Happy chemicals

Happy chemicals are those molecules in the brain linked to happiness. People feel good when the brain releases them. These chemicals include endocannabinoids, dopamine, oxytocin, endorphin, GABA, serotonin and adrenaline. We focus on discussion of dopamine, serotonin, oxytocin and endorphins.

Dopamine motivates us to take action toward goals and needs and gives a surge of reinforcing pleasure when achieving them. Procrastination, self-doubt, and lack of enthusiasm are linked with low levels of dopamine. Serotonin flows when you feel significant or important. Loneliness and depression appears when serotonin is absent. Oxytocin creates intimacy, trust and builds healthy relationships. Endorphin are released in response to pain and stress and help to alleviate anxiety and depression.

  1. Dopamine

Dopamine (3, 4-Dihydroxyphenethylamine, CAS number: 51-61-6) belongs the catecholamine and phenethylamine families. In brain, it functions as a neurotransmitter. The brain has several distinct dopamine systems, one of which plays a major role in reward-motivated behavior. Most types of reward increase the level of dopamine in the brain. Inside the brain, dopamine plays important roles in motor control, motivation, arousal, cognition, reward as well as a number of basic lower-level functions including lactation, sexual gratification and nausea. The dopamine produced by brain makes people feel good and have self confidence. On the other hand, without enough dopamine, people may feel sluggish, depressed and uninterested in life.

The biosynthesis of dopamine is from L-phenylalanine via L-tyrosine and L-DOPA as intermediates. Many plants synthesize dopamine to verying degrees. Bananas contains highest concentration of dopamine at levels of 40 to 50 ppm by weight. Potatoes, avocados, broccoli and brussels sprouts may contain dopamine at level of 1 ppm. Oranges, tomatoes, spinach, beans contain less than 1 ppm. However, the dopamine consumed in food can not act on the brain because it can not cross the blood-brain barrier. The precursor of dopamine, L-DOPA, can reach the brain and is the most widely used to treat Parkinson’s disease and dopa-responsive dystonia. The highest concentrations of L-DOPA are found in the leaves and bean pods of plants of the genus Mucuna, especially in Mucuna pruriens (velvet beans), which have been used as a source for L-DOPA as a drug. Vicia faba, the plant that produces fava beans, the seeds of Cassia and Bauhinia trees also contain substantial amounts of L-DOPA. The illegal drugs such as opioids, methamphetamine can increase dopamine release. But these drugs cause a loss of dopamine by releasing more than is produced and they can disrupt the way that the body naturally produces dopamine. The following is the right methods to increase dopamine:

1)   Through diet

Tyrosine is a material to synthesize dopamine in body. Almonds, avocados, bananas, low fat dairy, meat and poultry, lima beans, sesame pumpkin seeds contain tyrosine and may help body to produce more dopamine. Greens, orange vegetables and fruits, asparagus, broccoli, beets, peppers, strawberries, caul. Flower, brussels sprouts, sunflower seeds, carrots, vitamin C and vitamin E may protect the produced dopamine from damage by oxidation or free radicals.

2). Through lifestyle hacks

Exercise regularly: Exercise increases blood calcium, which stimulates dopamine release and uptake in the brain. Try 30 minutes to 60 minutes of walking, swimming or jogging to jump-start dopamine levels.

Get plenty of sleep: 7-8 hours sleep a night is necessary

Reach a new goal: Dopamine is all about pleasure. The brain can be trained to produce the dopamine by setting and reaching a goal regularly in daily life. It does not have to be big start, thinking of little daily activities as goals.

3). With supplements and medication

Vitamin B6 and L-phenylalanine may be helpful in elevating dopamine in brain. Phenylethylamine is also useful. Doctors often prescribes psychostimulants like Ritalin to treat ADHD, antidepressant to treat depression which is associated with low dopamine, L-DOPA to treat Parkinson’s disease.

  1. Serotonin 

Serotonin, 5-hydroxytryptamine (5-HT, CAS number: 50-67-9), is a monoamine neurotransmitter. Biochemically it is derived from tryptophan and is popularly thought to be a contributor to feelings of wellbeing and happiness. Its functions include regulating intestinal movement, mood, appetite, sleep, memory and learning. Serotonin is also a growth factor for some type of cells, which may give it a role in wound healing. Approximately 90% of the human body’s total serotonin is located in the enterochromaffin cells in the gastrointestinal (GI) tract. The remainder is synthesized in serotonergic neurons of the central nervous system. Serotonin receptors include 5-HT1 receptor family (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F) signals via Gi10 inhibition of adenylyl cyclase. 5-HT2 receptor family (5-HT2A, 5-HT2B, 5-HT2C) signals via G9 activation of phospholipase C and other 5-HT receptors (5-HT3, 5-HT4, 5-HT5A, 5-HT6 and 5-HT7). The 5-HT receptors for serotonin are located on the cell membrane of nerve cells and other cell type, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors. Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT uptake, including cocaine, dextromethorphan, tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). In patients who suffer from depression, the levels of the P11 protein related to serotonin transmission within the brain are decreased. Depletion of serotonin is common between disorders such as obsessive-compulsive disorder, depression, and anxiety. However depletion of serotonin also occurs in people who have recently fallen in love.

Serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: Tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. Serotonin can be synthesized from tryptophan in lab using Aspergillus niger and Psilocybe coprophila as catalysts. Some plants and vegetables contain serotonin. The highest values of 25-400 mg /Kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. 3-30 mg/Kg in plantains, pineapples, banana, kiwifruit, plums and tomatoes. 0.1-3 mg / Kg in a wide range of tosted vegetables. Serotonin and tryptophan have also been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 µg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27-13.34 µg/g) was found in 70-85% cocoa. Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and 5-hydroxytrytophan does cross the blood-brain barrier. These agents are available as dietary supplements.

Several classes of drugs including some antidepressants, antipsychotics, anxidytics, antiemetics, antimigraine drugs and the psychedelic drugs and empathogens target the 5-HT system. Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors(MAOIs) prevent the breakdown of monoamine neurotransmitters such as serotonin and therefore increase concentration of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs. Some drugs inhibit the reuptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. But the side-effects are a decrease in bone mass in elderly and increased risk for osteoporosis. However it is not clear whether it is due to SSRI action on peripheral serotonin production or action in the gut or in the brain. There is investigation into whether SSRIs benefits to mood are somehow related to dopamine receptor sensitivity indirectly influenced by antidepressant mechanisms. In one study, patients with depression taking an SSRI were given a low dose D2 receptor antagonist (sulpiride ?) and reported negative effect on mood.

Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. It has been observed that the benefit of SSRIs may decrease in selected patients after a long term treatment. A switch in medication will usually resolve this issue (up to 70% of the time). The antidepressants mirtazapine and mianserin (5-HT2 and 5-HT3 receptor antagonists) have mood-elevating effects. This is an evidence that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean that the individual’s situation has been improved, but only the individual’s perception of the environment. Sometimes a lower serotonin level might be beneficial. Extremely high levels of serotonin can cause serotonin syndrome with toxic and potentially fatal effects. Such toxic levels are impossible to reach through an overdose of a single antidepressant drug.

Raising brain serotonin level may not only improve mood and social functioning of healthy people, but also make it possible to help protect against the onset of various mental and physical disorders. The following methods may be helpful in increasing serotonin synthesis.

  1. Exposure to bright light: Bright light is a standard treatment for seasonal depression. It also reduces depressed mood in women with premenstrual dysphoric disorder. There is a positive correlation between serotonin synthesis and the hours of sunlight on the day.
  2. Exercise: Exercise is another strategy to raise brain serotonin. Exercise can improve mood in subclinical populations as well as in patients. The most consistent effect is seen when regular exercisers undertake aerobic exercise at a level with which they are familiar.
  3. Mood induction: The interaction between serotonin produce and mood might be a two-way relationship. Therefore alteration in thought through psychotherapy or self-induction could increase the level of serotonin. Also, relive happy memories may give the brain a serotonin boost. This may directly increase serotonin levels and keep you from fixating on less happy times if you are prone to depression. If you can not think of happy times, try talking to friends or family and looking at old journals or pictures.
  4. Diet: The tryptophan is an effective antidepressant in mild to moderate depression. Further it increases agreeableness, decreases quarrelsomeness and improves mood in healthy people. In US it is classified as a dietary but in Canada and European countries it is classified as a drug. Actually the purified tryptophan and foods containing tryptophan have different effect on brain serotonin. For example, the purified tryptophan increases brain serotonin while the foods containing tryptophan do not. α-Lactalbumin, a minor constituent of milk, is one protein that contains relatively more tryptophan than most proteins. Acute ingestion of α-lactalbumin can improve mood and cognition in some circumstances. But enhancing the tryptophan content of the diet chronically with α-lactalbumin is not probably not practical.  The L-tryptophan in food is bound in protein rather than free form. Soybeans contains about 0.58% of tryptophan; sugar free cocoa (0.29% tryptophan); cashews(0.29%); raw chicken breast (0.28%); dried peas (0.27%); raw pork (0.23%); raw salmon (0.2%); oats (0.18%); walnuts (0.17%); chicken eggs (0.16%); brown rice (0.1%); corn flour and cow’s milk also contain tryptophan. In addition, eating dark chocolate improves both serotonin and endorphins levels.  Chickpeas contains tryptophan. The cultivated chickpeas contains more tryptophan than wild ones and almost two third of the tryptophan in cultivated chickpeas is in free form.

As discussed above, the foods containing L-tryptophan also contain other amino acids. Valine, leucine and isoleucine are three amino acids that are most in contention with tryptophan for absorption and uptake into the central nervous system. This is different with the synthesized pure tryptophan as supplements.

5. Supplements and medication

L-tryptophan : L-tryptophan is one of the essential amino acids and it is a precursor of serotonin. It is not available in most stores and pharmacies in United States, which may be a result of claims of contamination in the past. But L-tryptophan supplement is available in Canada and European countries. The conversion of tryptophan to 5-HTP is the rate-limiting step in the production of serotonin in the body. Therefore, by increasing tryptophan levels through its supplement, serotonin levels in the brain can be increased too.

5-HTP: 5-HTP, 5-hydroxytryptophan, is the direct precursor of serotonin. It is produced from tryptophan. It is a naturally occurring amino acid, but it is rarely found in food or crops. Instead, 5-HTP used in supplements is from the seeds of West African plant, Griffonia simplicifolia. 5-HTP is the best supplement to take for increasing serotonin levels. Unlike tryptophan, it does not compete with other amino acids to cross into the brain. It can increase serotonin levels faster than tryptophan supplements. Recommended doses of 5-HTP supplement is 50-300 mg daily. This can be divided into 1-4 doses in a day. Also, It is important to know the following points of view:

i) Care should be taken to avoid serotonin toxicity(serotonin syndrome).

ii)Acomprehansive literature search of the use of 5-HTP for treating depression revealed that administration of 5-HTP alone is not very effective. To compensate for this efficacy problem, 5-HTP is often used in combination with other drugs and /or substances.

iii) Synthesis of serotonin from 5-HTP and dopamine from L-dopa is catalyzed by the same enzyme. Administration of 5-HTP alone facilitates depletion of dopamine, norepinephrine and epinephrine. L-Tryptophan also depletes dopamine. When dopamine depletion is great enough, 5-HTP will no longer function. L-Dopa may deplete serotonin, L-tryptophan, L-tyrosine and sulfur amino acids.

iv) The most significant side effects and adverse reactions may occur with long-term use of 5-HTP (many months or longer).

v) Based on monoamine transporter optimization (MTO) studies, managing depression and other centrally acting monoamine-related diseases requires a combination of properly balanced dopamine and serotonin amino acid precursors. The administration must be in proper balance. Improperly balanced administration of serotonin and dopamine precursors may leads to decreased efficacy and increased incidence of side effects.

Vitamin B6: The conversion of 5-HTP to serotonin is catalyzed by 5-HTP decarboxylase which needs a cofactor vitamin B6. Therefore, vitamin B6 can speed up the catalytic synthesis of serotonin in the brain. For this purpose, the standard dose of vitamin B6 supplement is 100 mg and this is usually taken alongside 5-HTP and tryptophan supplements.

Selective serotonin reuptake inhibitors (SSRIs): Some SSRIs such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva) and sertraline (Zoloft) have been used to treat conditions such as depression and anxiety disorders by blocking the reabsorption of serotonin to change the balance of serotonin. But as discussed above some SSRIs may not be helpful for long term use. SSRIs are the first choice for physicians to treat depressive disorders and they appeared also effective in panic disorders, obsessive-compulsive disorders, social phobias and generalized anxiety disorders. Fluvoxamine, for example, has been registered for OCD in USA in 1995.

3. Endorphins

Endorphins are endogenous opioid inhibitory neuropeptides and they are produced by the central nervous system and pituitary gland. At least 20 types of endorphins have been demonstrated in humans. They are known as natural pain and stress fighters. They can inhibit the transmission of pain signals and may enhance pleasure. The brain naturally produces the endorphins in response to pain or extreme exertion to take the edge off and make people feel amazing. There are several methods to coax the body into making more endorphins:

1) By eating:   Take a bite of chocolate. Dark chocolate contains more the endorphin anandamide, which mimics the effects of marijuana. Eating hot peppers such as cayenne peppers, jalapeno peppers, banana peppers and other hot peppers. These hot peppers contain capsaicin which releases endorphins. Try eating a piece of raw pepper.  Taking ginseng has been shown to enhance the production of endorphins. Try incorporating a ginseng supplement into your daily routine.Having some comfort food such as pasta with cheese, ice cream or other carbohydrate-rich comfort food may help to release endorphins. Smelling vanilla extract may help the production of endorphins.

2) Connecting socially to release endorphins: For example, find more reason to laugh; smile, but make sure it is a real one; give in to gossip; be open to love and have more sex.

3) Exercising to release endorphins: Do any kind of exercise which is a quick, effective and long-lasting way to increase the production of endorphins. All types of exercise cause endorphins to be released into your bloodstream, considerably improveing your mood. Try a group exercise class can stimulate extra endorphin production. Try daredevil activities such as skydiving, bungee jumping, hang gliding and roller coasters etc.

4) Sunlight may also be helpful.

 

  1. Oxytocin

Oxytocin is a mammalian neurohypophysial hormone that helps relax and reduce blood pressure and cortisol levels. It increases pain thresholds and has anti anxiety effects. It stimulates various types of positive social interaction and promotes growth and healing. It may play a role in various behaviors including orgasm, social recognition, pair bonding and maternal behaviors. The oxytocin is a peptide of nine amino acids and its sysyematic name is cysyein-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide. It is produced in the supraoptic and paraventricular nuclei of the hypothalamus by nerve axons and stored in the posterior pituitary gland. The oxytocin is also called the love hormone or bonding hormone. When it is released, we feel softer, more nurturing, more cuddly and more loving. It may change our visual and mental perceptions allowing us to see the oneness of all things, the interconnectedness of all of us. For a brief moment, it turns us into right brained systems thinker, rather than analytical critics. If no oxytocin gets released or misregulation, it becomes harder to see the point of being loving. We may become self-centered, short sighted and egotistical. Without oxytocin, our testosterone would cause us to be more fear-based in our decisions.

In order to create more oxytocin naturally, try any or all of following: stop arguing, get touchy and get hugs, let tears flow, participate in something great, having love sex, build empathy, soak in a hot tub, meditate while focusing on others, listen with your eyes and use social media and more. Studies show that the more one releases oxytocin, the easier it becomes to do so.

 

Some references on serotonin and 5-HTP

1) Is serotonin an upper or a downer ? The evolution of the serotonergic system and its role in depression and the antidepressant response, Neuroscience & Biobehavioral reviews, 51, 164-168 (2015)

2) Serotonin: A never-ending story, European Journal of Pharmacology, 753, 2-18 (2015)

3) Research progress in correlation between 5-HT receptors and depressive disorder, Yixue Zongshu, 20(5), 772-775 (2014)

4) Research advances on serotonin, its receptors and depression, Guoji Yaoxue Yanjiu Zazhi, 39(5), 409-413

5) Serotonin (5-HT) in the regulation of depression-related emotionality: insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models, Current Drug Targets, 14(5), 549-570 (2013)

6) Serotonin-kynurenine hypothesis of depression: historical overview and recent developments, Current Drug Targets, 14(5), 514-521 (2013)

7) Involvement of serotonin receptor subtypes in the antidepressant-like effect of beta rece[ptor agonist Amibegron (SR 58611A): An experimental study, Pharmacology, Biochemistry and Behavior, 105, 12-16 (2013)

8) The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 1Arg439His knockin mouse, Philosophical Transactions of the Royal Society, B: Biological Sciences, 367(1601), 2444-2459 (2012)

9) 5-HTP efficacy and contraindications, Neuropsychiatric Disease and Treatment, 8, 323-328(2012)

10) Mood effects of the amino acids tryptophan and tyrosine: ‘food for thought’ III, Acta Psychiatrica Scandinavica, 124(6), 417-426 (2011)

11) Serotonergic pathways in depression, Neurobiology of depression, 143-170 (2012)

12) Serotonin, depression, and cardiovascular disease: sex-specific issues, Acta Physiologica, 203(1), 253-258 (2011)

13) Beyond the serotonin hypothsis: Mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders, Progress in neuro-Psychopharmacology & Biological Psychiatry, 35(3), 730-743 (2011)

14) The double edged sword of neural plasticity: Increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover, Psychoneuroendocrinology, 36(3), 339-351 (2011)

15) Increased endogenous serotonin level in diabetic conditions may lead to cardiacvalvulopathy via reactive oxygen species regulation, Biologia (Berlin, Germany), 70(2), 273-278 (2015)

16) The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects, Molecular Psychiatry, in press.

17) Facilitation of serotonin signaling by SSRIs is attenuated by social isolation, Neuropsychopharmacology, 39(13), 2928-2937 (2014)

18) Use of glycyl glutamine against depression and anxiety, WO2014109725 A2 20140717

19) Second-tier natural antidepressants: Review and critique, Journal of Affective Disorders, 130(3), 343-357 (2011)

20) Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan, Pharmacology & Therapeutics, 109(3), 325-338 (2006)

21) 5-Hydroxytryptophan plus SSRIs for interferon-induced depression: Synergistic mechanisms for normalizing synaptic serotonin, Medical Hypotheses, 65(1), 138-144 (2005)

22) 5-Hydroxytryptophan synergistic combination with (-)-hydroxycitric acid for treating obesity, US20030187055

23) Synergistic pharmaceutical combinations of 5-hydroxytryptophan for treating obesity with EGCG and caffeine, US20030162725

24) Methods and materials for treating depression and mood disorder with 5-hydroxytryptophan and an ext. of Hypericum perforatum or other extract and vitamins, US6068846

25) Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder, Neuropsychopharmacology, 17(1), 1-11 (1997)

26) Studies in mechanism of action of serotonin precursors in depression, Psychopharmacology Bulletin, 20(3), 599-602 (1984)

27) In search of the mode of action of antidepressants: 5-HTP/tyrosine mixture in depression, Advances in Biochemical Psychopharmacology, 39, 301-314 (1984)

28) The indoleamine hypothesis of depression: an overview and pilot study, Diseases of the Nervous System, 38(8), 646-653 (1977)

29) Tryptophan and 5-hydroxytryptophan for depression, The Cochrane database of systematic reviews (1), CD003198 (2002)

30) L-5-htp in the treatment of sleep disorders in patients with depression and anxiety states, Schweizerische Rundschau fur Medizin Praxis = Revus suisse de medecine Praxis, 77(34A), 24-27 (1988)

31) Serotonin precursors in the treatment of depression, Advances in biochemical psychopharmacology, 34, 259-286 (1982)

32) Clinical evaluation of 5-hydroxy-L-tryptophan as an antidepressant drug, Folia psychiatrica et neurologica japonica, 32(2), 223-230 (1978)

33) 5-Hydroxytryptophan (5-HTP) and a MAOI (nialamide) in the treatyment of depressions. A double-blind controlled study, International Pharmacopsychiatry, 11(1), 8-15 (1976)

 


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