Before taking any pharmaceutical, read this first.
Monoamine neurotranmitters include serotonin, dopamine, epinephrine (adrenaline), norepinephrine (noradrenaline), histamine, and a host of other trace amines.
I'm finding studies and articles that disagree with the current trend of treatment, influenced by capitalism, for depression and other afflictions of supposed monoamine imbalance. See in this article review, all the reasons why pharmaceuticals for depression don't make sense, and consider that they have side effects worse than the benefit they may derive. (The article review is based on the 2015 study: Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response)
Another 2011 study is Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression: “ Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. ”
A 2012 article by Shai Mulnari of Lund University: Monoamine Theories of Depression: Historical Impact on Biomedical Research: “ The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas. ”
Monoamine Transporter Optimization MTO, from the study “Relative nutritional deficiencies associated with centrally acting monoamines”: “ Humans suffering from chronic centrally acting monoamine-related disease are not suffering from a drug deficiency; they are suffering from a relative nutritional deficiency involving serotonin and dopamine amino acid precursors. Whenever low or inadequate levels of monoamine neurotransmitters exist, a relative nutritional deficiency is present. ”
MTO is a treatment strategy where you supply 5-htp, l-tyrosine, and l-dopa, in a supposed case that the body's natural physiology/metabolism is altered such that a nutritional deficiency exists, causing lowered level of a monoamine(s). Apparently there are monoamines, and there are trace amines, with the trace amines existing at levels 100 fold below those of the monoamines. I have yet to thoroughly search info on maintaining the balance or of depletion of the trace amines, if there is such articles. MTO may seem speculative to me, but less speculative than applying pharmaceuticals such as SSRI's.
The most common drugs used for depression are SSRI's (selective serotonin reuptake inhibitors). These drugs are generally toxic to your body. They are used as an alternative to just providing more serotonin by supplementing 5-htp, a metabolite of the amino acid tryptophan. Although tryptophan is naturally occurring in food, it's metabolism creates toxic by-products in addition to 5-htp, so taking 5-htp is viewed as healthier. Also, 5-htp only metabolizes to serotonin, whereas tryptophan can take other routes.
Taking 5-htp long term can be problematic. I've done it, and I didn't have any side effects that were obvious (like when I took high doses of niacin and my skin was flushing). The blood brain barrier is a bottleneck in terms of delivery of building blocks to the brain, so 5-htp supplementation can crowd out the other amino acids that produce the other monoamines. Also, there is a feedback loop, such that if the level of serotonin is high, the level of monoamine oxidase is increased (homeostasis). Since the enzyme is not selective of serotonin, it reduces the levels of all the monoamines. So you will be burning the candle at both ends, when it comes to the levels of other monoamines besides serotonin.
Another alternative, is to use MAOIs, monoamine oxidase inhibitors. Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. Taking a MAOI will supposedly raise the levels of all the monoamines. However, I wonder about homeostasis, as mentioned in the “Blue Again” article above. Does the human metabolism have other systems besides these enzymes to keep levels in check? For example, COMT is also responsible for the degradation of catecholamines.1.
source: Behavioral Outcomes of Monoamine Oxidase Deficiency BOMOD, 2011
Serotonin, melatonin, norepinephrine, and epinephrine are mainly broken down by MAO-A.
Phenethylamine (PEA, widely regarded as an endogenous amphetamine) and benzylamine and certain other trace amines are mainly broken down by MAO-B.
Both forms break down dopamine equally, as well as trace amines like tyramine and tryptamine. 1
MAO-B activity is increased during aging in the brain of humans and other mammals. 123 “ In this review, we address several factors contributing to a possible role for MAO-B in normal brain aging and neurological disease and also discuss the use of MAO-B inhibitors as drug therapy for these conditions. ”4 “ To the best of our knowledge, there have been no reports of clinical conditions characterized by selective MAO-B deficiency. However, in few cases of atypical Norrie disease (ND) subjects with MAO-B deletion, the latter deficit was reported to result in increased urinary excretion of PEA, but no overt behavioral abnormalities or cognitive deficits (Berger et al., 1992; Lenders et al., 1996). ” BOMOD, 2011
“ Rich evidence shows a robust correlation between low MAO-B platelet activity and a spectrum of psychological traits related to behavioral disinhibition, such as sensation-seeking and novelty-seeking personality, extraversion, poor impulse control, and proclivity to engage in risky behaviors (Buchsbaum et al., 1976; Fowler et al., 1980; von Knorring et al., 1984; Reist et al., 1990; for a review, see Oreland and Hallman, 1995). ” BOMOD, 2011
Rhodiola is a herb that, aside from being an adaptogen, is also a MAOI 1 (see also here and here). Although only tested in vitro, Rhodiola should act on both MAO-A and MAO-B. The article “Blue Again” states: “ Of the ADMs, dual MAO-A/B inhibitors exert the most powerful effects on monoamine levels. Due to differences in regional effects of ADMs, many ADMs do not increase monoamine levels when averaged across the whole rodent brain, yet dual MAO-A/B inhibitors are powerful enough to do so (Campbell and Marshall, 1974; Fuller et al., 1974; Renard et al., 2004; Bano et al., 2010). ” I think of adaptogens as being nutrition, which is why I take them as dietary supplements.
“ Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. ” 1
“ Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM). Structural differences of kava pyrones resulted in a different potency of MAO-B inhibition. The order of potency was desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. The two most potent kava pyrones, desmethoxyyangonin and (+/-)-methysticin displayed a competetive inhibition pattern with mean Ki 0.28 microM and 1.14 microM respectively. ” 1
So what metabolic systems drive homeostasis? Are they fully known? Probably not. I've been searching, and I found what seems like a good article, but it is behind a paywall: Brain Monoamines, Homeostasis, and Adaptive Behavior https://onlinelibrary.wiley.com/doi/pdf/10.1002/cphy.cp010413
If one can alter homeostasis, then, for example, the bad effects of MAO-B with aging can be curbed. We can also start to consider ways to maximize or tune cerebrum performance. Homeostasis would be governed by DNA programming, and which part of this programming is being invoked (epigenetics). I wonder if there is a feedback mechanism, such that if you alter the default over time, the default balance is altered. Of course, there is also the hypothetical system clock which governs which parts of the DNA is read according to your age. If you could tune the epigenetics to express a younger age, then the MAO-B levels may follow suite, along with other age related factors. Is there one master system clock, or multiple ones running on different schedules according to different inputs?
According to the “Handbook of Physiology”, chapter 13 “Brain monoamines, homeostasis, and adaptive behavior”:
“ Rather than reflect ing alterations in input with high fidelity, monoam inergic systems resist change and exhibit instead a homeostasis of their own (195). Such synaptic homeo stasis can occur because the rate of amine release is regulated, as is the extent to which they can elicit a postsynaptic response.
Monoamine release is regulated in part through homeostatic control over impulse flow. This is achieved both by short feedback loops, which permit these neurons to regulate themselves (4,67,182, 185), and in some cases by longer, multisynaptic feedback loops involving target cells (29, 127, 181; see also ref. 67). Release is also regulated at the presynaptic ter minal, where released amines can act on the terminal and influence any subsequent release (36,53,152). In addition other humoral signals can act on the terminal to modulate release [Fig. 4; (72, 95, 163)].
Despite these feedback loops, transmitter release does change under certain conditions. However, by adjusting the sensitivity of the postsynaptic cell to its afferent input, the ultimate objective of synaptic ho meostasis still can be maintained. Rapid, reciprocal changes in target cell sensitivity during changes in transmitter availability have been described, espe cially in model systems involving peripheral adreno ceptive cells such as erythrocytes and pineal gland cells (89, 122; see also ref. 180). In the brain the primary focus has been on more long-lasting changes, those that presumably involve alterations in the num ber of available receptor sites. Thus it has been shown that a chronic drug-induced reduction in monoamin ergic activity leads to an increase in receptor density [Fig. 5; (14, 30, 48)]. ”
Time-release 5-htp: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946063.
Negative effects of SSRI's on fetuses: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686152
“ However, multiple negative effects of SSRI treatment during pregnancy have recently been identified, with the limitation that it is often difficult to control for confounding effects of maternal psychopathology. Ultrasonic investigation of human fetuses provides evidence that SSRIs taken during pregnancy alter the brain physiology starting as early as the beginning of second trimester (Mulder et al., 2011). Combined recordings of general motor activity, rapid eye movements, and fetal heart rate variability indicate that fetuses exposed to SSRIs during gestation have abnormal increases in motor movements during phases of non-REM sleep compared to fetuses from drug-free mothers with comparable levels of anxiety and depressive symptoms. Furthermore blood flow recordings at 36 weeks gestation in the middle cerebral artery were significantly decreased in fetuses exposed to SSRIs during gestation (Rurak et al., 2011). At birth, babies prenatally exposed to SSRIs display a wide range of neurobehavioral alterations, including lower APGAR scores, increased irritability, and blunted pain reactivity (Casper et al., 2003; Oberlander et al., 2005), as well as reduced fetal head growth (El Marroun et al., 2012). More recently prenatal antidepressants were shown to shift developmental milestones on infant speech perception tasks in utero and at 6 and 10 month of age (Weikum et al., 2012), suggesting a role for 5-HT in modulating critical time period maturation in humans. At later time-points, children exposed to SSRIs during pregnancy display increased internalizing behaviors (Oberlander et al., 2010) and decreased scores on psychomotor developmental scales (Casper et al., 2011). The most worrisome finding comes from a recent study reporting a two-fold increase in the risk for autism-spectrum disorders in children exposed to SSRIs during pregnancy (Croen et al., 2011). ”
“ The results suggest that the reduced peripheral monoamine function, associated with cholesterol, is a characteristic feature of personality disorders. ”