Alternative Therapies that can Help You Control Drinking and Drug Use

Reducing drinking and drug use and withdrawal symptoms without medications

This is the first post in a series on alternative and integrative approaches to alcohol and drug abuse. In this post I briefly comment on the limitations of mainstream conventional (pharmacologic and psychotherapeutic) treatments of alcohol and drug abuse and introduce readers to a variety of non-medication therapies that can help you cut down or stop drinking, reduce hangover symptoms, and control craving. Future posts will go into more depth on specific alternative and integrative approaches including concise reviews of research evidence, safety issues when they exist.

Limitations of mainstream conventional treatments of alcohol and drug abuse

Controlled studies and patient surveys show that existing conventional pharmacological and psychosocial treatments of alcohol and drug abuse and dependence have a mixed success record in helping individuals to stop drinking or abusing other substances and maintain abstinence. It is estimated that one year after stopping drinking or using a drug approximately one third continue resume drinking or abuse the same substance at the previous level, one third use the same or another substance but in a more controlled way, and roughly one third remain abstinent. Following the one year mark, abstinence rates continue to decline. There are no effective conventional treatments of cocaine addiction, and recovering alcoholics engaged in 12-step programs continue to experience high relapse rates. Only one third of recovering alcoholics who attend regular Alcoholics Anonymous meetings remain sober for more than one year.

Alternative and integrative treatments for alcohol and drug abuse

There is consistent positive evidence for the beneficial effects of lifestyle changes and a variety of non-pharmacologic treatments of alcohol and drug abuse. Reducing caffeine and refined sugar in the diet while increasing omega-3 consumption is associated with reduced relapse rates in abstinent alcoholics.

Supplementation with select natural products may have significant beneficial effects on reducing drinking and reducing withdrawal symptoms. For example, there is evidence that the amino acid taurine reduces alcohol withdrawal symptoms, SAMe (S-adenosylmethionine) reduces alcohol intake, and L-tryptophan reduces alcohol craving. The amino acid acetyl-L-carnitine may improve cognitive functioning in abstinent alcoholics.

Anti-oxidant vitamins taken before heavy drinking may reduce the severity of hang-over symptoms, and nicotinic acid may reduce the risk of developing dependence in chronic drinkers. Alcoholics who take magnesium and zinc supplements may mitigate the long-term neuropsychological consequences of chronic alcohol abuse. Emerging research findings suggest that some traditionally used herbs in Chinese medicine and Ayurveda are beneficial treatments of alcohol and drug abuse and dependence.

Relaxation, meditation and mindfulness training

There is evidence that the regular practice of relaxation techniques such as guided imagery and others, may reduce withdrawal symptoms following discontinuation of benzodiazepines. The regular practice of yoga, meditation or mindfulness training probably improves general functioning in alcoholics and may reduce the rate of relapse in abstinent alcoholics and addicts.

EEG biofeedback, virtual reality graded exposure therapy (VRGET) and acupuncture

EEG biofeedback using an alpha-theta training protocol probably reduces the rate of relapse in abstinent alcoholics. The application of weak electrical current to the brain may significantly reduce symptoms of alcohol and opiate withdrawal while improving associated symptoms of anxiety. Virtual reality graduated exposure therapy is emerging as a potentially effective non-drug therapy for reducing nicotine and cocaine craving. Regular exposure to dim morning light may reduce the risk of relapse in abstinent alcoholics. Some acupuncture protocols may reduce symptoms of withdrawal after chronic alcohol or cocaine abuse is discontinued.

I will review the evidence for these and other non-pharmacologic therapies in more detail in future posts. You can find a concise overview of alternative and integrative approaches to alcohol and drug abuse and practical methods for using them for alcohol or drug abuse, in my book “Alcohol and Drug Abuse: The Integrative Mental Health Solution.”

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3 Top Ways to Fight the Winter Blues: Exercise, SAMe and DHEA

Finding a non-pharmacologic treatment that works for you

This post is offered as a brief re-cap of highlights in my recent series of posts on complementary and alternative ways to fight the winter blues. Research studies consistently report the mood enhancing benefits of regular exercise, and two unique molecules that occur naturally in the human body that can be safely taken as supplements alone or in combination with an antidepressant: S-adenosylmethionine (SAMe) and dehydroepiandrosterone (DHEA). Below I briefly review the evidence for all three approaches. You can find detailed discussions of antidepressant mechanisms, analysis of research findings including links to studies cited, and comments on safety in my recent posts. On my website you can find practical information on a broad range of complementary, alternative and integrative ways to fight the winter blues, several full-text papers I’ve published over the years, and links to my books and e-books.

Regular exercise as an ‘antidepressant’ therapy

Findings of controlled trials report consistent mood-enhancing effects of regular exercise including both aerobic exercise and non-aerobic strengthening exercise. Regular aerobic exercise may improve cognitive functioning in chronically depressed individuals who often experience difficulties with thinking and memory. Meta-analyses of studies on exercise show consistent mood-enhancing benefits from exercise alone and improved response to antidepressants. Regular exercise may be as effective as St. John’s wort and other alternative treatments of depressed mood.

SAMe: effective for depressed mood and may reduce sexual side effects of antidepressants

Meta-analyses of placebo-controlled studies show that SAMe is as effective as many widely prescribed antidepressants when taken alone and improves overall response and may accelerate response rate when taken with an antidepressant. An important study published in the American Journal of Psychiatry reported that SAMe may also have significant mood enhancing benefits in individuals who do not respond to antidepressants. Combining SAMe with an antidepressant is a safe integrative way to treat depressed mood that may permit a reduction in the dose of a prescription antidepressant by as much as 30% in some cases. In addition to improving the efficacy of antidepressants, there is evidence that the adjunctive use of SAMe may reduce sexual side effects frequently caused by SSRIs and other antidepressants. Finally, taking SAMe 400mg twice daily together with an antidepressant may improve memory and other cognitive problems that often accompany depressed mood.

DHEA: mood enhancing and cognitive benefits and may improve sexual functioning

Like SAMe, DHEA taken alone may reduce the severity of depressed mood and can be safely used in conjunction with antidepressants increasing their efficacy. DHEA levels in the body and brain decline with normal aging, which may help explain some cases of late onset depression. Many individuals who respond to DHEA report improvements in sexual functioning.

DHEA may be an effective treatment of depressed mood individuals with HIV/AIDS, and may reduce symptoms of psychosis, anxiety and cognitive impairment all of which can occur together with depressed mood. Finally, there is some evidence that DHEA supplementation may reduces the rate of cognitive deterioration in Alzheimer’s disease and may improve anxiety and reduce the severity of psychotic symptoms in individuals diagnosed with schizophrenia.

Bottom line

If you’ve been struggling with depression, have had a disappointing response to antidepressants, or are looking for safe and effective non-pharmacologic approaches to boost the effectiveness of your antidepressant, think about adding exercise to your daily routine, or finding a quality brand of SAMe or DHEA. Before starting either supplement please take time to read the more detailed blogs posted in recent weeks.

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Exercise: An Effective Treatment for Depressed Mood

This post is part of a series on non-medication treatments of depressed mood. Previous posts reviewed the evidence for folate, B-12, SAMe, omega-3 fatty acids, the amino acids L-tryptophan and 5-HTP, and the prohormone dehydroepiandrosterone (DHEA). This post is offered as a concise review of the evidence for the benefits of regular exercise in depression. You can find out more about a wide range of alternative and integrative approaches for depressed mood and other mental health problems on my website

How exercise improves depressed mood

The beneficial mood-elevating effects of exercise are probably related to short-term transient responses in the brain immediately following exercise, as well as long-term changes following two or more periods of exercise. Findings of animal and human studies suggest that both the immediate and long-term beneficial effects of exercise on mood are mediated by multiple factors that increase brain levels of mood-elevating endorphins, dopamine, norepinephrine, and serotonin, promote the development of new neurons in the brain (i.e. neurogenesis), reduce oxidative stress, and enhance immune functioning (Schuch 2016).  Findings of a recent fMRI pilot study suggest that regular exercise may promote increased neuroplasticity in certain brain regions, resulting in improved mood (Gourgouvelis 2017).

In addition to the direct and indirect effects of exercise on brain function, regular exercise also enhances self-sufficiency and ensures positive social interactions with other people. It is difficult to separate beneficial effects of exercise from other lifestyle factors, and it is possible that exercise contributes to overall feelings of wellness while not having specific mood elevating effects. Finally, regular exercise has been shown to improve sleep quality in individuals who do not respond to antidepressants (Rethorst 2013). This may be a significant benefit of exercise on overall resilience and day to day functioning in view of the high prevalence rate of insomnia in chronically depressed individuals.

Review of research findings

The following section is a brief review of research findings on exercise as a stand-alone therapy for depressed mood, and as an ‘add-on’ therapy for individuals taking an antidepressant, engaging in cognitive behavioral therapy, or using bright light exposure therapy.

Mood enhancing benefits of regular exercise 

Findings of controlled trials and systematic reviews report consistent mood-enhancing effects of regular exercise. Individuals who are less sedentary have a reduced risk of both depressed mood and cardiovascular disease (Schuch 2017). Both aerobic exercise and non-aerobic strengthening exercises are believed to be equally efficacious. The optimum duration and frequency of exercise needed to improve depressed mood have not yet been determined but probably vary with age and conditioning. Regular aerobic exercise may improve cognitive functioning in chronically depressed individuals who often experience difficulties with thinking and memory (Oertel-Knochel 2014).

Regular exercise as an ‘add-on’ therapy to antidepressants and other treatments

A recent meta-analysis of controlled studies (977 total subjects) on exercise used either as a single intervention or in combination with antidepressants reported that regular exercise has consistent beneficial effects on depressed mood (Kvam 2016). A systematic review of studies on exercise as an add-on therapy in individuals diagnosed with major depressive disorder found that depressed individuals who exercise regularly respond consistently better than individuals who take an antidepressant but do not exercise (Mura 2014).

Adding regular exercise to ongoing antidepressant and cognitive therapy improves treatment response (Gourgouvelis 2018). Moderately depressed individuals who exercise in addition to receiving regular cognitive behavioral therapy (CBT) are less depressed and report less frequent suicidal thoughts compared to individuals engaged in CBT only (Abdollahi 2017).  Antidepressants and exercise probably have equivalent effects on moderate depressed mood (Blumenthal 2007). The therapeutic benefits of regular exercise may also be comparable to validated complementary and alternative (CAM) treatments of depressed mood such as St. John’s Wort (Hypericum perforatum) (Ernst 1998).

Depressed patients who exercise in a brightly lit (2500 to 4000 lux) indoor environment experience more significant improvements in mood and greater feelings of vitality compared to depressed individuals who exercise indoors in ordinary room light (400 to 600 lux) (Partonen 1998). Depressed women patients who combined exercise with bright light exposure while taking a daily vitamin regimen reported significant improvements in mood (Brown 2001).

Safety considerations

Individuals who have chronic pain conditions, heart disease, or other medical problems that might limit the amount of exercise they can do should consult with their family doctor, cardiologist, or other qualified health care provider before starting a regular exercise program or increasing their current level of activity.

Bottom line

Regular exercise has established mood-enhancing benefits in depressed individuals that may be equivalent to cognitive therapy. Regular exercise improves overall life quality and improves cognitive functioning and sleep quality—problems that often accompany chronic depressed mood. Combining regular exercise with an antidepressant enhances antidepressant response. Regular exercise may also enhance response to bright light exposure therapy and select alternative therapies. As exercise has established beneficial effects on the heart and body everyone struggling with depression should be encouraged to engage in a regular exercise program (i.e., unless a medical problem limits their activity).

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Acupuncture: A Safe and Effective Treatment for Depression

This post is part of a series on alternative and integrative treatments of depressed mood. Previous posts in the series reviewed research findings on anti-depressant benefits of SAMe, folate, vitamin B-12, omega-3s, DHEA, bright light exposure therapy, and exercise. This post is on acupuncture as a treatment of depressed mood. Acupuncture has been a central part of Chinese medicine for millennia and is widely used around the world to treat a variety of medical and mental health problems.

Mechanism of action

From a Western medical perspective the antidepressant effects of acupuncture may be mediated by nerve impulses transmitted at the point of needle insertion in the skin to the hypothalamus and other brain regions stimulating the release of norepinephrine, serotonin, dopamine, ?-endorphin, enkephalin and possibly other neurotransmitters. According to Chinese medical theory, symptoms of depressed mood reflect deficiencies or imbalances in qi energy in certain meridians or organs.

Review of research

Findings of several sham-controlled double-blind studies support that acupuncture, including conventional manual acupuncture, electroacupuncture, laser acupuncture, and ear acupuncture (i.e. ariculotherapy) has antidepressant effects, however other sham-controlled studies report negative or equivocal results. These differences may reflect methodological problems inherent in designing studies on acupuncture related to heterogeneity in the severity of depressive mood symptoms being treated, high rates of comorbidity in many studies, concurrent use of other alternative therapies or medications in patients receiving acupuncture, and the use of different acupuncture treatment protocols depending on the energetic formulation (MacPherson 2004).

A meta-analysis of 13 studies comparing acupuncture vs an antidepressant plus acupuncture in in depression found that individuals receiving combined treatment responded better–and more rapidly– compared to individuals treated with an antidepressant alone (Chan 2015). The authors of a systematic review on acupuncture for depression concluded reported that acupuncture significantly reduces the severity of depressed mood symptoms (Wang 2008). However, the authors of a subsequent systematic review that included more studies found low quality evidence for an antidepressant effect of acupuncture (Smith 2018) when used alone or in conjunction with an antidepressant. The authors commented that significant variations in outcomes of individual studies may depend on differences in study design, the severity of depressive mood symptoms being treated, the acupuncture protocol used, and antidepressant medication being compared to acupuncture. In addition to the above factors, findings of meta-analyses may  also reflect cultural and ideological differences between researchers in different countries as well as differences in publication bias in medical journals published in China and Western countries.

Findings of a small double-blind sham-controlled study suggested that traditional manual acupuncture (ie, in the absence of electrical current) may be an effective treatment of severely depressed outpatients (Allen 1998). By the end of this 8-week study 68% of 33 female outpatients being treated with an acupuncture protocol directed at depressed mood had achieved full remission. The significance of these findings is limited by the fact that depressed women patients who were not receiving any treatment in a wait-list group showed equivalent improvement in depressed mood.

In a large six week multi-center study 241 depressed inpatients were randomized to receive electro-acupuncture plus placebo versus electro-acupuncture plus the antidepressant amitriptyline (Luo 1998). Both groups experienced equivalent improvement in depressed mood. It is interesting that patients treated with electro-acupuncture had significantly elevated plasma norepinephrine concentrations following a six-week course of treatment consistent with the hypothesis that electro-acupuncture may stimulate release of norepinephrine in the brain. Depressed patients who failed to respond to electro-acupuncture did not show significant changes in serum norepinephrine levels. Findings of a several studies support that acupuncture is a safe and effective treatment of depressed mood in pregnant women (Manber 2004; Sniezek 2013). In addition to its beneficial effects as an add-on therapy, emerging findings suggest that acupuncture may reduce the incidence of sexual side effects to antidepressants (Wu 2012).

A recent innovation in acupuncture uses computer-guided modulation of the frequency and waveform of the current delivered through acupuncture needles. Findings from open trials of computer-controlled electro-acupuncture (CCEA) suggest that high frequencies (1,000 Hz) yield responses in depressed patients that are superior to both conventional acupuncture and electro-acupuncture (Luo 1996).

Few safety issues

Acupuncture generally causes transient minor side effects such as soreness and bruising. A meta-analysis of studies of complications related to acupuncture identified infrequent cases of infection with HIV, hepatitis B and C due to use non-sterilized needles. Rare cases of pneumothorax and cardiac tamponade have been reported as a result of accidental puncturing of lungs or the pericardium (Ernst 1997; Wang 2018).

Bottom line

After decades of research, the evidence for acupuncture as a stand-alone therapy for depressed mood remains inconsistent however increasing numbers of well designed sham-controlled studies show efficacy. Differences in outcomes in different studies can probably be explained by the large variety of acupuncture techniques (manual, electroacupuncture, ear acupuncture and laser acupuncture) and protocols used, as well as subtle psychological, cultural and biological factors that translate into response differences and are difficult to characterize in Western medical terms. Accumulating research findings suggest that acupuncture may have significant adjunctive effects when combined with antidepressant therapy. Many studies support that acupuncture is a safe and effective treatment of major depressive disorder in woman and emerging findings suggest that acupuncture may help reduce the incidence of side effects caused by SSRIs and other antidepressants, including sexual side effects.

On the basis of the above, acupuncture should be regarded as a reasonable choice for depressed individuals who fail to respond to antidepressants, pregnant depressed women and for depressed individuals who are seeking non-pharmacologic ways to deal with medication side effects. 

To find out more about evidence-based alternative and integrative treatments of depressed mood check out my e-book “Depression: The Integrative Mental Health Solution.” 

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DHEA: A Safe and Effective Treatment of Depressed Mood

Fighting the winter blues with DHEA

This is the sixth in a series of posts on complementary and alternative therapies for depressed mood. Previous posts reviewed the evidence for SAMe, bright light exposure therapy, omega-3 fatty acids, and folate. The topic of this post is dehydroepiandrosterone (DHEA) a molecule that plays many key roles in the human body and brain that has been extensively investigated for its antidepressant and cognitive enhancing benefits.

Multiple mechanisms of action

Dehydroepiandrosterone (DHEA) is a prohormone (i.e. a precursor of both male and female sex hormones) that occurs naturally in the body and brain and plays key roles in mood regulation and the body’s stress response, and has general neuroprotective, antiinflammatory and anti-oxidant effects.  DHEA and a related molecule (DHEA-S) are both manufactured in the adrenal cortex and testes, and are later converted to androgens and estrogens–the male and female sex hormones–in peripheral tissues. DHEA-S is the sulfonated form of DHEA and the most abundant steroid hormone in the body. The antidepressant mechanism of DHEA has not been fully elucidated but may involve androgen receptors, estrogen receptors, or well defined neurotransmitter systems including serotonin, GABA, NMDA and norepinephrine. Estrogen manufactured from DHEA affects the synthesis and binding of serotonin at multiple receptors sites. A recent study found that elevated DHEA-S serum levels correlated with higher rates of response to SSRI antidepressants consistent with research findings that supplementation with DHEA has antidepressant benefits and significantly enhances antidepressant efficacy (Hough et al 2017).

Promising research findings when taken alone or together with an antidepressant

Research findings show that DHEA supplementation alone may reduce the severity of depressed mood and can be safely used in conjunction with antidepressants increasing their efficacy. Blood levels of DHEA decline with normal aging. An early study found that physiological replacement doses of DHEA (ie, 30 to 90mg/day, a dose range corresponding to DHEA serum levels that are normal in people younger than age 40) may improve mood in middle-aged or elderly depressed patients (Wolkowitz et al. 1997).

This above findings are consistent with the findings of a small randomized placebo-controlled trial in which individuals with mid-life onset depression experienced significant and sustained improvements in mood following several weeks of supplementation with DHEA (Schmidt et al 2005).  In the study 46 moderately depressed adults were randomized to DHEA 90mg/day for three weeks followed by DHEA 450mg/day in three equal doses, for three weeks versus placebo. None of the patients used antidepressants concurrently. A 50% or greater reduction in depressive symptoms was observed in the majority of patients in the DHEA group, which also reported improvements in baseline sexual functioning. Significantly, most patients who responded to DHEA remained asymptomatic at 12 months follow-up.

Two systematic reviews support that DHEA is an effective monotherapy for depressed mood and may be safely combined with antidepressants augmenting their efficacy (Peixoto et al 2018; Peixoto et al 2014). Research findings on DHEA in depressed mood are limited by the small size of many studies, differences in dosages used, and heterogeneous study designs.

DHEA for depressed mood in HIV/AIDS, Alzheimer’s disease and schizophrenia

DHEA may also be an effective treatment of depressed mood individuals with HIV/AIDS. In one study depressed HIV positive patients experienced significant improvements in mood and fatigue when taking DHEA 200 to 500mg/day (Rabkin 2000). Serum testosterone levels and CD4 T-cell counts were not affected. Psychotic or demented patients often experience significant co-morbid depressed mood. In addition to its established antidepressant benefits, emerging findings suggest that DHEA may also reduce symptoms of psychosis, anxiety and cognitive impairment all of which can occur together with depressed mood.

Research findings suggest that DHEA supplementation may reduces the rate of cognitive deterioration in Alzheimer’s disease (Knopman 2003), and may improve anxiety and negative psychotic symptoms (i.e., apathy, withdrawal, paucity of thought) in individuals diagnosed with schizophrenia. In a double-blind placebo-controlled study 30 inpatients diagnosed with schizophrenia treated with DHEA 100mg/day in addition to their antipsychotic medications experienced significant improvements in depressed mood, anxiety and negative psychotic symptoms (Strous 2003). For unclear reasons, women improved more than men.

Safety issues

Most individuals who take DHEA at doses that have been shown to reduce the severity of depressed mood report few mild adverse effects. Case reports show that DHEA can cause hirsutism (i.e. abnormal hair growth) and acne and can interfere with normal blood clotting. DHEA may promote cancer in women who have a history of estrogen receptor positive breast cancer, and should be avoided in this population. However, a metabolite of DHEA called 7-keto-DHEA is not converted into androgens or estrogens and can probably be safely used in this population. Preliminary findings suggest that DHEA supplementation may increase the risk of prostate cancer in men with early or undetected prostate cancer (Arnold 2005).

Bottom line

At dosages established to be effective against depressed mood DHEA has few adverse effects. Combining DHEA with psychiatric medications is a safe and reasonable integrative approach in depressed individuals who fail to respond–or have a partial response–to antidepressant therapy, and in depressed individuals with co-occurring anxiety, psychosis or cognitive symptoms. The beneficial effects of DHEA on libido and sexual functioning is a significant added benefit of DHEA in view of the high percentage of depressed individuals who report reduced libido due to depressed mood or the side effects of antidepressants. Finally, DHEA should be considered when depressed mood occurs together with anxiety, psychosis and cognitive impairment including in patients diagnosed with schizophrenia and Alzheimer’s disease. .

Further research is needed to replicate the findings reported in this post, evaluate the efficacy of DHEA as a monotherapy for severe depressed mood, further elucidate the mechanism for a synergistic or independent antidepressant effect of DHEA and determine optimal safe dosing strategies.

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Omega3s Have Established Antidepressant Benefits

This is the fifth in a series of posts on non-pharmacologic treatments of depressed mood. Previous posts briefly reviewed research findings on S-adenosylmethionine (SAMe) and folate. This post is offered as a concise review of omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the treatment of depressed mood.

Multiple mechanisms

Epidemiologic studies have found an inverse relationship between consumption of fish and other foods high in omega-3 fatty acids and the prevalence of depression suggesting that individuals who consume foods richer in omega-3s are at reduced risk of developing depressed mood. Human and animal studies point to several mechanisms of action underlying the antidepressant effects of omega-3 fatty acids, including increased CNS serotonin activity, anti-inflammatory effects, suppression of phosphatidyl-inositol second messenger activity, and possibly increased heart rate variability.

In addition to the above mechanisms, another proposed mechanism of action that may be similar to that of antidepressants, including SSRIs and older so-called ‘tricyclic’ antidepressants, involves the suppression of pro-inflammatory cytokine release by immune cells, resulting in beneficial changes in the brain that manifest as improved mood (Maes 1998). Evidence in support of an anti-inflammatory mechanism of omega-3s is consistent with the observation that increased production of pro-inflammatory cytokines takes place in the initial or “acute phase” of severe depressed mood (Maes 1996). Further, animal studies show that direct administration of pro-inflammatory cytokines into the brain causes dysregulation in serotonin metabolism that mirrors changes observed in depressed individuals. Reports that Omega-3 fatty acids may reduce the incidence of coronary artery disease by influencing the production of pro-inflammatory cytokines in the heart may help to explain the observed correlation between heart disease and major depressive disorder.

Research highlights

Findings of studies on antidepressant effects of omega-3s when used alone or when taken adjunctively with an antidepressant are highly inconsistent, however, over time there has been a trend toward more positive findings of well designed placebo-controlled trials. In some studies patients who had previously been refractory to antidepressants improved significantly when Omega-3s were added to their antidepressant.  Most studies support that EPA has greater antidepressant efficacy than DHA both alone and when used in combination with an antidepressant. There is still no consensus on an effective antidepressant dose of EPA; however, it is probably at least 2gm/day typically taken in divided doses with food for optimal absorption.

Findings on DHA in depressed are highly inconsistent possibly reflecting complex relationships between ratios of Omega-3s and other fatty acids (i.e., Omega-6) in the blood and brain and associated anti-inflammatory effects. In a small double-blind study on the efficacy of DHA alone for severe depressed mood patients treated with DHA 2g/day versus a placebo improved at the same rate (Marangell 2003). However, a subsequent DHA augmentation pilot study found an inverse correlation between dose and antidepressant response, with patients receiving 1gm/day reporting significantly greater improvement in depressive mood symptoms compared to individuals taking DHA at doses of 2gm/day and 4gm/day ( Mischoulon 2008). The authors speculated that an optimal ‘therapeutic window’ may take place when a dose of DHA or EPA results in changes in ratios of omega-3s (which have anti-inflammatory effects) to omega-6 fatty acids (which are pro-inflammatory) in the blood needed to achieve an ‘optimal’ balance between pro- and anti-inflammatory forces.

A meta-analysis of studies on omega-3 supplementation alone found consistent anti-depressant benefits of omega-3 supplementation in individuals diagnosed with major depressive disorder, in depressed individuals who were not diagnosed with MDD, but not in women diagnosed with prenatal depression, or in children and adolescents (Grosso et al 2014). A meta-analysis of 241 placebo-controlled studies on EPA, DHA or combined EPA/DHA augmentation of antidepressants found greater benefits with EPA and combined EPA/DHA; however, the authors reported that their findings were limited by methodological flaws in many studies, heterogeneous study designs, small study sizes, short study duration and (in some cases) evidence of publication bias (Martins 2009).

The above findings support the use of EPA in combination with antidepressants, including bipolar depressed patients and patients who are refractory to antidepressants. It remains unclear whether EPA (or specific ratios of EPA to DHA or other fatty acids) has an independent antidepressant effect or possibly enhances the efficacy of antidepressants via second messenger systems in a manner that is similar to the postulated mechanism for lithium augmentation (Nemets 2002).

Unanswered questions

Many questions about fatty acid composition, optimal dosing strategies and treatment duration have not been answered. Confirmation of the size of an augmentation effect in individuals taking antidepressants and further clarification of the antidepressant mechanism(s) of action of essential fatty acids will require large, long-term placebo-controlled trials designed to answer these questions.

Side effects and safety issues

Gastrointestinal side effects have been reported and Omega-3s may interfere with glucose metabolism in diabetic patients (Glauber 1988). There is one case report of increased bleeding risk when Omega-3 fatty acids are used together with coumadin (Buckley 2004).

Bottom line

Supplementation with EPA may enhance response to available antidepressants. EPA may be safely used in combination with antidepressants and other psychotropic medications. Omega-3s have established cardiovascular benefits and are well tolerated. The majority of people who take EPA at dosages recommended for depressed mood report mild or no adverse effects. On the basis of available data, depressed patients should be encouraged to take EPA (1 to 2g/day) as an augmentation strategy in conjunction with their current antidepressant regimen. Diabetics and individuals taking Coumadin or other anticoagulant medications should consult with their physician before considering taking omega-3s. 

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Bright Light Exposure May Improve Seasonal Depressed Mood–More Studies are Needed

Regular morning exposure to bright light may improve seasonal depressed mood

This is the third post in a series on non-pharmacologic treatments of depressed mood. Previous posts provided brief reviews of the evidence for S-adenosylmethionine (SAMe) and folate. This post is offered as a concise discussion of bright light exposure therapy as a treatment of depressed mood. In addition to commenting on findings of individual studies I comment on the disparity in meta-analysis findings and the resulting debate on the efficacy of bright light therapy.

Mechanism of action is probably multi-factorial 

The mood enhancing benefits of bright light are probably related to many mechanisms of action that affect regulation of the synthesis of melatonin and neurotransmitters, especially the monamine neurotransmitters serotonin, dopamine and norepinephrine. Recent theoretical work suggests that the beneficial effects of light on the body and brain may be consistent with meridian theory in Chinese medicine (Cocilovo 1999).

Many studies support that exposure to bright light (10,000 lux) in the early morning, for one to two hours daily over several weeks (10,000 lux) has therapeutic effects in moderately or severely depressed patients. This effect is especially robust in patients who report recurring seasonal depressed mood changes–so-called seasonal affective disorder (SAD).

Small studies, short duration and methodological differences limit findings

Many studies report that morning exposure and evening exposure to bright light are probably equally effective in seasonal depressed mood however there are reports of insomnia with evening exposure. In addition to artificial full-spectrum bright light, exposure to natural sunlight, especially in the early morning, also has a significant anti-depressant effect, and may reduce the length of hospital stays in severely depressed bipolar inpatients (Benedetti 2001). Findings of a randomized double-blind study (89 total subjects) suggest that bright light delivered transcranially by LED inserted into the ear canals may have both antidepressant and anti-anxiety benefits in individuals diagnosed with seasonal affective disorder (Jurvelin 2014).

Findings of a small randomized trial suggest that bright light therapy may be an effective alternative to antidepressants in pregnant depressed women (Epperson 2004). In another study depressed patients who exercised regularly improved more when exposed to bright light than ordinary room light (Partonen 1998). A study published in the Journal of Affective Disorders in 2018 found that individuals diagnosed with seasonal affective disorder randomized to bright full spectrum exposure vs narrow spectrum low intensity blue light reported equivalent improvements in depressed mood symptoms (Meesters 2018).

Meta-analyses report conflicting findings

Although the above studies and many other controlled studies published in the peer-reviewed medical journal literature have reported beneficial effects of bright light exposure on seasonal depressed mood–and in some cases non-seasonal depressed mood, the conclusions of meta-analyses are inconsistent. For example, in an early meta-analysis Golden et al (Golden 2005) reported on large therapeutic benefits (i.e., a large ‘effect size’) of bright light exposure vs sham. The authors concluded that bright light exposure or dawn simulation for seasonal depressed mood, and bright light exposure (but not dawn simulation) for non-seasonal depression has comparable efficacy to conventional antidepressants (Golden 2005).  However, a more recent meta-analysis using more stringent selection criteria found only equivocal evidence in support of bright light exposure for depressed mood (Martensson 2015) arguing that findings of most studies are limited by small size, short duration and methodological differences in terms of light intensity, exposure duration, light source and wavelength examined, etc. Martensson et al also pointed out that selection bias in the Golden et al meta-analysis had led to unsubstantiated claims on the basis of 3 very small studies reporting positive outcomes.

Side effects can include headaches, insomnia and nausea

Some patients exposed to bright morning light 10,000 lux on a regular basis report transient side effects including mild jitteriness or headaches, and mild nausea. Sporadic cases of hypomania have been reported, especially in winter depressives or Bipolar patients exposed to early morning bright light. Almost two thirds of patients who use bright light exposure therapy in the evening report insomnia. Because of the risk of insomnia with evening bright light exposure, everyone who considering the use of bright light exposure to treat depressed mood should do so in the morning only.

Bottom line

Despite decades of research on full spectrum bright light (and more recently, dim blue light) exposure as a treatment of seasonal depressed mood, there is still no consensus among researchers on the antidepressant efficacy of this therapy. The wide disparity in reported outcomes reflects methodological differences in study designs, and suggests that factors that influence response to bright light exposure may not yet be adequately characterized. These factors may include the relative intensity of light, exposure duration, timing of exposure, frequency of exposure and wavelength. In addition, variation between individuals undergoing bright light therapy such as genetic, epigenetic and other poorly characterized inter-individual differences may help explain the disparity in response. Large prospective studies identifying and controlling for these factors are needed to elucidate the complex mechanisms of light therapy and to clarify its potential antidepressant effects.

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Folate augmentation in the form of l-methylfolate enhances antidepressant response

This is the third post in a series on complementary and integrative treatments of depressed mood. The previous post reviewed the evidence for SAMe (S-adenosylmethionine). In this post I briefly review the evidence for folate in depressed mood. Future posts will take a look at omega-3 fatty acids, vitamin D, the supplement DHEA and other non-pharmacologic approaches to fighting the winter blues.

Antidepressant mechanism of action

The mechanism of action by which folate affects mood has not been definitively established however its antidepressant effects are probably related to the central role this vitamin plays in the synthesis of neurotransmitters involved in mood regulation, including serotonin, dopamine and norepinephrine. Specifically, folate is a co-factor in the re-methylation of homocysteine into S-adenosylmethionine, required steps in synthesis of serotonin, dopamine and norepinephrine.

Folate in the diet is converted in the body to l-methylfolate, the only form of this vitamin that can cross the blood-brain barrier and contribute to neurotransmitter synthesis. It has been suggested that a significant percentage (perhaps as many as 75%) of individuals who fail to respond to antidepressants (so-called refractory depressed mood or treatment-resistant depression) may have a genetic mutation in the enzyme required for conversion of dietary folate into l-methylfolate, resulting in abnormal low levels of l-methylfolate in the brain and correspondingly low levels of neurotransmitters involved in mood regulation. Emerging research findings suggest that individuals with treatment-resistant depression respond better when high dose folate in the form of l-methylfolate (7.5 to 15mg/day) is added to their antidepressant regimen (Duprey 2016).

Folate enhances antidepressant response

Findings from controlled trials support that folate is an effective adjunctive treatment of depressed mood. One study found that the efficacy of fluoxetine (Prozac) and other antidepressants is significantly enhanced by the addition of daily folate. In another study the response of depressed patients treated with a SSRI antidepressant taken together with l-methylfolate (0.5-1mg/day) was as much as 30% greater than patients treated with a SSRI only (Papakostas 2004). An early systematic review of three controlled studies involving a total of 247 subjects concluded that “folate may have a potential role as a supplement to other (i.e., antidepressant) treatments” of depressed mood however findings were inconsistent (Taylor 2003). Patients who took folate 1mg with an antidepressant experienced incrementally greater reductions in depressed mood compared to those taking an antidepressant alone. However, one study included in the review failed to show a differential effect when folate was combined with trazodone, a widely used antidepressant. The significance of these findings was limited by small number of studies done and small study size. Shelton et al (Shelton 2013) provide a review of more recent research findings, which support that l-methylfolate augmentation is safe and results in statistically significant improvement in response compared to individuals taking an antidepressant alone (Shelton 2013).

Bottom line

In view of the high incidence of treatment non-response to antidepressants, the fact that the majority of non-responders may lack the enzyme required to convert dietary folate into its active form (i.e. l-methylfolate) needed for neurotransmitter synthesis, and consistent positive findings of l-methylfolate augmentation in this population, taking l-methyl folate together with an antidepressant is a reasonable integrative approach for managing depressed mood.

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Fighting the Winter Blues with SAMe

Fighting the winter blues with complementary and alternative therapies

This is the second in a series of posts on complementary and alternative (CAM) approaches to depressed mood. As I write I am thinking of many of my own patients who find themselves struggling more as the days grow shorter. This post is about S-adenosyl-methionine (SAMe), a widely used natural supplement with an established track record for treating depressed mood.  Future posts will review the evidence for other natural supplements, mind-body approaches, exercise, and a variety of other complementary and alternative approaches you can use to fight the winter blues.

How SAMe works to improve depressed mood

SAMe is a naturally occurring molecule in bacteria, plants, and animals and plays many important roles at the level of genes, immune function, and amino acid metabolism. In humans, SAMe is an important methyl donor, an essential step in the synthesis of several neurotransmitters from amino acids in the diet. The antidepressant effects of SAMe are probably related to multiple mechanisms of action including increased brain levels of serotonin, dopamine, and norepinephrine. The synthesis of these neurotransmitters by SAMe requires vitamin B12 and folate. Many depressed individuals are deficient in B vitamins thus individuals taking SAMe for depressed mood will benefit from taking vitamin B12 and folate (especially in the form of l-methyl-folate) concurrently. In addition to the effects of SAMe on the above neurotransmitters, it has been suggested that antidepressant effects of SAMe are mediated by anti-inflammatory effects, changes in neuronal membrane fluidity, increased rate of serotonin turnover, inhibition of norepinephrine reuptake, and beneficial synergistic effects of SAMe on dopamine activity. Antidepressant effects of SAMe may also be mediated by anti-inflammatory effects and changes in neuronal cell membrane fluidity.

Research findings show efficacy comparable to antidepressants

SAMe has been widely used for decades to treat depressed mood and osteoarthritis in many European countries where it is available on a prescription basis in oral form, as an intramuscular injection, or for intravenous use. SAMe degrades rapidly when exposed to air and stable oral preparations posed manufacturing challenges for many years. Thus, many early studies investigated the antidepressant efficacy of SAMe administered intramuscularly or intravenously. Early studies reported that effective antidepressant doses of SAMe are significantly smaller when administered intravenously, and showed that few patients receiving SAMe intravenously had adverse effects.

In the U.S., SAMe is available in oral form only and can be purchased as an over-the-counter tablet in pharmacies and health food stores. Shelf-life can be prolonged by refrigeration and protecting SAMe from degradation in blister packs. e-counter supplement in pharmacies and health food stores. Oral SAMe is available in two different forms. Oral forms of SAMe are combined with other molecules to reduce the rate of oxidative degradation and extend shelf life. The butane-disulfonate is available as an enteric-coated tablet and may have significantly greater bioavailability and longer shelf life than the tosylate form.

The standard maintenance regimen of oral SAMe for depressed mood is between 800 and 1600 mg/day in two to four divided doses. A common dosing strategy is to start SAMe at a dose of 200mg twice daily, and gradually increase to 400mg twice daily, monitoring for side effects and therapeutic response. Absorption is improved when SAMe is taken on an empty stomach (i.e., before meals).

Advantages of SAMe compared to prescription antidepressants

Most currently available antidepressants have a delayed onset of action thus consistent improvement in mood may be noticeable only after four to six weeks of daily use. In contrast, SAMe has a relatively rapid onset of action, usually within one week of starting treatment. Another important advantage of SAMe is the absence of clinically significant interactions with prescription medications and relatively few side effects compared to antidepressants.

In addition to its mood enhancing effects, there is evidence that augmentation with SAMe 400mg twice daily in individuals who are not responding to antidepressant therapy, may improve memory and other cognitive problems that often accompany depressed mood (Levkovitz 2012)

SAMe enhances response to antidepressants

Meta-analyses of placebo-controlled studies support that SAMe when used as a monotherapy is as effective as many widely prescribed antidepressants (Hardy et al 2003; Sharma et al 2017). Studies published in peer-reviewed medical journals support that combining SAMe with an SSRI antidepressant or venlafaxine (a serotonin-norepinephrine reuptake inhibitor) improves overall response and may accelerate response rate equivalent to results achieved when augmenting an SSRI antidepressant with bupropion or venlafaxine. The mechanism of action by which SAMe augments the effects of widely used prescription antidepressants in cases where a patient has become non-responsive may involve re-externalizing neurotransmitter receptors that have been internalized by the nerve cell membrane during prolonged exposure to an antidepressant.

Findings of a landmark study published in the American Journal of Psychiatry provided “preliminary evidence that SAMe can be an effective, relatively well-tolerated, and safe adjunctive treatment strategy for SSRI non-responders diagnosed with major depressive disorder (Papakostas 2010).” Individuals included in the study continued on recommended doses of commonly prescribed antidepressants including paroxetine, citalopram, duloxetine and other, while also taking SAMe. The authors noted that significantly more patients treated with adjunctive SAMe experienced clinical improvement and remission compared to matched patients receiving a placebo. The significance of findings was limited by small study size (73 total patients), the short duration of the study (6 weeks), failure to include a comparison group taking an antidepressant only.

Combining SAMe with an SSRI or other antidepressant is an integrative approach that improves outcomes while permitting a reduction in the dose of the conventional antidepressant by as much as 30% in some cases. The advantages of reducing the dose of a conventional antidepressant include fewer side effects and improved adherence to treatment. In addition to improving the efficacy of antidepressants, there is evidence that the adjunctive use of SAMe may reduce sexual side effects frequently caused by SSRIs and other antidepressants.

 

Safety issues

Although SAMe is well tolerated, transient anxiety, insomnia, gastrointestinal side effects, dry mouth, and dizziness have been reported. With continued treatment, most side effects resolve within days or a few weeks. Although many studies (including those reviewed above) show that SAMe may be safely used in conjunction with antidepressants, as SAMe affects serotonin synthesis, taking it together with another supplement or medication that increases CNS serotonin may cause serotonin syndrome, a potentially serious syndrome characterized by anxiety, agitation and insomnia. Please consult with your physician before taking SAMe together with an SSRI antidepressant or another medication that increases brain levels of serotonin. Rare cases of hypomania have been reported in patients diagnosed with Bipolar Disorder and it is advisable to avoid SAMe if you have been diagnosed with bipolar disorder.

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Fighting the Winter Blues the Natural Way

Dealing with depression over the holidays

Many people who struggle with chronic depressed feel more depressed as the holidays approach, the weather gets colder, and the days get shorter. If you currently take an antidepressant but you are having disappointing results or side effects, and you’re interested in learning about evidence-based non-pharmacologic treatments of depressed mood, research findings show that select natural supplements and other complementary and alternative (CAM) approaches may help you feel and function better.

Complementary and alternative therapies for depressed mood

This is the first in a series of blog posts on complementary and alternative (CAM) treatments of depressed mood. This post is offered as an overview of natural supplements and other CAM approaches widely used to treat depression. Future posts will focus on specific CAM modalities including natural supplements such as St. John’s wort (Hypericum perforatum) S-adenosyl-methionine (SAMe), 5-hydroxytryptophan, Omega-3 fatty acids, mind-body approaches, acupuncture, EEG-biofeedback, and others. In addition to reviewing the evidence for particular CAM modalities, I will comment on emerging research findings for combining specific natural supplements or other CAM modalities with antidepressants aimed at improving response or mitigating adverse effects.

Available mainstream treatments often fail to alleviate depressed mood

Depression is one of the most serious and costly health problems facing the world today. Because of the high incidence of suicide and other medical or mental illnesses in depressed individuals, depression is regarded as the leading cause of death and disability from adolescence through middle age. Although available mainstream treatments such as medications and psychotherapy are often beneficial, existing conventional approaches fail to alleviate depressed mood in many cases. These problems have resulted in ongoing debate over the efficacy and safety of antidepressants in the medical community and in the public at large.

Research findings on the efficacy of antidepressants are inconsistent and disappointing. Several independent analyses have concluded that most trials of antidepressants sponsored by pharmaceutical companies fail to show significant response differences between antidepressants and placebos. It is estimated that in United States, the U.K., and West European countries more than two thirds of depressed patients never receive adequate treatment with antidepressants. This is due to both inadequate screening of depressed mood by physicians and under-reporting by patients. Over half of all patients who take antidepressants are not treated by psychiatrists and have never been formally diagnosed with depression. Among those who are diagnosed and receive recommended doses of antidepressants, between 40% and 70% fail to respond.

Select CAM modalities have been validated as effective treatments of depression

Several non-pharmacologic treatment modalities used to treat depression and other mental health problems have been empirically investigated in well designed placebo-controlled studies and fulfill biomedical criteria for efficacy and safety but are not in widespread use in Western countries because of economic, social or ideological factors, including limited post-graduate training in the evidence-based use of complementary and alternative (CAM) therapies in mental health care, and widespread prescribing of antidepressants by physicians. Many CAM modalities are widely used to treat or self-treat depressed mood, and–as is true for widely used antidepressants–CAM therapies have limitations and drawbacks. However, select natural products and other non-pharmacologic treatments have been substantiated by consistent positive findings from large, well-designed placebo-controlled, double-blind studies, and in some cases, systematic reviews and meta-analyses.

Examples of empirically validated CAM treatments of depressed mood include St. John’s Wort, S-adenosyl methionine (SAMe), the amino acid 5-hydroxytryptophan (5-HTP), a form of the B vitamin folic acid, the essential fatty acid ecosapentanoic acid (EPA), and to a lesser extent, the amino acid Acetyl-L-carnitine and the pro-hormone dehydroepiandrosterone (DHEA). Placebo-controlled double blind studies and meta-analyses show that SAMe has equivalent or superior anti-depressant efficacy compared to tricyclic antidepressants. In contrast CAM therapies with a known biological mechanism of action, mindfulness, mind-body approaches, and other CAM modalities that do not have a clearly defined biological mechanism of action, have not been as rigorously examined by Western science, and therefore have relatively weaker empirical evidence supporting claims of efficacy.

Integrative strategies may be more effective than single conventional or CAM treatments

In addition to the use of single CAM therapies, emerging research findings support that taking an antidepressant while engaging in a mind-body practice, exercising, using bright light exposure therapy, or taking certain natural product supplements may accelerate the rate of treatment response or improve overall outcomes. This is the perspective of integrative mental health care, which is the focus of all my posts.

You can find out more about CAM and integrative treatments of depression by reading my e-book “Depression: The Integrative Mental Health Solution.”

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