Better Living Through Neurochemistry - A guide to the optimization of serotonin, dopamine and the neurotransmitters that color your world

by James Lee

Nicotine (like most drugs, including caffeine, for example) is far from being completely harmless, with addiction risk remaining a factor even if it is determined to be beneficial for the brain. However it may surprise you to note that even nicotine’s addictive qualities are being questioned, with many researchers now believing that much of tobacco’s addictiveness comes from other substances found in the plant. As nicotine’s primary benefits are cognitive in nature (with the most noticeable effects being on concentration levels), I have covered this topic at greater length in my book Brain Hacks. However nicotine also appears to be a moderately potent way to boost dopamine. As I mention regularly, anything which boosts dopamine naturally creates an addictive quality, as dopamine is the neurochemical of reward and reinforcement. Whatever addictive qualities nicotine possesses will most likely occur through this pathway.

There is no single illness called “depression” or “anxiety” and there are countless variations of each (as I will explain later). For example, whilst many people have depression caused by a lack of serotonin (or impaired serotonergic functioning), many do not. Depression can be caused by faulty thinking, life stressors, low dopamine, low noradrenaline, too much glutamate, thyroid problems and sleep disorders, to name but a few.

Well, did you know that there is another antidepressant drug called Stablon (tianeptine) which is a selective serotonin reuptake enhancer? Yes, that’s right. Stablon does the exact opposite thing in your brain yet it also treats depression for some people.

The main excitatory neurotransmitters are glutamate, acetylcholine and norepinephrine (and epinephrine), while the primary inhibitory neurotransmitters are GABA and serotonin. Serotonin is actually a complicated one and is more accurately called a neuromodulator because, depending on the context, can be either excitatory or inhibitory. Despite this, by far the most common neurotransmitters in your nervous system are glutamate and GABA.

Popular herbal antidepressants such as St. John’s Wort and Rhodiola Rosea treat depression the same way that certain drugs do, so the “natural” tag is, in some ways, a misnomer.

There is a molecule known as the SERT (serotonin transporter) which acts like a bus that picks up the serotonin and takes it back to its “home base” neuron for processing. By blocking the action of SERT, more serotonin can build up in the synapse and hopefully, lead to improved mood or reduced anxiety. This is how the popular SSRIs (selective serotonin re-uptake inhibitors such as Prozac and Zoloft) work.

Another way serotonin is recycled after it has done its job is via an enzyme known as monoamine oxidase (MAO), which breaks down serotonin (as well as dopamine and noradrenaline) via an enzymatic process. Similarly to SSRIs, if you block this process, the serotonin doesn’t get broken down at the same rate and then has a chance to build up in the synapse. Drugs that do this are called MAOIs (monoamine oxidase inhibitors) and were an older class of medications that are rarely used these days due to safety concerns. The main problem with MAOIs is that they require dietary restrictions. If someone taking a MAOI consumes food or drink high in tyramine (such as aged cheese), it can trigger a massive spike in blood pressure and can lead to death. So it’s not surprising that these have been largely ditched since the advent of SSRIs, which are virtually impossible to overdose on or accidentally kill yourself with.

Substances known as receptor agonists can artificially activate receptors, triggering the effects that would occur if the neurotransmitter itself did the job.

The class of anti-anxiety (and sleep) medications known as benzodiazepines (such as Xanax, Temazepam and Valium) act as GABA receptor agonists and therefore calm you down.

This is because there are a range of sub-types of the serotonin receptor and each sub-type has different effects when activated. For example, activating the 5-HT1A receptor can reduce anxiety (such as the drugs buspirone and trazodone), whereas activating 5-HT2A (such as psychedelics such as LSD do) can make you believe that there is a clown in your closet who wants you dead. Or alternatively, activating 5-HT1B (as the triptan class of drugs do) will treat migraines and cluster headaches. If you go messing around with serotonin, you’d better make sure you target the right receptor!

serotonin and other neurotransmitters are classified as agonists of their relevant receptors.

In the case of serotonin, the most potent releasing agent is the drug ecstasy which basically drains your brain of not only serotonin but also tryptophan, the amino acid precursor. This is why, unsurprisingly, you feel rather depressed after an ecstasy “trip”. As a side note, next time someone tries to tell you that depression has nothing to do with serotonin, you can helpfully point out ecstasy, where serotonin depletion causes a perfect analogue of depression (albeit for a few days only).

(Note – As I will mention repeatedly, this does not mean that all depression is caused by serotonin. There is depression cause by low dopamine and a multitude of other causes. However depression related to low serotonin is undeniably common. I should also point out that we don’t yet know whether low serotonin causes depression or is the result of depression. That’s how complicated this picture is!)

In general, releasing agents are fraught with danger because they tend to rob future neurotransmitters to feed the present. For example, reuptake inhibitors gradually increase serotonin over time, whereas releasing agents dump everything into the synapse, leaving none for tomorrow. This means, as a general rule regarding depression and anxiety, releasing agents make you feel much better today and then much worse tomorrow as your brain just can’t replenish levels of neurotransmitters quickly enough to keep up.

Essentially, natural antidepressants work as either mild SSRIs or mild MAOIs, with often conflicting research as to which. For example, researchers are currently divided as to whether St. John’s Wort is an SSRI or a MAOI. At the end of the day, this is relatively unimportant.

SSRIs tend to suppress dopaminergic function whereas MAOIs give all three mood-related monoamine neurotransmitters a boost. So if low dopamine is an issue, you would either need to focus on a supplement that purely works on dopamine (such as mucuna pruriens) or a MAOI like rhodiola rosea. Next, let’s dive into the treacherous waters of neurotransmitters.

However if you place 100 people with depression into a trial for a new SSRI, you would expect that the only ones to improve would be those whose depression is serotonergic in nature. It wouldn’t help those whose depression is related to dopamine, noradrenaline, NMDARs, cortisol or any of the other common causes of depression.

For example, the only option at present for someone with depression caused by low dopamine is either an old-school MAOI or the smoking cessation aid bupropion (Wellbutrin when used for depression and Zyban when used for quitting smoking).

A stressful life or a dead-end job will mess up serotonin more swiftly than any of the pathways mentioned above.

For example, on many forums you will see people claiming that tryptophan or 5-htp (5-htp is another supplement which is one step closer to serotonin, biochemically) are effective antidepressants. If low levels of tryptophan are behind your particular issues, then this will be the case. However if you are depressed, yet have no issues with tryptophan, taking these types of supplements will be unlikely to help.

The greatest single difference between tricyclics and SSRIs is that, if you were insane enough to consume an entire packet (or jar) of SSRIs, you would probably live. If you did the same with tricyclics, you would probably die.

The only legal serotonin releasing agent available (the pain reliever tramadol) is also fraught with danger as it also has a mild opiate agonist action, making it potentially addictive for some. I actually have a vaguely controversial opinion regarding tramadol. It is one of the few legally available drugs which you can take and it improves your mood within a few hours. As you know, antidepressants take weeks to lift your mood. This is because tramadol does a few things as the same time, making it quite an interesting drug. Among other things it acts as a – Serotonin releasing agent (improving mood) Noradrenaline re-uptake inhibitor (gives you energy and lifts mood) Opiate agonist (dulls both mental and physical pain) NMDA antagonist (NMDA antagonists are the latest subject of research into new antidepressants as certain NMDA antagonists such as ketamine have been shown to lift depression in hours, not weeks!) I believe there is a role to play for a drug like tramadol, if respected appropriately and only in very specific circumstances. There is a growing band of people claiming that when nothing else worked, tramadol lifted them out of their dark hole. However I should also point out that there is an equally large group of people telling of the horrors of quitting either large doses or long term use. This is another drug not to be trifled with and I am still not convinced of its effectiveness as a long term treatment for depression, due to the serotonin releasing p...

St. John’s Wort is the undisputed king of herbal antidepressants for good reason. It potently increases levels of serotonin, has a long history of widespread use (making clinical studies more statistically significant) and is associated with none of the severe side-effects usually associated with pharmacological antidepressants.

The other major component of hypericum’s mode of action is its ability to also concurrently treat the biomarkers of chronic stress.

So, while we know that hypericum functions as MAOI to at least some extent, it is unclear from these studies whether it functions as a MAOI at the dosages people are likely to take.

Rhodiola rosea belongs to a class of herbs known as adaptogens. Adaptogens are substances which restore homeostasis in the body. So if, for example, you are too wired and anxious, an adaptogen will calm you down. If you are lethargic and lacking energy, an adaptogen will give you energy.

Low magnesium is now clearly linked with low serotonin. Not only this, but a certain study also concluded that for certain patients, magnesium therapy was as effective as antidepressant medication!

New research is showing that magnesium is involved in a range of vital functions in the brain at the cellular level. Importantly, magnesium is a key co-factor in the production of serotonin, along with other vitamins such as folate and B6.

Curcumin therefore increases levels of serotonin and dopamine in the brain.

Curcumin happens to be a powerful anti-inflammatory, which is interesting in that recent research has shown a clear link between inflammation and depression.

5-htp is undoubtedly bioactive, as users of the drug MDMA (“ecstasy”) tend to report that 5-htp markedly reduces the time it takes to recover, which is a useful piece of anecdotal information, considering the fact that MDMA boosts mood by acting as a releasing agent, forcing your brain to “dump” its supplies of serotonin into the synapse. Thus, exhausted of both serotonin and endogenous 5-htp, a 2-3 day mini-depression results.

If you put a mouse in an environment where it receives electric shocks but is able to escape to a safe area or platform, they tend to cope OK. However if you put the same mouse in a situation where it is receiving electric shocks yet has no means of escape, soon the mouse starts exhibiting signs of depression! Post mortem tests on these rodents also show clearly reduce serotonin levels or changes in receptor density. The human equivalent is the dead end job, the abusive relationship or any other way a person can lose the sense that they are “in control”. Many therapists have observed the phenomenon where people can actually handle a large degree of adversity and stress, in general coping adequately.

The prescription here is clear – Take charge of your life. Particularly regarding things which are affecting your mental well-being. Even sitting down to make a plan on how to rectify your situation will send dopamine and serotonin levels dramatically higher. Go ahead and try it. Identify something in your life that you would like to regain control over. Sit down and write down a plan on how you are going to remedy this situation. I think you will be blown away by the results. In the planning and execution stage, the dopamine boost will be more obvious, however once you have achieved your goal and the dopamine spurt slows down you will find that gradually serotonin levels will rise.

Serotonin is innately linked to home mammals socialize. Alpha male gorillas have high serotonin and submissive gorillas with no power or mating privileges have low serotonin. The human correlate to this is the corporate world with the energetic, resilient CEO and the unhappy bottom-rung drones.

Boosting serotonin is quite simple and logical. Avoid the things that make you feel bad and do the things that make you feel good. Anything relaxing and enjoyable will usually boost serotonin. Massage? Yep. Getting out in the sunshine?

Alcohol is probably the most common serotonin-killer in modern society. Not only does alcohol send serotonin levels lower after the initial high, it keeps you from entering into the deep sleep stage where your serotonin levels are usually replaced. If you think you may have low serotonin, sorry however you will need to either cut it out completely for a while or at least cut back to levels that won’t cause you problems.

Joint Spanish and American study found that it is also dopamine that drives you to seek out these rewards in the first place. Not only this, they also found that persistence is likely linked to high dopamine, so the higher the dopamine levels, the more you are likely to soldier on through adversity to achieve a particular goal.

If you discover a way to boost dopamine, your brain will force you, with some degree of urgency, to do whatever is was, over and over. Then, as tolerance takes hold, you will need larger and larger doses to achieve the same effect. This is contrasted with serotonin, which is not typically associated with tolerance and addiction. This is a potential explanation for why methamphetamine (which works mainly on dopamine and noradrenaline) is highly addictive, yet the closely related MDMA (ecstasy), which works predominantly on serotonin and much lesser so on dopamine, is not considered addictive. My general feeling when it comes to boosting dopamine is to first exhaust all non-drug options before you consider the pharmaceutical route. I believe that dopamine is much more responsive to certain behaviors and thought processes than serotonin is – at least in the short term, as therapies like CBT can, over time, also boost serotonin.

Not only does CBT boost serotonin, it also boosts dopamine due to the effort-based rewards principle. CBT is very goal-oriented, involving the setting of a range of short and medium term goals as part of your therapy. Setting (and achieving) goals is one of the most powerful ways to boost dopamine that we know of.

There is a reason why stimulants used to treat ADHD work so well – Noradrenaline is a powerful modulator of attention. This is not surprising when you think back to our evolutionary past. If your distant ancestors encountered a dangerous animal, it would be fatal if their mind drifted off and started thinking about that lovely cave painting they just finished. Your brain triggers the release of noradrenaline to tell you “This is really important so you’d better pay attention”.

There is a great deal of debate in psychiatry around our focus on serotonin’s role in depression. As some researchers have pointed out, if someone presents in a doctor’s office complaining of the above symptoms, most of the time they will walk away with a prescription for an SSRI. This is despite the apparent fact that depression caused by problems with serotonin, dopamine and noradrenaline looks quite different.

Compared to serotonin, dopamine and noradrenaline, an endorphin deficiency or dysfunction is actually rather rare, in the absence of opiate use. However I believe there may be a key exception to this. I think that adults who experienced chronic or acute stress as a child may be at increased risk of endorphin system dysfunction later in life. As endorphins are key stress-fighters, there is a chance that someone’s endogenous opioid system could become dysfunctional after intense demands are put on it through severe or long-lasting stress.

Boosting serotonin makes you love everyone. Boosting dopamine and noradrenaline makes you feel a million dollars. However boosting endorphins makes you feel like you have gone to heaven, riding on a pain-free cloud.

Exercise and its effects on the brain and mood is another topic championed by Benjamin Kramer, who, in his book Jump Start said - Study after study has clearly shown that cardiovascular exercise and/or weight training works just as well as antidepressant medication, but with one key advantage - Those subjects who treat their anxiety and depression with exercise tend to stay well, whereas those who treat their depression with medication have a significantly higher relapse rate.