Nootropics for Depression

Depression is a disorder caused by chronic stress and impaired neuroplasticity.

Humans are well-adapted to brief intervals of stress. Stressful situations can even be beneficial; they get your heart rate up and your blood flowing. For example, the calibrated release of adrenaline and noradrenaline might help you perform better on an exam.

There’s actually a TED talk by McGonigal where she develops the idea of eustress. A key feature of eustress is that it is self-limited; it resolves when the challenging situation resolves.

But chronic, unpredictable stress leads to synaptic remodeling, impaired neurogenesis, and other neurophysiological alterations that compromise your ability to cope, stay plastic, and bounce back. At this level, depression resembles almost a kind of neurotoxic process.

That’s why I’m a big fan of aggressively treating depression.

Cultural biases favor “sucking it up” rather than seeking treatment. Often when people finally do seek treatment, they’ve been coping with depression for years.

For some, lifestyle changes like getting more exercise can keep depression at bay. In other cases, it’s not enough. You may want to try supplements and nootropics before turning to an antidepressant. In my case - I actually used antidepressants and found them ineffective. That’s why I pivoted to alternatives like nootropics.

Having personally struggled with depression, these are the supplements and nootropics that I’ve found most helpful.

Tianeptine

Tianeptine is prescribed in Europe for the treatment of depression. Its mechanism is poorly understood. For many years it was labeled as an SSRE (selective serotonin reuptake enhancer). But this effect is unlikely to play a role in its primary antidepressant effect.

Tianeptine reverses stress-induced impairments in neuroplasticity. Practically, this menas that chronic stress induced brain alterations that impair plasticity - and that tianeptine restores these impairments. The mechanism underlying this effect remains unclear.

Lavender

Lavender is often overlooked, despite the fact that there’s quantitative, empirical evidence for benefit and neglibile side effects. In particular, lavender works wonders for anxiety.

Anxiety and depression work in a kind of feedback loop. I remember being depressed and feeling anxious around friends because I didn’t want to seem like a buzz kill.

Lavender took the edge off. It’s ideal because it’s not a heavy hitter like a benzodiazepine but it tangibly reduces anxiety. There are also studies with lavender that vindicate my experience.

Further reading: Lavender oil preparation Silvan is effective in generalized anxiety disorder—a randomized, double-blind comparison to placebo and paroxetine. - PubMed - NCBI

SAMe

Personally, I did not respond well to SAMe. I found it agitating and my sleep quality deteriorated. But I have a sensitive nervous system. My experience should not be taken as representative because there are tons of people who respond well to SAMe.

SAMe stands for S-adenosyl methionine. It’s a methyl donor; it donates a methyl group in specific biochemical reactions.

One thing you have to watch out for is the accumulation of homocysteine in the blood. Homocysteine is a biomarker for depression, hypertension, and other ill health effects. Fortunately, you can offset any increase in homocysteine by taking a B multivitamin.

Further reading: Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. - PubMed - NCBI

Vitamin D

Megadosing vitamins in general is a bad idea. Ideally, you’d get most of your nutrition from food. There are few reasons that supplementation doesn’t work quite as well as we might’ve hoped.

It was Linus Pauling that originally popularized the idea of megadosing vitamin C for a range of health problems, from the common cold to schizophrenia. This theory was discredited decades ago but vitamin C supplements still market themselves as immune boosters.

I take very few vitamins, but one of them is vitamin D. Many physicians recommend supplemental vitamin D. The average human in a developed country does not spend enough time outside. Vitamin D synthesis in the skin requires sun exposure. One workaround is supplementing with Vitamin D.

Vitamin D is actually a neurosteroid - it’s biologically active in the brain. It’s lipophilic and crosses the blood brain barrier. Vitamin D deficiency in utero and early childhood stunts the development of the central nervous system. There’s a paper that attempts to correlate the decreased incidence of schizophrenia along the equator, where sun exposure and vitamin D synthesis are at their apogee.

Adequate vitamin D is neuroprotective and likely has a protective effect against depression. Seasonal affective disorder may be exacerbated by modest vitamin D deficiency in the winter months.

Modafinil

The suggestion to take modafinil for depression will probably be controversial. I encourage you to remain skeptical.

Unlike lavender, SAMe, and vitamin D, modafinil is a prescription drug with rare but serious side effects. For example, less than 1 per 10,000 patients that take modafinil may get the Steven Johnson Syndrome or SJS. SJS is a potentially fatal rash that covers the whole body and requires immediate hospitalization.

I’m willing to accept the risks associated with modafinil because it’s one of the few drugs I’ve taken that reliably combats anhedonia (the inability to experience pleasure) and diminished motivation. Apathy is a persistent symptom of depression that can lead to occupational dysfunction, academic underachievement, etc.

I've written previously about the mechanism of action of modafinil here.

Conventional antidepressants make the lows less intense but do little for apathy. SSRIs - which are now first-line agents for depression - often worsen apathy. There’s such a thing as SSRI-induced apathy and hypofrontality.

Further reading: SSRI-Induced Indifference

One exception is Wellbutrin (bupropion), which does improve motivation. Wellbutrin is atypical in that it doesn’t target serotonin. Instead, it’s a nicotinic acetylcholine receptor antagonist and dopamine booster (DRI).

Modafinil is not FDA-approved for depression, but it is occasionally used off-label for this purpose. Modafinil is a good choice when anergy, fatigue, etc are prominent symptoms of depression.

Atypical depression (verses major depression) is associated with excessive somnolence, sluggishness, and carbohydrate cravings that respond well to modafinil.

Why Modafinil for Depression?

I take 200 mg of modafinil every morning. For me, it combats the cognitive symptoms of depression. When you first come down with the blues, the symptoms of depression are almost exclusively mood-related. You feel down, but your working memory and executive function are intact.

But other time, as you have more depressive episodes, you’ll encounter cognitive symptoms like distractedness, poor memory, brain fog. I remember feeling unable to get excited about life events that should be exciting.

These cognitive symptoms are far more terrifying than depressed mood because they erode your underlying ability to function in society.

Modafinil is no magic bullet for depression-induced cognitive impairment. But it’s the best thing I’ve tried to-date.

Omega-3 Polyunsaturated Fatty Acids

Melatonin

Melatonin is a benign substance that helps entrain your circadian rhythm.

Nighttime melatonin release peaks in childhood/adolesensce and declines with aging. As melatonin drops off, circadian rhythms become less robust. If you think of the propensity to sleep as a sine wave oscillating about an x-axis, the amplitude of this wave diminishes as you age. Concomitantly, sleep becomes less restorative. You stop releasing as much human growth hormone during slow wave sleep.

Depression and insomnia tend to accompany one another (they’re co-morbid). I take melatonin because it’s neuroprotective and it’s one of the most powerful antioxidants. Also, because sleep dysregulation comes with the territory of depression, and melatonin helps offset this. I doubt that melatonin by itself will pull you out of a severe depressive episode. But it might help as an augmentation agent - and it’s highly unlikely to cause harm.

(I don’t know if you’ve noticed, but many people take supplements to hedge their bets. They aren’t confident that supplements will enhance their health, but take them nevertheless as a kind of “Pascal’s Wager.”)

Saffron

A few studies have cropped up that suggest that saffron (the ingredient in cooking) has an antidepressant effect. I’ve benefited from it personally, but it’s expensive.

Akhondzadeh (2004). Result: saffron and imipramine similarly effective in improving HDRS. Akhondzadeh (2005). Result: saffron had better outcome on HDRS. Akhondzadeh Basti (2007). Result: saffron and fluoxetine similarly effective in improving HDRS. Moshiri (2006). Result: saffron had better improvement on HDRS scores than control. Noorbala (2005). Result: both groups similarly effective in treating depression.

Other Supplements I Take

While not explicitly for depression, some other nootropics I take include:

Curcumin

Omega-3 Polyunsaturated Fatty Acids

Magnesium

CDP-Choline

Bacopa monnieri

Many of these compounds have subtle antidepressant effects and can work well as augmentation to a full-blown antidepressant. The subreddit /r/depressionregimens is a great place to learn about nootropics for depression.