately mood.
- Energy increase: Those that take phentermine at clinically relevant doses for weight loss generally report a significant increase in energy. This energy increase results from activation of the sympathetic nervous system and release of catecholamines. Individuals with depression that are struggling with symptoms such as: drowsiness, fatigue or lethargy, and/or tiredness – may find that phentermine gives them enough energy to be productive and accomplish tasks at home, school, and work.
- Efficacy: The efficacy of phentermine as an intervention for depression is unknown. However, there are anecdotal reports circulating from a subset of users suggesting that phentermine transformed their personality and enhanced their mood. These anecdotal reports indicate that phentermine may be an effective antidepressant among a subset of those who use it.
- Fast-acting: In many cases, it takes between 4 and 8 weeks for the therapeutic effects of an antidepressant to emerge. A major problem with antidepressants taking so long to work is that a person with depression may be unable to wait – the person may need immediate benefit in order to function and avert his/her suicidal ideation. An advantage of using a drug like phentermine that triggers release of catecholamines (norepinephrine and dopamine) is it’s fast acting mood enhancement. Some users may experience noticeable mood improvement on their first day of treatment, providing nearly instantaneous symptomatic relief.
- Habit instillation: During treatment with phentermine many patients introduce new lifestyle habits in effort to lose weight. Phentermine is known to improve physical stamina and self-control associated with food intake. This may lead patients to engage in regular exercise, reduce caloric intake, and modify their diets (e.g. eliminate unhealthy foods and increase nutrient-dense foods). Instilling the habits of exercise, caloric restriction, and consumption of nutrient-dense diets – may improve overall health while simultaneously improving mood.
- Motivation increase: Anecdotal reports from humans suggest that phentermine is capable of increasing motivation. Studies of phentermine administration in mice discovered that the drug activates a specific pathway in the nucleus accumbens of the brain, resulting in increased motivation to attain reward. Many serotonergic antidepressants have no significant effect upon motivation and/or may uplift mood while simultaneously decreasing motivation. The motivation increase derived from phentermine may help with productivity and reverse underlying reward deficiencies.
- Side effects: The side effect profile of phentermine may be preferred to the side effect profile of conventional antidepressants. Unlike standard antidepressants, phentermine isn’t associated with weight gain or sexual dysfunction. A reason numerous people complain about SSRIs and/or end up discontinuing treatment has to do with the fact that they gain a lot of weight or are no longer interested in sex. Those taking phentermine are more likely to gain weight and experience heightened libido – making it preferable for some patients.
- Weight loss: It is well known that phentermine is FDA approved for the short-term treatment of obesity by promoting weight loss. Research suggests that many individuals with depression also suffer from obesity and/or are overweight. Since phentermine helps with weight loss, and may also improve mood – it could be used to treat both conditions simultaneously. Additionally, weight loss may be a direct mechanism by which the drug improves mood. Someone who is overweight may feel worse about their body image and/or stressed about other obesity-related health conditions (e.g. diabetes). Losing weight should improve self-esteem, decrease stress associated with obesity-related health conditions, and may also help a person attract a mate – all of which may have positive implications for those with depression.
Drawbacks of Phentermine for Depression (Possibilities)
Despite the possible benefits to be attained from utilizing phentermine as an antidepressant, significant potential drawbacks should be discussed. Arguably the biggest drawback associated with phentermine usage for depression is that it may exacerbate the severity of depressive symptoms in certain users and suicidal ideation. Additionally, even if phentermine proved effective for the short-term treatment of depression, its antidepressant effect is unlikely sustainable over the long-term. Moreover, long-term administration of phentermine may lead to serious medical conditions such as heart valve damage, pulmonary hypertension, or stroke.
- Abuse & addiction: Despite having a lower potential for abuse than amphetamine isomers, phentermine is classified as a Schedule IV substance – indicating that it still could be abused. Studies have shown that high doses of phentermine cause feelings of euphoria, likely as a result of its simultaneous release of central norepinephrine and dopamine. Assuming someone begins abusing phentermine, it is possible that this abuse may lead to development of a phentermine addiction. Both abuse and addiction are problematic in that they increase risk of serious adverse effects – especially following tolerance onset.
- Contraindications: Phentermine is contraindicated for usage among those with: a history of drug abuse or dependence, diabetes, neuropsychiatric disorders, hyperthyroidism, glaucoma, kidney disease, cardiovascular disease, and hypertension. Taking phentermine with one of the aforestated medical conditions may provoke adverse effects and/or lead to fatality. For example, someone taking phentermine with cardiovascular disease could experience a heart attack resulting from excessive vasoconstriction and hypertension. These contraindications my limit the number of individuals that could safely take phentermine for depression.
- Controlled substance: It is understood that phentermine is classified as a Schedule IV controlled substance. While this scheduling indicates that phentermine may be less habit forming and/or risky than substances in other schedules, it suggests that it may result in abuse and/or dependence. In addition to the possibility of abuse and/or dependence, the scheduling of phentermine as a controlled substance makes it more difficult for users to attain a prescription. Even if you were able to attain a prescription, some doctors may require frequent visits for a phentermine refill. Frequent visits are required to ensure patient safety and rule out possibility of abuse.
- Dependence: Taking phentermine for depression may work well initially, but should an individual attempt to discontinue treatment, he/she may realize that it is impossible to function without the drug. A person may become reliant upon phentermine in order to socialize with others, perform at work and/or school, as well as for well-being. While some may argue that dependence is fine as long as depression is treated, the dependence may be problematic in that it may lead to high-dose/long-term treatment – resulting in deleterious long-term effects.
- Depression increase: There’s no research to suggest that phentermine is likely to reduce depression, but there is some evidence noting that phentermine can worsen depression. Many individuals with depression exhibit already-high concentrations of norepinephrine, epinephrine, T4, and cortisol. Phentermine ingestion may further increase the problematic neurobiological underpinnings of certain depressive subtypes, leading to exacerbation of depression and possibly suicidal ideation. Since phentermine may significantly increase depression in some users, and isn’t a proven intervention, it may be worth avoiding.
- Interactions: Phentermine is contraindicated for usage with other antidepressants, as well as sympathomimetic agents due to interactions. Administering phentermine along with antidepressants such as SSRIs, SNRIs, TCAs, and MAOIs may cause “serotonin syndrome” or abnormally high serotonin within the CNS. Medical professionals also recommend avoiding usage of phentermine with alcohol, drugs that increase blood pressure, psychostimulants, and many other agents that modulate central and/or peripheral nervous system function. Furthermore, it is possible that phentermine may decrease the efficacy of various medications due to pharmacokinetic interactions (e.g. inhibition of absorption). As a result of the myriad of possible phentermine interactions, it fairly impracticable as an adjunct.
- Long-term effects: The long-term effects of phentermine could be downright dangerous for some users, especially those that use the drug at high doses. The cumulative effect of phentermine administration over an extended duration may lead to heart valve damage, pulmonary hypertension, cardiac events, and/or transient ischemic attacks. For this reason, the drug is generally reserved solely for short-term administration. Since individuals with depression often require long-term treatment (exceeding 3 months) and will likely want to avoid long-term effects – phentermine is a poor treatment choice.
- Non-evidence based: Among the most substantial drawbacks associated with using phentermine for depression is that it’s non-evidence based. In other words, there’s zero scientific evidence to support the usage of phentermine as an antidepressant. For this reason, it is unlikely that any medical professional would prescribe phentermine, even as an off-label intervention to an individual struggling with depression. There are a multitude of other antidepressants that have undergone rigorous scientific testing (in RCTs) and are considered safe and effective. There hasn’t even been so much as a proof of concept trial of phentermine for depression in humans.
- Short-term only: It is widely known that phentermine is approved by the FDA for the treatment of obesity. However, it is intended to be used for a duration of less than 3 months. Anyone using phentermine for a duration exceeding a 3-month term may increase likelihood of serious adverse reactions such as heart valve dysfunction and cardiac complications. Subjecting a person’s body to ongoing vasoconstriction and enhanced sympathetic tone for months, without taking a break, may take a cumulative toll on organ function and other endogenous processes. Moreover, it is highly likely that users could become tolerant to high doses of phentermine if used in excess of 3 months, and upon onset of tolerance, its therapeutic antidepressant effect subsides.
- Side effects: Various phentermine side effects that you may experience during treatment include: anxiety, dizziness, hair loss, headache, insomnia, nausea, and vomiting. Many of these side effects are problematic in that they may indirectly worsen depressive states and/or neuropsychiatric comorbidities. For example, if phentermine were to cause anxiety and insomnia as side effects – this combination of feeling tense and being unable to get proper sleep may exacerbate your depression. Moreover, side effects such as dizziness, nausea, and vomiting may impair your ability to function – leaving you with no option but to discontinue phentermine.
- Superior options: While phentermine exhibits a unique mechanism of action, it acts primarily upon the peripheral nervous system and less significantly upon the central nervous system. The reduced effect exerted upon the CNS may make it a poor fit for the treatment of depression and neuropsychiatric conditions. What’s more, even if phentermine turned out to be safe and efficacious as an antidepressant, it may be significantly less safe and effective when compared to already-approved antidepressants. In other words, there may be plenty of superior psychopharmacological treatment options. Moreover, those in search of non-serotonergic interventions have plenty of choices – including Bupropion (Wellbutrin) which is FDA approved as an antidepressant and has been compared to phentermine as a result of its mechanism.
- Tolerance: Those that take phentermine for long enough are bound to develop some sort of tolerance to its effect. Tolerance occurs due to the fact that neurochemistry and physiology of the users adapts to the effects of the drug and adjusts itself accordingly. Regular phentermine-induced release of norepinephrine and dopamine will essentially train the brain to downregulate its endogenous production of each neurotransmitter, as well as decrease receptor sites due to saturation. As a result of these changes, those that experience a mood lift in the early weeks of phentermine treatment may report that it stops working as an antidepressant. Since it is a psychostimulant, tolerance may develop quicker to phentermine than it would with other pharmacological interventions. When tolerance is developed, users will have no choice but to: discontinue (and face withdrawal), maintain dose (and experience the same low mood), or elevate the dose (to improve mood but also provoke potentially serious side effects).
- Withdrawal symptoms: There are numerous reasons as to why someone using phentermine for depression will end up discontinuing treatment. The most obvious reason is that medical professionals restrict usage of phentermine to a short-term of under 3 months. As soon as you hit the 3-month mark of treatment, your prescription may not be refilled and you’ll end up facing withdrawal. Even if you are allowed to continue using phentermine for your depression, you may eventually discontinue simply as a desire to function without medication and/or because the side effects have become debilitating. Upon cessation of treatment, you’re bound to experience some severe phentermine withdrawal symptoms including: anxiety, dizziness, headache, weight gain – and even a worsening of depression. It takes some individuals months to fully overcome these discontinuation effects and fully revert back to their pre-phentermine selves.
Phentermine for Depression (Review of Evidence)
As of current, zero randomized controlled trials (or even proof of concept research) has been conducted to assess the efficacy of phentermine for the treatment of depression. Therefore, it is unknown as to whether phentermine could be an efficacious standalone antidepressant or viable adjunct. For now, it is only possible to prognosticate as to what effect phentermine may have upon mood based documentation from case reports and trials in which mood changes of participants was recorded.
2013: Phentermine, sibutramine and affective disorders.
A study by An, Sohn, and Chung (2013) discussed the association between phentermine and affective (mood) disorders. Researchers reported that the pharmacodynamic action of phentermine appears comparable to that of Bupropion (Wellbutrin), a common atypical antidepressant that functions as a reuptake inhibitor of norepinephrine, and to a modest extent, dopamine. Manufacturers of phentermine (Adipex-P) warn that adverse effects resulting from treatment can include euphoria and dysphoria.
Although significant shifts in mood such as euphoria and dysphoria may not be a common occurrence, the fact that they are reported as possible effects of phentermine indicate that the drug can impact mood. Upon further investigation, the team of researchers were only able to find 4 case reports and 2 studies documenting phentermine-induced mood changes. A total of 3 of the 4 case reports reported the occurrence of mania-related symptoms.
In one of the case reports, phentermine was administered with fenfluramine (in the combination known as “Fen-Phen”), triggering drug-induced psychosis in an individual with major depression. A second distinct case involved administration of phentermine plus fluoxetine, resulting in restlessness and expedited psychomotor function in a patient with depression. The third case reported phentermine-induced mania among an individual without any diagnosable psychiatric disorder.
That said, the third case study was interesting in that the individual who experienced mania had a family history of mood disorder, possibly making him more prone to drug-induced mania. The fourth case reported onset of depression following administration of Fen-Phen (Fenfluramine plus Phentermine) in an individual diagnosed with bipolar disorder (Type 1). Since case reports are generally not a reliable indicator of phentermine’s predictable effect upon mood in the general population, results from 2 credible studies necessitates discussion.
In each of these 2 studies, the effect of phentermine upon mood was measured as a secondary outcome. One study from 1983 administered phentermine to 50 women diagnosed with refractory obesity. A total of 7 women discontinued the study as a result of adverse effects – one of which was a result of experiencing drug-induced depression.
The second study referenced by researchers was a randomized controlled trial published in 2012 evaluating the safety and efficacy of the drug Qsymia (phentermine plus topiramate). In this trial, a total of 1,267 participants received a placebo, low-dose Qsymia, or high-dose Qsymia – for a 56-week term. The primary outcome measure was weight loss, but depression was analyzed as a secondary measure based off of results from the Patient Health Questionnaire-9.
Despite noticeable mood improvements after 56 weeks among participants receiving Qsymia, similar mood improvements were derived among those receiving the placebo. In other words, although Qsymia appeared to enhance mood, the degree of mood enhancement was no different than that derived from the placebo. Of additional interest is the fact that the high-dose Qsymia users ended up exhibiting higher rates of trial discontinuation as a result of depression – compared to the placebo users.
Since all individuals with a history of major depression or prior depressive episode were excluded from trial participation, it is unclear as to how Qsymia may alter mood among depressive patients. It is important to emphasize the fact that Qsymia is not standalone phentermine, rather it is phentermine combined with topiramate. Some of the mood alterations among individuals taking Qsymia may have been more related to topiramate or the unique pharmacodynamic combination – rather than standalone phentermine.
For this reason, it is likely best to avoid discussing Qsymia when attempting to elucidate specifically how its phentermine constituent affects mood. Nevertheless, researchers outline three possibilities in regards to how phentermine may influence mood including: induction of depression in a subset of patients, a dose-dependent depressive effect (e.g. only at high doses), or that phentermine doesn’t induce depression. If accounting for individual variation in neurobiology, it may be that all three hypotheses are accurate.
The work by An, Sohn, and Chung does show that phentermine can alter mood. In some individuals the drug is likely to exacerbate depressive symptoms, whereas in others it may uplift mood as is evidenced by case reports of mania-esque symptoms. To pinpoint the exact effect of phentermine upon mood among those with major depression, further research is required.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23678348
Research of Phentermine for Depression: Limitations and Recommendations
There are numerous limitations associated with research of phentermine for depression. The biggest research limitation is that zero studies have assessed the effect of phentermine upon mood among individuals diagnosed with major depression. Even trials conducted with healthy adults haven’t researched the effect of phentermine upon mood as a primary outcome.
Future studies should be conducted only among those that have been diagnosed with major depression, and implement a randomized controlled design. Preferably these studies should be of a moderate duration (e.g. several months) and incorporate several hundred participants. Moreover, phentermine should be tested as a standalone agent rather than as part of a combination drug (e.g. Qsymia) for better understanding of its ability to modulate mood.
- Animal models: Unfortunately, zero research has even tested the effect of phentermine in animal models with depression. Assuming it would be unethical to immediately the effect of phentermine on humans with depression, animal models may be a good place to start. For the most part we already know that phentermine is safe and tolerable in humans, but it may be unwise to risk exacerbation of depressive symptoms and/or provoke suicidal ideation without prior establishment of preliminary efficacy in animal models.
- Adjunct: It may be useful to investigate the efficacy of phentermine as an adjunct treatment among those with major and/or refractory cases of depression. Many cases of refractory depression benefit from adjunctive (intermittent) administration of psychostimulants, possibly due to the additional modulation of norepinephrine and dopamine. Though phentermine is contraindicated with numerous psychopharmacological agents, its concurrent administration may be a safe with a subset of antidepressant medications. Researchers may wish to determine whether it is safe and effective as an antidepressant adjunct.
- Depression diagnosis: To determine whether phentermine is helpful as a treatment for depression, it needs to be tested among those with major depression. Testing its effect upon mood of healthy individuals may yield irrelevant results in regards to whether it could help those with major depression. For this reason, any future research investigating phentermine as a potential depression treatment should consist solely of participants with diagnoses of depressive disorders.
- Depressive subtypes: For a more accurate understanding of whether phentermine is likely to be useful as an antidepressant, it may be helpful to test its effect among those with various subtypes of depression. Someone dealing with depression primarily as a result of low norepinephrine signaling may benefit significantly from phentermine due to the fact that it triggers norepinephrine release. Conversely, someone who’s depressed with high norepinephrine and low serotonin may find that phentermine worsens their depression. Pinpointing the specific depressive subtypes that would benefit most from phentermine would be useful.
- Design: The currently available literature is comprised of 4 case reports and 1 study in which phentermine’s effect upon mood is documented. While several case reports and a standalone study may provide preliminary data as to whether phentermine may be useful in the treatment of depression, randomized controlled trials are needed. Randomized controlled trials of moderate size and duration will yield more accurate data as to whether phentermine may be useful as an antidepressant.
- Dosage: Although we know phentermine is safe and effective for weight loss when administered at dosages up to 37.5 mg per day, it is unknown as to what an optimal dosage of phentermine would be for depression. Due to the fact that phentermine exerts a modest central effect at low doses, it may be that individuals require a much higher dose of the drug for alleviation of depression than weight reduction. Research may show that while phentermine is able to uplift mood, the dosage necessary for amelioration of depression is high and increases risk of serious adverse events.
- Primary outcomes: None of the current research has evaluated the efficacy of phentermine upon depression, or its effect upon mood as a primary measure. Since the drug has a strong peripheral effect and a less significant central effect, it is most commonly researched for weight loss. Any additional studies should implement depressive symptoms and/or mood as primary outcome measures.
- Sample size: Of all studies reporting phentermine’s effect upon mood, the largest incorporates 50 female participants. To gather accurate data regarding the efficacy of phentermine for depression, it is necessary to conduct a randomized controlled trial with a large sample size of several hundred participants. With a larger sample, it will be easier to determine whether phentermine is likely to help individuals with depression.
- Standalone phentermine: It is difficult to extrapolate the effect of phentermine upon mood from studies in which it was used as part of a combination drug (e.g. Fen-Phen or Qsymia). While data compiled from Fen-Phen and Qsymia studies may give us some idea as to how phentermine could affect mood, it’s impossible to confirm that the effects are solely from phentermine. In all trials of combo drugs (of which phentermine is a constituent), it may be the other agent responsible for mood modulation and/or the unique combination of phentermine plus the other agent. Further research should examine the effect of standalone phentermine on mood rather than that of combo treatments.
Why it may be useful to test the efficacy of phentermine for depression…
As of current there are no published trials that have investigated the safety and efficacy of phentermine as an antidepressant in humans. There are numerous reasons as to why phentermine hasn’t been subject to investigation as an antidepressant including: potential for abuse and dependence, lack of effect upon the CNS, long-term effect profile, as well as the fact that it may further aggravate preexisting depressive symptoms. Despite these risks, some may argue that it may be worth exploring phentermine’s therapeutic potential for the treatment of depression.
A notable reason as to why phentermine warrants additional research as an antidepressant is that it may prove helpful in the ~one-third of patients suffering from refractory depression. For these individuals, traditional pharmaceuticals provide limited or no benefit – and alternative pharmacology is generally welcomed. Another reason as to why phentermine may be worthy of further investigation for depression is due to the common comorbidity of obesity among those with depression.
Phentermine is already FDA approved for the treatment of obesity, and failure to treat obesity is understood to yield deleterious long-term implications for one’s mental health. Obesity is associated with gut dysbiosis, hormonal abnormalities, lack of exercise, excessive caloric intake, etc. – each of which can affect brain function. By treating obesity with phentermine, users may notice that in the act of losing weight – their mood significantly improves.
The mood improvement may be related to phentermine promoting physical activity and decreased caloric intake, thereby also improving gut bacteria, hormone production, neurotransmitter concentrations, etc. Most would agree that if phentermine were to be tested as an antidepressant, a logical population for testing would be one diagnosed with obesity plus comorbid depression. If it were effective for those with obesity plus depression, then testing could be expanded to encompass non-obese depressed populations.
We should also consider that, even if phentermine were only safe and/or effective for a short or limited duration (e.g. 3 months), it is reasonable to consider that this may be more than enough time for successful treatment. Hypothetically, phentermine could be utilized as a transient therapy by providing individuals with extra physical energy and motivation to make the much-needed lifestyle and/or habit changes that they’ve been neglecting. Assuming healthy habits are consolidated during treatment (e.g. exercise, nutrient-dense food intake, staying productive) – it may be possible to maintain these habits even after phentermine is discontinued.
While there may be a rocky transition upon ceasing phentermine usage, if an individual can stay disciplined enough to maintain his/her positive habits that were formed on the drug – depression may never fully return. Furthermore, it is necessary to consider that phentermine may end up maintaining its safety and/or efficacy as an antidepressant for a longer duration than researchers suspect. Research may show that a stable dose of phentermine is able to mitigate depressive symptoms for the same duration as a serotonergic antidepressant.
Many psychiatrists are aware that psychostimulants such as Adderall for depression can be highly therapeutic adjuncts for some individuals. Although phentermine is not the same as Adderall, it may turn out to be preferred over amphetamine-related compounds due to the fact that it exerts a less potent central dopaminergic effect – making it less subject to abuse and/or dependence. Perhaps the strong peripheral effect exerted by phentermine would turn out to be more useful in a subset of those with depression due to the fact that they may solely need increased peripheral activation to combat physical lethargy.
It is also important to note that phentermine is already being purchased on an illicit basis via the internet by individuals with depression who claim that it is highly effective in reducing their symptoms. The surfacing of these anecdotal testimonials to the drug’s antidepressant efficacy is yet another reason as to why further investigation would be useful. By investigating phentermine, we could determine its safety and efficacy for depression, as well as inform users of possible long-term effects associated with its usage.
Should phentermine prove effective for the treatment of depression, scientific research would help researchers establish clinically relevant dosing guidelines. As of now, most users are taking phentermine at the same dosage as is needed for the treatment of obesity. Learning more about the way phentermine works within the brain could also help pinpoint the useful mechanisms and design a closely-related drug geared towards treating atypical depression.
Who may benefit most from phentermine for depression?
Since phentermine hasn’t been subject to significant research as an antidepressant, it is difficult to prognosticate as to which patients are likely to benefit most from its administration. Administration of phentermine to an individual with one particular “neurobiological footprint” of depression may respond extremely well to its administration. On the other hand, someone with an entirely different “neurobiological footprint” of depression may respond poorly to phentermine and regret trying it.
Knowing that phentermine functions as a sympathomimetic agent to increase activation within the sympathetic nervous system is critical. With this knowledge, we can hypothesize that a depressed individual exhibiting abnormally low sympathetic nervous system function is likely to benefit from the increase provided by phentermine. Contrarily, a depressed person exhibiting already-high sympathetic tone may find phentermine to be a disastrous intervention. Included below is a list of speculated characteristics of an individual that may benefit from using phentermine for depression.
- Arousal deficit: Low arousal is associated with some cases of depression, often resulting in brain fog and severe fatigue. Phentermine is likely to ameliorate any deficits in arousal by activating the sympathetic nervous system. Although it may increase physiological arousal to a greater extent than mental arousal – it can enhance both. Those with depression characterized predominantly by low arousal may find phentermine more helpful than those with normative or high arousal.
- Catecholaminergic deficits: There are numerous genetic polymorphisms such as of the NET (norepinephrine transporter) and DAT (dopamine transporter) genes that could lead to deficient catecholaminergic signaling. Lack of catecholaminergic signaling is generally implicated in ADHD, but could also cause depressive symptoms in a subset of individuals. Though without definitive genetic data and research it is difficult to pinpoint whether someone has depression caused by deficient catecholamine signaling, abnormalities in catecholaminergic signaling may be suspected based on responsiveness to previous antidepressant medications. A person who responded well to an agent that modulated norepinephrine and/or dopamine may respond well to phentermine compared to a person that derived no benefit from a catecholaminergic modulator.
- Cognitive impairment: Depressed individuals that struggle with comorbid cognitive deficits and/or ADHD may be likely to benefit from phentermine, largely due to the fact that it increases arousal. Symptoms of cognitive impairment and ADHD are often reversed with administration of a psychostimulant as a result of bolstered catecholaminergic signaling, and consequently – increased arousal. Assuming you struggle with cognitive impairment and/or ADHD stemming from low neurophysiological arousal, an upregulation in arousal provided by phentermine may enhance mood.
- Cortisol deficiency: As a sympathomimetic agent, phentermine may enhance the secretion of cortisol and/or prolong its circulation throughout the body prior to its metabolism. Though up to half of all individuals with depression are thought to exhibit abnormally high secretion of cortisol, another subset may exhibit deficient cortisol secretion. Those with cortisol deficits may benefit most from taking phentermine in effort to enhance cortisol production and/or levels.
- Depression without anxiety: Those with depression but no anxiety may be likely to benefit from the arousal-promoting properties of phentermine. This speculation is based on the fact that a lack of anxiety with depression may signify an underlying deficit in arousal. Phentermine is understood to increase neurophysiological arousal, which may prove useful in combatting cases of depression in which no anxiety is present. Additionally, some patients with depression plus atypical anxiety (e.g. relaxation-induced anxiety) may benefit from the arousal elevation provided by phentermine.
- Low T4: Individuals with depression exhibiting subclinical levels of T4 (thyroxine) may benefit from phentermine administration due to the fact that it slightly increases T4. Although most cases of major depression are characterized by elevated T4 and low T3, those with low T4 may find phentermine useful in correcting minor T4 deficits – possibly a means by which it affects mood. By comparison, those with depression plus high T4 may find that phentermine worsens thyroid-related mood problems.
- Motivational deficits: While motivational deficits are not always synonymous with depression, suboptimal motivation is commonly a symptom. The low motivation experienced by individuals with depression may be related to poor catecholaminergic signaling and/or dysfunction within regions such as the nucleus accumbens. Phentermine releases catecholamines and reverses dysfunction in the nucleus accumbens, possibly making it an ideal fit for those with poor motivation and depression.
- Non-serotonergic abnormalities: Those who are depressed despite exhibiting normal serotonin function may benefit from phentermine. Though it is not yet possible to determine whether serotonergic transmission is “healthy” in spite of depressed mood, it is known that many patients fail to derive benefit from serotonin modulators. Treating depression among those suspected to be devoid of serotonergic abnormalities may be best accomplished with catecholaminergic modulators such as phentermine.
- Normative CYP3A4 expression: Phentermine undergoes partial metabolism through the CYP3A4 isoenzyme pathway. The function of CYP3A4 is dictated by expression of the CYP3A4 gene (encoding for the isoenzyme). Those with normative expression of CYP3A4 (or “extensive metabolizers”) may be more likely to benefit from phentermine as an antidepressant compared to those with CYP3A4 polymorphisms. Polymorphisms of CYP3A4 may lead to poorer metabolism of phentermine and make it less efficacious as an antidepressant.
- Obesity: Individuals classified as being clinically obese may respond better than non-obese patients to phentermine as an antidepressant. Obesity and depression are intricately linked in that obesity can lead to depression and/or exacerbate symptoms of depression [and vice-versa]. Since neurobiological underpinnings of obesity overlap with those of depression, and phentermine is effective in treating obesity – it would be reasonable to hypothesize that obese patients would attain greater antidepressant benefit from phentermine than non-obese depressives.
Who is unlikely to benefit from using phentermine for depression?
There are many individuals that would not benefit from using phentermine as an antidepressant. Those with underlying serotonergic abnormalities and normative catecholaminergic function may find phentermine useless in terms of mood enhancement. Additionally, those with high arousal may find that phentermine worsens their depressive symptoms directly by activating the sympathetic nervous system, or indirectly by causing side effects such as insomnia/sleep disturbances.
- Addictive personalities: Anyone with an addictive personality and/or that has a history of substance abuse may derive some initial euphoria from phentermine, but depression may be exacerbated over the long-term. This is due to the fact that individuals with addictive tendencies are more likely to abuse phentermine by taking supratherapeutic doses for intoxication. When the intoxication “wears off” after a high dose, depression may reemerge with greater severity than prior to treatment.
- Comorbid anxiety: Depression with comorbid anxiety is likely to worsen as a result of phentermine treatment. Those with depression plus an anxiety disorder tend to exhibit heightened arousal, agitation, and usually find it difficult to remain calm. Phentermine is a sympathomimetic and would be a poor fit for anyone with anxiety due to the fact that it increases arousal. An increase in arousal is likely to exacerbate anxiety, as well as depression.
- Eating disorders: In some cases, eating disorders may directly cause depression, and if phentermine enables behaviors implicated in eating disorders (e.g. prolonged bouts of starvation), mood may further plummet. Individuals with certain eating disorders (e.g. anorexia, bulimia, etc.) and/or body dysmorphic disorder may find that phentermine worsens depression as a result of eating disorder exacerbation.
- High arousal: Anyone with already-high neurophysiological arousal characterized by rapid thinking, excessive physical energy, agitation, etc. – may find that phentermine worsens their depression. High arousal could be a sign that excessively high norepinephrine, epinephrine, and cortisol secretion are at the root of depressive symptoms. Since phentermine enhances release of these stimulatory neurochemicals, exacerbation of depression is possible.
- High cortisol: There’s some evidence to suggest that amphetamine isomers (e.g. dextroamphetamine) may increase concentrations of cortisol. Since phentermine is closely related to amphetamine, it may also upregulate cortisol secretion. Many cases of depression are associated with hypersecretion of cortisol and various depressive symptoms often diminish when cortisol is reduced. If you secrete cortisol at a higher-than-average rate, taking phentermine may worsen (rather than enhance) your mood.
- High T4: Some studies discovered that phentermine administration slightly increases T4 (thyroxine) concentrations. If you are depressed, there’s around a 50% chance that your T4 is at a higher-than-average level. Assuming your T4 level is already high, and you take phentermine – any further increases in T4 may exacerbate severity of your depression.
- Insomnia: If you’re unable to sleep while depressed, there’s a chance that your arousal may be already high. Taking phentermine is likely to worsen your insomnia, impair with sleep quality, and disrupt your circadian rhythm – all of which promote depression. Depressed individuals that sleep excessively and have no insomnia may be better fits for phentermine.
- Normative catecholaminergic signaling: In cases of depression in which catecholaminergic dysfunction isn’t a problem, phentermine may be ineffective as an antidepressant. Phentermine exerts negligible effect upon serotonergic transmission and primarily targets norepinephrine. A depressed individual with normative catecholaminergic concentrations may find that using phentermine worsens his/her mood. Worsening of mood is likely due to abnormally high norepinephrine release, leading to elevated concentrations [which have been implicated in low mood].
- Serotonergic abnormalities: A multitude of individuals with depression exhibit abnormalities in serotonergic transmission rather than norepinephrine and/or dopamine. These individuals would be best suited to utilize a serotonin modulator such as an SSRI, which functions by inhibiting the reuptake of serotonin. Since phentermine doesn’t adequately modulate the signaling of serotonin, it may have zero mood elevating effect among those with serotonergic abnormalities.
- Skinny/underweight: A person with depression that’s skinny and/or underweight may end up losing a significant amount of weight during treatment with phentermine, possibly exacerbating his/her low mood. Additional weight loss for a skinny individual may take a toll on his/her confidence and self-esteem, as well as physical health. Most underweight persons with depression are trying to gain weight in order to improve body image and confidence, making phentermine a poor treatment.
Have you tried Phentermine for depression?
If you’ve used phentermine and found that it worked well as an antidepressant or mood enhancer, share your experience in the comments section below. Assuming you found phentermine to be therapeutically effective for the treatment of your depression, how long did it take for you to notice the antidepressant effect? To help others better understand your situation, provide details including: dosage of phentermine you used, how long you took it, and whether you used any other substances (drugs, supplements, etc.) along with it.
Also be sure to document the ways in which you believe phentermine was most helpful for uplifting your mood such as: increasing your motivation, helping you lose weight, enhancing your cognition, boosting energy levels, etc. Prior to taking phentermine, had you tried any other antidepressants? If you had tested other antidepressants before taking phentermine, mention how they compared in terms of efficacy and tolerability.
Do you believe that your depression responds better to drugs that target catecholamines (norepinephrine and dopamine) or those that modulate serotonin? If you found phentermine effective, had you tested other FDA-approved antidepressants such as Wellbutrin that upregulate norepinephrine and dopamine? Among those that used it for an extended duration, did phentermine’s antidepressant efficacy eventually wear off as a result of tolerance?
Overall, it is important to understand that there’s been zero credible research examining the safety and efficacy of phentermine for depression. While the drug may work well as an antidepressant for a small percentage of users, there are [likely] safer and more effective treatment options. Many phentermine users will notice a significant mood boost in the early weeks of treatment, but this transient euphoria will fade as tolerance is established.
Additionally, long-term usage of phentermine may be riskier than other psychiatric drugs due to the fact that it may inflict damage upon the heart valves. Other risks associated with utilization of phentermine for a duration exceeding 3 months include: cardiac events, hypertension, and stroke. Moreover, most published evidence indicates that phentermine is more likely to induce and/or exacerbate depression – rather than alleviate it.