Link to depression and brain changes — Part 2

Neurotransmitters in adult neurogenesis

Several neurotransmitter systems may regulate adult CNS neurogenesis. Monoamine neurotransmitters are known to influence multiple aspects of neural development, including precursor proliferation, cell survival, axonal growth and synapse formation (29). The neurotransmitter systems covered here encompass the ‘traditional’ neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate, and neuromodulatory transmitters or neuromodulators such as dopamine, serotonin, and acetylcholine that are secreted by a small group of neurons and can affect neuronal activity through large brain areas. It is often suggested that the delayed therapeutic response for antidepressants could be due to their effects on neurogenesis. Such as, although SSRIs increase serotonin levels hours after drug administration if their administration leads to beneficial impacts, it usually takes 2–4 weeks of daily administration for those effects to appear. One would assume that if serotonin levels were causally linked to depression, then soon after serotonin levels increased, the mood would begin to improve much more rapidly. (30)

neurotransmitters and neurogenesis

GABA & Glutamate

Glutamate is the primary excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex. Changes in glutamate and GABA metabolism may play essential roles in the control of cortical excitability (31). Growing evidence suggests that the neurotransmitters GABA and glutamate have a significant role in setting the timing for survival, proliferation, migration, synapse formation and integration of newly formed neurons in established synaptic networks (32).

“Even modest chronic deficits in GABAergic transmission in GABAAR γ2+/− mice impair the survival of adult-born hippocampal neurons, an effect that may explain hippocampal volume reductions were seen in chronically depressed patients”(33)

“Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression….Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be undermined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system).”(34)

“…an excitotoxic concentration of glutamate, which killed between 60–80% of granule cell neurons on day 8 in vitro, mediated its toxic effect via a time-dependent apoptotic pathway.”(35)


Dopamine controls multiple physiological functions in the brain and periphery by acting on its receptors D1, D2, D3, D4, and D5. Dopamine receptors are G protein-coupled receptors (also called seven-transmembrane receptors) involved in the regulation of motor activity and several neurological disorders such as Parkinson’s disease (PD), schizophrenia, bipolar disorder, Alzheimer’s disease, and attention-deficit/hyperactivity disorder (ADHD). Reduced dopamine content in the nigrostriatal pathway is associated with the development of PD, along with the degeneration of dopaminergic neurons in the substantia nigra region.

“Dopamine receptors are widely expressed in the hippocampal dentate gyrus and SVZ [subventricular zone] region and are actively involved in the modulation of neurogenesis in basal forebrain structures, thereby supporting the hypothesis that dopamine plays a role in neurogenesis and brain plasticity.”(36)

“On top of its role in motor control, mood and as a neurotransmitter, dopamine also plays a vital role in neuronal proliferation and differentiation in the adult CNS. The dopaminergic projections directly innervate the SVZ and hippocampus, thus directly influencing the microenvironment of these niches to regulate neural stem cells dynamics…suggested that chronic treatment with the D2-like antagonist, haloperidol, in adult rats led to an increase in the number of primary neurospheres obtained from the SVZ.”(37)

“Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation [loss of nerve supply].”(38)

Serotonin & Norepinephrine 

Serotonin or 5-hydroxytryptamine (5-HT) has a popular image as a contributor to feelings of well-being and happiness, though its actual biological function is complex and multifaceted, modulating cognition, reward, learning, memory, and numerous physiological processes such as gut function. In the human body, the majority of serotonin is made, stored, and released by cells in the gut lining. These cells make serotonin from the amino acid L-tryptophan. Norepinephrine (NE) also called Noradrenaline (NA), or Noradrenaline, is a neurotransmitter that functions in the human brain and body as both a hormone and neurotransmitter. In the brain, norepinephrine increases alertness and arousal, promotes vigilance, enhances the formation and retrieval of memory, and focuses attention. In the other parts of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, inhibits urination and slows the gut flow.

serotonin and norepinephrine

“Lesion of the 5-HT system is reported to decrease neurogenesis (Brezun and Daszula 2000), and preliminary studies demonstrate that administration of fenfluramine, which causes the release of 5-HT, increases adult neurogenesis in the hippocampus (Jacobs et al. 1998). In contrast, administration of a 5-HT1A antagonist, WAY 100,635, blocks fenfluramine-induction of neurogenesis, as well as the basal rate of neurogenesis in the absence of fenfluramine (Jacobs et al. 1998). These studies suggest that regulation of the 5-HT system and 5-HT1A receptors could contribute to the induction of adult neurogenesis by antidepressants, at least the effect of a 5-HT selective reuptake inhibitor.” (39)

“These results show that the effects of fluoxetine on LTP [long-term potentiation ] and behaviour both require neurogenesis and follow a similar delayed time course. The effects of chronic fluoxetine on the maturation and functional properties of young neurons may, therefore, be necessary for its anxiolytic/antidepressant activity and contribute to its delayed onset of therapeutic efficacy.”(40)

“Likewise, the lack of lesion effects upon progenitor survival or differentiation reported by Kulkarni et al. (2002), three weeks after BrdU [5-Bromo-2′-deoxyuridine (5-BrdU) is a thymidine analogue which is incorporated into DNA. 5-BrdU is routinely and extensively used to measure DNA synthesis and to label dividing cells. Consequently, 5-BrdU is used to study cell signalling and other processes that induce cell proliferation. Labelling was consistent with that detected here over a similar period. Thus, a noradrenergic control is likely to be exerted upon cellular and molecular factors that either directly or indirectly influence SGZ [subgranular zone ] progenitor proliferation, but not upon those influencing progenitor survival or differentiation.”(41)

“The dentate gyrus granule cell layer, whose neurons are generated following monoamine innervation, exhibited a 16.2% decrease in absolute neuron number. Thus in the absence of En2, developmental deficits in forebrain growth occur that correlate with reductions in norepinephrine levels and innervation.”(29)


Acetylcholine, Ach, is an ester of choline and acetic acid and is the most widely spread neurotransmitter. It is also the most plentiful neurotransmitter, which may be found in both the peripheral and central nervous systems. It was discovered by Henry Hallett Dale in the year 1914, and its existence was later confirmed by Otto Loewi. Acetylcholine works in various brain regions, for instance, basal ganglia, cortex, and hypothalamus and is required for memory and cognition, as well as motor control. The action of acetylcholine released at a synapse is ended through the breakdown of ACh by the enzyme acetylcholinesterase. (42)

“The cholinergic system also seems likely to regulate hippocampal neurogenesis in the adult brain, positively promoting proliferation, differentiation, integration and potentially survival of newborn neurons.”(43)

“We find that changes of forebrain ACh level primarily influenced the proliferation and/or the short-term survival as opposed to the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggests that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.”(44)

Putting it all together

Now that we’ve established some of the factors involved in neurogenesis, it’s time to examine how we can leverage these inputs to optimise for neurogenesis and mitigate some of the assumed damage that is incurred due to long term stress and depression. To keep this post at readable length (already much longer than I expected) I won’t go into great depth on each item, but I’ll add plenty of references in that you can follow up yourself.

Optimising hormones for neurogenesis

The best way to begin optimising your hormones will be getting a full hormone blood panel performed. Dr Mark Gordon from who specialises in treating traumatic brain injury via hormone modulation recommends getting these tested first;

Once you’ve had these tests done, you can start working with your primary care doctor (or an endocrinologist) to begin to address any irregularities. Some options could be; Testosterone replacement therapy (TRT)/Hormone replacement therapy (HRT), Clomiphene monotherapy, human chorionic gonadotropin (HCG), supplementing with; pregnenolone, DHEA, IGF-1, natural desiccated thyroid etc. It’s essential you work with a doctor due to the many feedback loops involved.

Optimising neurotrophic growth factors for neurogenesis

* Lion’s Mane Hericium erinaceus (45), (46), (47)
* PQQ Pyrroloquinoline quinone (48), (49)
* Noopept (50), (51), (52)
* Exercise (53), (54)
* Lithium (55), (56), (57)
* Curcumin (58), (59), (60)
* Semax** (61), (62)
* NSI-189** (63)
* NSI-189** (63)
* Selegiline* (64), (65), (66)
* Vitamin D (67), (68)
* Luteolin (69), (70 confounded by use of PEA as well and possible conflicts of interest)

(* = Prescription)
(**= Usually classed as a research chemical, as such long-term safety profile is undetermined)

Reducing neural inflammation
* Resveratrol (71), (72), (73)
* PEA N-Palmitoylethanolamine (74), (75), (76)
* CBD (77), (78), (79)
* Curcumin (80), (81)

Optimising neurotransmitter neurogenesis

Increasing neurotransmitters is the most common method for treating depression. It’s outside the scope of this article to go into detail on the variety of drugs that are used in this capacity. As such, I’ve limited this to a few over the counter methods, which are usually well tolerated and widely used as nootropics. If you want to do further research into prescription methods of modulation, I personally like these resources:

* Ashwagandha (82), (83)
* Lemon Balm (84), (85)
* NAC N-acetyl cysteine (86), (87)
* Sarcosine (88), (89)
* BPC157** (90), (91)
* SAM-e (92), (93)
* Rhodiola Rosea (94)
* Bacopa (95), (96)
* Rhodiola Rosea (97)
* Alpha GPC (98), (99)
* ALCAR (100), (101)

Concluding remarks

To conclude this quite lengthy post, it appears that depression, particularly long bouts, can induce brain changes that may increase susceptibility to future mood disturbances. It may also be a case of the chicken and the egg where reduced growth factors produce a depressed state. I’d like to end on a note of caution though that the study of human neurogenesis is still in its infancy, let alone conclusively linking it to depression or influencing it. However, it’s an exciting new avenue of research, and many (if not all) of the methods mentioned also have corresponding research showing improvements in depressing in other studies whether that effect is achieved via neurogenesis or not.


I’m not a doctor etc. no medical body or the like has evaluated this information. Information is shared for educational purposes only and acquired through studying for myself. You should consult your primary care doctor before acting on any content, especially if you are taking medication, or have a medical condition/s.

Please let me know in the comments if you have any idea’s or suggestions on this post. Also, if you’ve found this post useful please consider sharing it and/or subscribing. I also have a twitter page where I share studies or posts I’ve found interesting on mental health issues.


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92. Sharma A, Gerbarg P, Bottiglieri T, Massoumi L, Carpenter LL, Lavretsky H, et al. S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry. 2017 Jun;78(6):e656.

93. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. — PubMed — NCBI [Internet]. [cited 2019 Mar 21]. Available from:

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Link to depression and brain changes — Part 1

This post is a bit of a long one, so I’m breaking into two sections for readability. Firstly, I’ll discuss how depression affects the brain and how long-term depression I believe it can make it harder to get out of depressive cycles. I mention this not to be a downer and pessimistic; instead, for me knowing this has made it possible to go easier on myself and become somewhat less frustrated through slow/lack of progress. Change takes time along with effort. Secondly, we’ll go into what influences these changes and how we can attempt to take advantage of these mechanisms to benefit us.

“Nothing in the world is worth having or doing unless it means effort, pain and difficulty… I have never in my life envied a human being who led an easy life. I have envied a great many people who led difficult lives and led them well.” 
― Theodore Roosevelt

Although the research is in its initial days (although the connection between hippocampal volume and depression has been reported for over 20 years), there’s a growing amount of data pointing to structural changes in the brain due to depression and other mood disorders. “One fMRI study published in The Journal of Neuroscience studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% [some studies indicate up to a 20% loss] smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus.”(1). The hippocampus is an area of the brain responsible for processing long-term memory and recollection. It’s a part of the brain which registers fear from a given situation, the memory of which may affect how you relate and respond to that situation again. How does this occur? Possibly due to long-term stress. Firstly, stress can cause retraction of dendritic processes (a branching extension from the neurone cell body that receives information from other neurones. See figure below.)

in hippocampal neurons. A second adverse effect of stress is the inhibition of neurogenesis in the adult hippocampus. Finally, in some studies, sustained stress can cause loss of preexisting hippocampal neurons (i.e., neurotoxicity)(2)

The amygdala seems to be a bit more tricky when it comes to correlating volume loss and depression. The amygdala, crucial to perception and where emotional memories are retained, is often more active in depressive illness and post-traumatic stress disorder (PTSD). Repeated stressors may enlarge the amygdala. An overactive amygdala, coupled with atypical activity in other brain regions, leads to disturbed patterns of physical activity and sleep. It can also induce abnormal secretion of hormones and other chemicals that affect many systems of the body. A 2008 meta-analysis of magnetic imaging resonance studies wrote:

“Stress-induced glucocorticoid excitotoxicity, which has been postulated to underlie hippocampal atrophy in psychiatric illness, stands as a potential moderator of amygdala volume loss in depression. This is a possible hypothesis given that the amygdala, like the hippocampus, is dense with glucocorticoid receptors. However, if cumulative effects of glucocorticoid exposure are responsible for the volumetric reduction of the amygdala during depression, then we would also predict a negative correlation between amygdala volume and recurrence or level of chronicity of depression, which has been shown in studies of hippocampal volume and depression.”(3)

What was interesting in this particular analysis was that they found unmedicated depressed people showed a reduction in amygdala volume, however, medicated people showed an increase in size. 


Drevets et al. using positron emission tomography (PET) imaging reported an increase in amygdala activation and metabolism in depressed patients. The fact that more significant amygdala activity was often observed after negative stimuli would explain the increased ability for depressed people to encode and remember negative rather than positive information, therefore contributing to the negative bias often seen in depressed patients. So the relationship between amygdala size and depression doesn’t seem to be fully elucidated yet. 

The prefrontal cortex (PFC), an essential structure in emotional regulation, decision-making and memory, may also shrink with depression. The prefrontal cortex is connected with several brain structures, for processing sensory input and mediating executive motor functions. The ventromedial PFC, located in the frontal lobe and the orbitofrontal cortex, located above the eyes, is involved in the cognitive processing of emotional stimuli originating from the limbic system (e.g., amygdala, ventral striatum, hippocampus, and hypothalamus) and is chiefly engaged in memory consolidation and retrieval. As such, the PFC plays a significant role in regulating appropriate emotional responses, including mood, fear or anxiety. Furthermore, the PFC has been associated with decision-making, personality expression and social behaviour. Neuroimaging studies showed a reduction in the size of multiple areas of the PFC in subjects diagnosed with depression. In line with these studies, post-mortem brain analysis of depressed patients affirmed reduced neural cell size and neural and glial cell densities as well as synapse number in both the dorsolateral and subgenual PFC (4).

Psychology Today summed up these new findings saying; 

“[The] evidence is increasingly pointing to the possibility that in addition to being a biological disorder with immediate implications, over time depression may also alter the brain in ways requiring different forms of treatment…”(5).

So what do we do with all this information and how does it help us with treatment?

Adult Neurogenesis


Adult neurogenesis was first proposed in the 1960s; however, it wasn’t until the 1990s that the theory became widely accepted and that neurogenesis could play a substantial role in brain function. Although the functional significance of adult neurogenesis in humans — due to the difficulty in studying observing it, remains to be established, increasing evidence has implicated compromised neurogenesis as a possible contributor in the development of mental illnesses; one of which being major depressive disorder (MDD). Neurogenesis has been shown to occur in the hippocampi of adult humans, and more recently it has been accepted to occur in the amygdala, both of which we’ve established could become altered due to long-term depression.

The neurogenic niche, which is characterised by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid is a specialised microenvironment that has a significant role in maintaining and regulating neural stem cells (NSC) proliferation. Neural stem cells in the adult brain continuously supply new neurons to the hippocampal dentate gyrus(6). The dentate gyrus (DG) are thought to contribute to the formation of new episodic memories, the impromptu exploration of new environments, and other functions. Many intrinsic factors, such as hormones, trophic factors, glia (non-neuronal cells), and vasculature (the vascular system of a part of the body), contribute to the neurogenic niche.

Hormones and neurogenesis

Hormones are signalling factors of the neuroendocrine system with essential functions in regulating human physiology and behaviour. The hippocampus shows a high degree of plasticity when exposed to gonadal hormones and stress hormones. The hippocampus regulates the hypothalamic-pituitary-adrenal (HPA) axis through a negative feedback mechanism via mineralocorticoid (MR) and glucocorticoid (GR) receptors, both of which are expressed highly in the DG. Interestingly, newly-generated neurons in the DG may be particularly crucial in the HPA negative-feedback mechanism. Depressed patients show abnormal HPA function such as abnormal day secretion of cortisol, which results in an abnormal circadian rhythm, and the hypersecretion of cortisol. There may also be a significant difference in how hormones act in females and males. For example, peak levels of ovarian hormones during cycle is correlated with increased levels of proliferation; conversely, it has been noted in some animals less testosterone is associated with a reduction of new neurons. Given the dysregulation of HPA negative-feedback in depression, normalising the HPA axis is one of the leading targets of recent psychiatric interventions.

“The removal of testicular hormones through castration increases HPA activity in males, whereas testosterone replacement reverses this effect, acting to reduce corticosteroid levels. Conversely, ovariectomy results in decreased HPA activity, whereas oestradiol replacement reverses this effect through the enhancement of corticosteroid output in females…These findings suggest a causal relationship between gonadal hormones and HPA output, albeit in different directions in males and females. Given the apparent roles of testosterone and oestradiol in reducing and enhancing glucocorticoid release, respectively, both hormones have been implicated in depression and antidepressant treatment.”(7).

“To contrast estrogen, the depletion of androgens by castration in adult male rats didn’t impact proliferation in the hippocampus but reduced the survival rate of new neurons…However, androgen-receptors are absent from the dentate gyrus, which suggests that testosterone effects on new neuron survival may have indirect mechanisms.”(8)

“The chronic administration of corticosterone…reduced cell proliferation and the density of immature neurons in the adult hippocampus in both male and female rats. Furthermore, the depletion of glucocorticoids, through the removal of the adrenal gland, resulted in an increase in adult hippocampal neurogenesis and removed stress-induced suppression of cell proliferation in the hippocampus.”(8)

Neurotrophic growth factors

Endogenous neurotrophic growth factors, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived nerve factor (GDNF), vascular endothelial growth factor (VEGF) and insulin-like growth factor-one (IGF-1), have integral roles in stimulating neural stem cells proliferation, differentiation and central nervous system development. While it’s been established neurotrophic factors maintain the survival and function of cholinergic and dopaminergic neurons(9), there are emerging roles for neurotrophic factors, such as BDNF and NGF, in maintaining neurogenesis in the adult brain.


Nerve Growth Factor, NGF

Rita Levi-Montalcini discovered Nerve Growth Factor in the 1940s and pioneered the field of growth factor research. She identified NGF as a substance secreted from mouse sarcoma (cancerous, malignant tumours of the connective tissues) tissue that stimulated neuronal survival and neurite outgrowth from chicken ganglia (nerve clusters). This provided some of the first evidence of paracrine signalling, whereby cells in one tissue secreted a protein which readily diffused to another tissue to elicit cellular changes in the target tissue. NGF has been shown to promote the survival and differentiation of neurons, an outgrowth of neurites. NGF appears to play a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis-mediated stress response. The non-neural activity of NGF has also gained significant attention in recent years, and NGF has been shown to have roles in the development of the male and female reproductive systems, the endocrine, cardiovascular and immune systems(10).

“NGF levels were significantly reduced in depressed patients (p = 0.002) as compared with healthy elderly controls. Elderly control subjects [n=77] with previous depressive episode also showed a significant reduction in NGF levels as compared with controls (p <0.01); NGF levels were similar between patients with a current depressive episode and previous depressive episode (p = 0.2).”(11)

“Our study [n=40] showed a significant reduction in hippocampal NGF and [Tropomyosin receptor kinase A] TrkA and [messenger RNA] mRNA expression among the individuals who died by suicide compared to normal controls agree with the observations of Dwivedi et al.18 The results of the present study indicate significant insufficient brain neurotrophin environments in suicide victims, strengthening the role of neurotrophins in the pathophysiology of suicide.” 

However, additional nerve growth factor isn’t always a good thing, unfortunately. Because NGF increases the growth of neurons, it can contribute to more pain, exacerbating arthritis, psoriasis, and chronic injuries.

In some reports, NGF can increase the spread and life of some tumour cells as well. Unfortunately, NGF has a hard time picking which cells to maintain and protect versus the ones that it should not. In the case of some tumours, nerve growth factor helps increase the health of malignant cells.

Generally, NGF has a protective effect though, at times, it should be approached with caution(12).

Brain-derived neurotrophic factor, BDNF

BDNF is a neurotrophin involved in the production, differentiation, and survival of neurons and has also been shown to represent a vital factor in the regulation of neurogenesis and synaptic plasticity. It exerts its neurotrophic effects by stimulating the tropomyosin-related kinase receptor B (TrkB). An in-depth meta-analysis by Molendijk et al. showed that, despite study heterogeneity, serum BDNF levels are overall lowered in patients with depression(13). Also, a reduction in BDNF and TrkB expression in the hippocampus and prefrontal cortex has been reported in post-mortem brain examinations of teenagers who committed suicide [n=29](14).

“Studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect.”(15)

“Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants.”(16)

“There is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression.”(17)


Glial cell line-derived neurotrophic factor, GDNF

HAMD = Hamilton depression rating scale also referred to as HDRS. Source:

GDNF was first discovered in a glial cell line but is expressed in many parts of the brain. It is a member of the transforming growth factor β (TGF-β) superfamily and is essential for neuronal survival, especially for dopaminergic and serotonergic neurons. Thus far, the exact involvement of GDNF in the biology of depression is not entirely understood, but its neuroprotective ability might make it an attractive future target for antidepressant treatment.

“Patients [n=34] with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 [Hamilton Depression Rating Scale] scores (r = -0.343, p = 0.003).”(18)

“Serum GDNF was significantly lower in MDD patients [n=76] before treatment than in control subjects. From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant. The present study suggests that lowered serum GDNF might be involved in the pathophysiology of MDD, and antidepressant treatment increases the GDNF in MDD.”(19)

Vascular endothelial growth factor, VEGF

VEGF concentrations in suicide attempters vs healthy controls (n=63), measured with an MSD immunoassay. Horizontal lines indicate mean concentrations and standard error of mean (SEM). Here VEGF levels are significantly decreased compared to the controls. Source:

VEGF is primarily known for its induction of angiogenesis (the process through which new blood vessels form from pre-existing vessels) and modulation of vascular permeability during embryogenesis and growth, as well as pathological events such as in tumorigenesis. “Chronic stress in rats decreased the expression of VEGF and its receptor in the hippocampus (Heine et al. 2005). Further, VEGF is required for the proliferation of neural stem-like cells in the hippocampus following [electroconvulsive treatment] ECT.”(4). Along with this VEGF is involved in increased learning, neuroprotective in cases of hypoxia, and it also has been shown to increase expression of other neurotrophic growth factors. However, current research seems to be mixed with many studies showing increased expression of VEGF in depressed patients. The hypothesis then contrasts this that some anti-depressants may elicit their clinical benefits via an increase in VEGF.

“Fourteen studies met our eligibility criteria [n=1633]. VEGF was significantly elevated in individuals with MDD when compared to healthy controls. Funnel plot inspection and the Egger’s test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, a sample for the assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender, emerged as significant sources of heterogeneity…Taken together, existing data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.”(20)

“Antidepressant drugs were shown to induce hippocampal expression of VEGF. Also, the experiments in animals models of depression have demonstrated that VEGFR2 signalling is indispensable for the cellular and behavioural response to antidepressant drugs.”(21)

“VEGF levels were increased in the plasma or serum of depressed patients versus controls in eight studies…On the other hand, two studies demonstrated decreased plasma or serum VEGF levels in depressed patients compared to healthy individuals. No significant difference in VEGF levels between cases and controls were reported in three studies”(22)

Insulin-like growth factor, IGF-1

IGF-1 and its receptor IGF-1R are produced in the liver but are found in many tissues, including the brain and influences growth and differentiation processes. IGF-1 has been proposed as a potential therapeutic target for neurodegenerative diseases such as MDD (23). Various effects have been attributed to IGF-1 in terms of its role in neural signalling, neurotrophic mechanisms, and neuroprotection in pro-neuroinflammatory conditions. Intranasal administration has been proposed to provide a shorter path for IGF-1 to enter the brain, avoiding unwanted effects of IGF-1 in peripheral tissues. As with VEGF, the association between IGF and depression appears to be a complex one, where more or less, isn’t always better.

“The results from both the cross-sectional and longitudinal analyses revealed a ‘U’-shaped [n=6017 mean age 65] pattern of association, such that lower and higher levels of IGF-1 were associated with a slightly elevated risk of depression, whereas the lowest risk was seen around the median levels.”(24)

“Most data are very consistent and show that IGF-1 treatment exerts antidepressant like-activity by normalization of behavioural disturbances in various animal models of depression…Furthermore, the antidepressant-like effects of IGF-1 were often associated with an increase in cell proliferation in the hippocampus.”(23)

Neuroinflammation and adult neurogenesis


Neuroinflammation is comprised of biochemical and cellular responses of the nervous system to infection, neurodegenerative diseases and injury. These responses are directed at alleviating the triggering factors by involving the central nervous system (CNS) immunity to defend against potential harm. Responses are complex and include the activation of glia, release of inflammatory mediators; such as cytokines (small proteins) including chemokines, and generation of reactive oxygen and nitrogen species. The innate immune response of the CNS can be both protective and toxic; abnormal microglial activation, mitochondrial dysfunction, and protein aggregation can trigger an acute inflammatory response that, if unresolved, becomes chronic and damaging (25,26). Interestingly, the impact of pro-inflammatory cytokines on neurogenesis is not confined to proliferation, cell death, and neuronal differentiation, but may also be double-edged by impacting the integration of newly generated neurons in the adult brain. At present, the effect of neuroinflammation on neurogenesis remains controversial; however, based on studies in neurodegenerative disorders, it appears that in general, chronic neuroinflammation negatively regulates neurogenesis(25).

“These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of the biological mechanisms underlying depression induced by neuroinflammation.”(27)

“Iptakalim (Ipt), an ATP-sensitive potassium (K-ATP) channel opener that can cross the blood-brain barrier freely, has been demonstrated to inhibit neuroinflammation and enhance adult hippocampal neurogenesis….treatment with Ipt (10 mg/kg/day, i.p [intraperitoneal injection]) for 4 weeks restored the decrease of sucrose preference and shortened the immobile time in forced swimming tests and tail suspension tests in mice. Further, we found that Ipt reversed the induced reduction of the adult hippocampal neurogenesis and improved cerebral insulin signalling in the CMS mice. Furthermore, Ipt negatively regulated nod-like receptor protein 3 (NLRP3) expression and, in turn, inhibited microglia-mediated neuroinflammation by suppressing the activation of the NLRP3-inflammasome/caspase-1/interleukin 1β axis in the hippocampus of CMS mice.”(28)

“…mounting evidence suggests that neuroinflammation affects both embryonic and adult neurogenesis, contributing to the pathogenesis of numerous neurodevelopmental, neuropsychiatric, and neurological disorders.”(25)

This concludes part one, and part two will deal with neurotransmitters, turning all this into actionable information and the full list of references.


I’m not a doctor etc. no medical body or the like has evaluated this information. Information is shared for educational purposes only and acquired through studying for myself. You should consult your primary care doctor before acting on any content, especially if you are taking medication, or have a medical condition/s.

Please let me know in the comments if you have any idea’s or suggestions on this post. Also, if you’ve found this post useful please consider sharing it and/or subscribing. I also have a twitter page where I share studies or posts I’ve found interesting on mental health issues.

My 3-month plan to overcome anxiety  – Part 2

Link to part 1 here


Exercise has never been much of an issue for me, it’s always been a natural part of my life and has always been a supportive habit during many difficult times. As such, I thought I’d include it in the routine as a reminder of the importance of exercise and mental health. As this post is centred around anxiety, I won’t go into the depression benefits (although I’d definitely suggest looking into the connection between exercise and depression if you’re currently battling depression too), but it also seems to have a link with reducing symptoms of anxiety.

Just one bout of moderate intensity exercise, 30 minutes of brisk walking outside found:

“…a significant decrease in self-reported trait anxiety measures when participants [n=36] underwent a single session walking exercise protocol.”

(Clarke et al. 2018)

Furthermore, Ensari et al., 2015, conducted a meta-analysis which included 36 randomised controlled trials. They concluded:

“The cumulative evidence from high-quality studies [n=1233] indicates that acute bouts of exercise can yield a small [yet still statistically significant] reduction in state anxiety.”

(Ensari et al. 2015)

Over the long-term research has shown that regular physical activity and a higher level of cardiovascular health reduces reactivity to stress, and thus a lower overall level’s of anxiety in life. A 2018 systematic review concluded:

“About half of the studies suggested that higher physical activity/fitness levels were associated with an attenuated response to psychosocial stress.”(Mücke et al. 2018). Further “exercise can reduce symptoms of anxiety and stress-related disorders, such as post-traumatic stress disorder, agoraphobia and panic disorder.”

(Kandola A 2015)

It should be noted that currently, it is unclear what the optimal protocol is to elicit an anxiolytic effect. My suggestion would be to do the exercise you enjoy; walking, weights, sport etc. this will boost your adherence and compliance to your routine. As opposed to just committing to running ‘X’ miles a day just to try to induce this response.

I’ve added a couple of templates to give you some ideas on possible routines that I would recommend;



Meditation (derived from the Latin meditari, meaning to concentrate) involves focusing your mind on a certain object, thought or activity, to achieve clarity and an emotionally calmer state. Meditation has been practised throughout history, mainly in a religious context, however, since the 19th century has spread across cultures. And beginning in the 1970s has moved more into the mainstream. Meditation practice offers; reducing stress, anxiety, depression, and pain, increasing peace, perception, and well-being. Meditation is currently being researched heavily to better define its health (psychological, neurological, and cardiovascular) benefits.


There are many many types of meditation; transcendental, zen, loving kindness etc. however, the one I want to focus on most is referred to as ‘mindfulness’. A systematic review published in the Journal of the American Medical Association assessed the results of 47 randomised clinical trials (RCT’s) involving a total of 3,515 participants and concluded:

“..mindfulness meditation programs, in particular, show improvements in anxiety, depression, and pain.”

(Goyal M 2014)

Mindfulness, to me, also seems a lot easier to learn and has multiple popular apps that can assist in this. Mindfulness has been characterised as “paying attention in a particular way: purposefully, in the moment, and non-judgmentally.” This is in contrast to traditional cognitive behavioural therapy (CBT) in which negative thoughts are targeted and challenged, the objective of mindfulness is to help people learn, and at times, to become aware of thoughts, feelings and bodily sensations rather than trying to contend with and attempt to modify them.

Evidence of the effects of mindfulness meditation has been studied at length, PubMed shows over 1000 different results, even the US Marines are using mindfulness to decrease stress. Meditation seems to work in multiple ways to improve the practitioners’ mood. One way meditation appears to work is by adjusting the balance of many essential neurotransmitters in the brain; GABA, serotonin, norepinephrine and dopamine. One hour of meditation involving 35 people was shown to produce a 27% increase in GABA and a significant increase in serotonin (meditators also showed a higher resting concentration of serotonin)(Guglietti 2012). Both low levels of serotonin and GABA levels have been linked to mood disorders, which is why we have whole classes of drugs dedicated to their modulation. A 2005 study (n=19) observed that meditation:

“..reduces sympathetic activation [as measured by a reduction of blood norepinephrine concentrations] and improves the quality of life in elderly patients with optimally treated heart failure.”

(Curiati et al., 2005)

A study from Denmark demonstrated a meditative state produced a 65% increase in endogenous dopamine levels. (Kjaer TW 2018). Low dopamine levels have been linked to increased occurrence of social phobia.

Additionally, research is pointing towards structural changes in the brain

“Meditative experiences and mindfulness are rooted not only in psychology but in neuroscience and neurobiology as well. They can be detected at the level of the brain in the area of functional, but also structural changes in grey and white matter, especially in those areas and networks associated with attention and memory, introspection, and sensory processing as well as with self and auto-regulation.”

(Esch 2013)

Hopefully, this can aid in a long-term sustained reduction in anxious thoughts and mannerisms, undoing the result chronic stress has over a lifetime, which has been proven to lead to degenerations in parts of the prefrontal cortex (PFC). This leads to among things, a decreased ability to regulate one’s emotions, and to a deterioration in executive functions and a reduced performance of the working memory in the dorsolateral PFC. As mentioned earlier, there may also be degeneracy in the hippocampus, which is incredibly stress-sensitive, while the amygdala may gain in size, with presumed long-term effects such as raised anxiety, resulting in conditions such as generalised anxiety disorder (GAD).


After doing some researching and testing out a couple of options for apps to assist in learning mindfulness, I’ve found a few options people might want to look at.

Paid options:
Headspace — is probably the most popular mediation app. The app mainly focuses on mindfulness and has some great little animations to demonstrate some of the points that are raised
10% Happier — Made by NY Times bestselling author it features many of the most well-known meditators in the world. The best bit about this app is variety, there are different methods of meditation and you can usually find someone you like on there.

Oak — offers a few different styles of meditation and breathing techniques. Nice simple and easy to use. 
Smiling Mind — Smiling Mind is a 100% not-for-profit organisation that works to make mindfulness meditation accessible to all. Their stated vision is to help every mind thrive. With a mission is to provide affordable, lifelong tools to support healthy minds.

Navy SEAL exercise to reduce stress (this technique is also now on Oak)
During my reading on mindfulness, I found a useful breathing exercise the SEALs use to prime themselves and quell stress and anxiety, I thought I’d share too. It’s called ‘box breaths’ or ‘4×4’ and is a simple breathing technique adapted from yoga.

1. Breathe in for 4 seconds

2. Hold for 4 seconds

3. Breathe out for 4 seconds

4. Wait 4 seconds

5. Repeat

When anxiety and panic begin to creep up, it may be useful using this technique and to follow best selling author Tim Ferriss’ advice and “stop everything and take 3 mindful breaths.”


Lastly, I just want to include a few books which I recommended checking out to help with anxiety, overall mood, and just dealing with adversity.

I’ve found these books all very interesting, in particular, the two stoic texts resonated with me on many levels. 


So that concludes the details of my plan to address long-term anxiety. TL;DR: I’m going to try various supplements and leverage exercise, meditation and reading to reduce my anxiety. If people find this useful let me know in the comments and maybe I’ll come back and add in my experiences/effects or create some journal posts. Hopefully, there’s some information in here that’s helpful, it was definitely informative researching and writing this, I’ve learnt a lot about anxiety and discovered that there’s a lot of treatment options out there extending beyond the usual SSRI’s and CBT. I encourage anyone who’s managed to read all this to explore the research further. My favourite resources to start with are PubMed and Google Scholar then using sci-hub to beat paywalls. Also, the sub-reddits r/depressionregimes and r/nootropics are some excellent places to ask questions and hear some anecdotal experiences.

Best of luck on everyone’s journeys.

If you’ve found this post useful please consider sharing it and/or subscribing to my where I share studies I’ve found interesting on mental health issues. 


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My 3-month plan to overcome anxiety  – Part 1

Link to part 2 here


I’ve struggled with mental illness all my life and a big part of that has been anxiety. One of my earliest memories is separation anxiety as a small child, and it’s been a constant presence in my life ever since. This has affected huge parts of my life, leading me to miss out on many valuable experiences, such as travelling overseas with friends, taking on challenging roles at work etc. During my adolescent years, due to recurring panic attacks, I got so bad I ended up being confined to my house for over 6 months. Although I’ve improved significantly since then (at least I can go outside now), it’s often a daily struggle to do many of the things others consider ‘normal’, going to busy places, parties, even talking on the phone can be a challenge. As such, I’ve decided to put in place a plan to try to overcome some of this during the next 3 months. Which I thought I’d share in the hopes it helps someone else.

When I say ‘overcome it’, I want to be clear I don’t plan on, or seek to eliminate anxiety; that would be unrealistic. Fear has its place, it stops us from doing stupid shit and often protects us. But when it becomes a controlling factor in one’s life, that’s when it has become an issue. 

That’s where this project comes in. I plan to attack my anxiety on many fronts;

  1. Diet 
  2. Supplements
  3. Exercise
  4. Meditation 
  5. ‘Other’ strategies, i.e. philosophical reading etc.

By dealing with anxiety on many fronts, I hope to ensure a measurable change. Although unfortunately, this isn’t the most scientific method, adding so many variables in all at once, the main point for me is the result — less anxiety. As opposed to evaluating how much each effort affected the overall goal. What effort contributed most can be figured out down the road. 

I want to premise this that I’ll have the support of both a psychiatrist and a psychologist along the way. Both of which I’ve been working with for a long time. This will take care of the prescribed medication along with talk therapy methods; cognitive behavioural therapy (CBT) and Acceptance and Commitment Therapy (ACT). This should be where everyone starts in my opinion (after seeing your primary care doctor) who is suffering from any sort of mental illness.

Please note, I’m not a doctor and information provided is for informational purposes only and is not meant to substitute for the advice provided by your own physician or other medical professionals.

Hopefully, someone reading this will be able to gain some sort of benefit from my experience and this process.


I think undertaking any sort of effort like this you need to set clear goals to define your success; otherwise, it’s easy to forget how far you’ve come and can feel like you’ve barely achieved anything if progress slows. This is especially true with something like anxiety, which can always be changing and evolving. I know for myself during the heightened emotions of an anxious state, reality can become a bit warped, and we can end up disregarding our progress so far. So that’s the first step for me — define clear goals.

SMART Goals 

Many of you will have probably heard of SMART goals, corporate places love to talk about these, but I think they’re a highly useful way to set clear and concise goals. 

“SMART is an effective tool that provides the clarity, focus and motivation you need to achieve your goals. It can also improve your ability to reach them by encouraging you to define your objectives and set a completion date. SMART goals are also easy to use by anyone, anywhere, without the need for specialist tools or training.”

(, 2017)

SMART stands for;
Specific — your goal should be clear, coherent and precise this way you’ll be able to focus your efforts and to feel motivated to achieve it.
Measurable — You need to have quantifiable goals, tracking your progress will help you stay motivated and stay on track. 
Achievable — there’s no point setting goals which are impossible. You should stretch yourself, but still, remain in the realm of what’s possible. 
Relevant — make sure your goals are relevant to you, this again will help you stay motivated and keep you accountable. 
Time-bound — set a timeframe that you want to achieve your defined objectives. This part of the SMART goal framework assists in preventing everyday tasks from taking priority over your long-term goals. Make this challenging but again within the realm of possibility.

So what do mine look like? 
Specific- I want to reduce my anxiety to the point I can do things that other people find normal, fun and natural. In this case, specifically regularly going to BJJ classes.
Measurable- Going to BJJ classes twice per week.
Achievable- Definitely.
Relevant- Yes. BJJ is something I really want to participate in and have tried on and off for the past few years. However, I’ve never been able to attend regularly due to the high level of stress I experience (mostly social anxiety).
Time-bound- You might have already guessed it but….3 months. I think this is an achievable time frame to implement all my plans and have them take effect.

Many of you may look at this goal and think how silly, or how simple etc. But for me, this is a good representation of many of the things anxiety stops me from doing. Going to social events, small talk with strangers, basically doing new social things in general. I used this example because I think it’s trackable and will express a change in my overall mentality if accomplished. The main thing I want to achieve by setting defined goals is something I can easily track my progress against. This will help me action plan in case I miss my targets later on down the road and also analyse what worked and what didn’t to apply to other areas in my life.


Diet is the first place I’m going to analyse, and although my diet is not “bad”, there’s definitely room for improvement. After much research, I believe this is going to be vital in reducing not only acute anxiety symptoms but generalised anxiety as well. I know this isn’t going to be a quick fix as “dietary changes often affect brain function rather slowly and the full impact of any diet may take many months to be realised.”(Psychology Today, 2017). I’ve looked through various diets from Atkins to Zone Diet and narrowed it down to 2 possibilities. I do, however, want to mention I also examined ketogenic (‘keto’) diet, but there’s already been a much better write up of the current research and results then I could do here: 
My reasoning for not trying this diet is it takes a bit of work to monitor if you’re in proper ketosis and is especially challenging if you consume a lot of protein. There’s also the zero-carb/carnivore diet which I’ve seen popularised lately and supposedly helps some people with issues from autoimmune diseases to depression; however, I’m not educated enough, and the research just isn’t out there to properly comment on it at the moment. I am concerned about how you could get all your micronutrient requirements in. I also worry about the environmental impacts (especially water use) of consuming purely meat in this diet. So with that said here are the 2 I’m looking at;

  1. Paleo
  2. Mediterranean

These both have many positive reported health benefits, and I believe each could be used effectively in this program. Because I think they each have their merits, I’ll go into a bit about each and then I’ll explain which I’ve chosen and why.

Palaeolithic Diet

Palaeolithic often referred to as ‘paleo’, is a diet which aims to mimic the diet of our cavemen ancestors. It does this by removing grains, refined sugar (so only sugar from fruit is ok) and processed foods. So what does the food you’ll be eating look like?

Meat — Grass-fed is probably preferable. Grain can cause similar problems in animals as they do in humans.
Fowl — Chicken, duck, hen, turkey.
Fish — Wild fish, as mercury and other toxins can be an issue in farmed fish.
Eggs — Look for cage-free eggs.
Vegetables — As long as these aren’t deep-fried, eat as many as you want.
Oils — Olive oil, coconut oil, avocado oil — think natural.
Fruits — Rich in vitamins and fibre.
Nuts — High in calories, so they’re good to snack on, but don’t consume bags and bags of them if you’re concerned about weight.
Tubers — Sweet potatoes and yams. Higher in calories and carbs, so these are good for right after a workout to replenish your glycogen levels. (Nerd Fitness, 2017)

All of this is purported to have many health benefits, one of which being improvements in mental health. A quick google search reveals many anecdotal success stories of people who implemented this diet:

“From personal experience with battling short bouts of depression and anxiety my entire life, changing my diet to paleo has made the single greatest difference to my mental state.” (Childs, 2017)

It’s postulated that results such as this could come from two changes, improved gut health 

“The results of recent studies have consistently shown that, compared to Westernized urbanites, rural dwellers and hunter-gatherers in Africa and South America have higher levels of microbial richness and diversity.”

(Alan C Logan 2014) 

And a reduction in inflammation. Both of which have been related to improving mood disorders, such as anxiety and depression. 
One 2014 piece of research examined the possible ramifications the modern diet has compared to a palaeolithic diet. Although the research is very early, and still developing rapidly, they found that 3 main changes from our ancestral diet to the modern diet could be contributing to mood disorders like anxiety

“a potential evolutionary mismatch between our ancestral past (Paleolithic, Neolithic) and the contemporary nutritional environment. Changes related to dietary acid load, advanced glycation end [AGE] products and microbiota via dietary choices and cooking practices may be of relevance to depression, anxiety and other mental disorders.”

(Logan AC, Jacka FN. 2014). 

The changes in dietary acid load, switching to a more acidic diet, i.e. increased consumption of processed food, sugary drink and so forth, seems to potentiate a possible cortisol response which in turn increases inflammation which is routinely linked to mood issues. Again the problem seems to be a lack of microbial diversity in the gut, as compared to our ancient counterparts (funnily enough confirmed by something called a “paleostool” analysis”). One interesting study referenced showed people with depression, anxiety and schizophrenia have low blood levels of a soluble receptor for AGEs. The receptor is tasked with binding and essentially halting some of the destructive consequences of AGEs, one of which being chronic inflammation. AGEs are elevated by cooking without water; baking, frying etc. Switching to a more traditional way of cooking, such as stewing, 

“[Lowered] the AGE burden by approximately 50%, significantly reducing systemic inflammation and oxidative stress” (n=26). 

(Luévano-Contreras 2013)

This expands the discussion from not only food but how we cook that food compared to historical methods. Anecdotally, I’ve noticed increased anxious symptoms during weeks where I’ve consumed a lot more processed foods.

Mediterranean Diet

The Mediterranean Diet is abundant in fruits, vegetables, whole grains, legumes and olive oil. It features fish and poultry — lean sources of protein — over red meat. Red wine is consumed regularly however in moderate amounts. It’s based on the traditional foods that people used to eat in countries like Italy and Greece during the ’60s.

So what does this diet look like?
Vegetables: Tomatoes, broccoli, kale, spinach, onions, cauliflower, carrots, brussels sprouts, cucumbers, etc.
Fruits: Apples, bananas, oranges, pears, strawberries, grapes, dates, figs, melons, peaches, etc.
Nuts and Seeds: Almonds, walnuts, macadamia nuts, hazelnuts, cashews, sunflower seeds, pumpkin seeds and more.
Legumes: Beans, peas, lentils, pulses, peanuts, chickpeas, etc.
Tubers: Potatoes, sweet potatoes, turnips, yams, etc.
Whole Grains: Whole oats, brown rice, rye, barley, corn, buckwheat, whole wheat, whole grain bread and pasta.
Fish and Seafood: Salmon, sardines, trout, tuna, mackerel, shrimp, oysters, clams, crab, mussels, etc.
Poultry: Chicken, duck, turkey.
Eggs: Chicken, quail and duck eggs.
Dairy: Cheese, yoghurt, Greek yoghurt, etc.
Herbs and Spices: Garlic, basil, mint, rosemary, sage, nutmeg, cinnamon, pepper, etc.
Healthy Fats: Extra virgin olive oil, olives, avocados and avocado oil.

The best thing about this diet is that it has been researched extensively lately and linked to improved mood and mental health. A team at the University of Melbourne inspected over 1000 randomly selected women, ages 20–93, assessing for symptoms of depression and anxiety and compared “traditional” diets to “western” diets. They established that the women who ate a “traditional”, i.e. the Mediterranean, a diet of vegetables, fruit, meat, fish, and whole grains had reduced symptoms of depression and anxiety than those who ate a “western” diet, characterised by processed or fried foods, refined grains, and sugary products. A four year long 2009 study (n=10,094) in Spain also showed that an intake rich in vegetables, fruits, fish, and whole grains and low in red meat and dairy was associated with a lower risk of depression (Sánchez-Villegas A).

My choice

As much as I liked the idea of the Paleo diet and may try it later down the track, the fact that the Mediterranean diet has such a wealth scientific evidence behind it, really made me prioritise attempting this first. Along with that, it also will be easier to implement, hence I think, stick to in the long term.


After diet is solidly in place, supplementation will be the next area I’ll be looking to tweak to obtain a boost from. Following hours of searching through the internet, from Reddit to PubMed, I’ve managed to find a few compounds that repeatedly sprung up along my searches. 

  1. Magnesium 400mgs
  2. L-theanine 200mgs
  3. Selan-K 250–500 mcgs
  4. Ashwagandha 600mgs
  5. CBD (Cannabidiol) 200mgs
  6. Rhodiola 450mgs
  7. Phenibut 750mgs MAX TWICE PER WEEK

Please also consult with your doctor before trialling any of these as they may have interactions with any medication your on causing problems such as ‘serotonin syndrome’. Here is a helpful resource to assist:


L-theanine is an amino acid that is rare in our daily diets. Its classed as a non-dietary amino acid. L-theanine is a relaxing agent without the associated sedation with such supplements. This is why it’s often coupled with caffeine to boost cognition without the common side effects of stimulants and acts synergistically. It can be found in tea leaves, namely green-tea, which contains about 8mgs. L-theanine is considered extremely safe and has been designated as a Generally Recognized as Safe supplement (GRAS) by the Food and Drug Administration (FDA) in the United States. L-theanine relieves anxiety primarily because it resembles the brain-signalling chemical glutamate. However, L-theanine produces the opposite effect in the brain, while glutamate in the brain is an important excitatory neurotransmitter, L-theanine binds to the same brain cell receptors which block them to glutamate’s effect. This action produces inhibitory effects. That inhibition of brain overactivity has a calming and relaxing effect. In addition to this, L-theanine also stimulates the production of the inhibitory neurotransmitter GABA.

One study examined the effects of chronic L-theanine administration in patients with major depressive disorder an open-label study (n=20) found; “..chronic (8-week) L-theanine administration is safe and has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with Major Depressive Disorder.”

(Hidese S, 2017)

An 8-week, double-blind, randomised, placebo-controlled study (n=40), also remarked; “L-theanine augmentation was associated with a reduction of anxiety (P = .015; measured by the HARS [Hamilton Anxiety Rating Scale] scale) and positive (P = .009) and general psychopathology (P < .001) scores (measured by the PANSS 3-dimensional model).”

(Ritsner MS, 2017)


Ashwagandha is an adaptogenic herb popular in Ayurvedic medicine (a traditional form of medicine native to India). Adaptogens are a unique category of herbal ingredients used to improve the health of our adrenal system, the system that’s in charge of managing your body’s hormonal response to stress. The name adaptogen stems from their ability to ‘adapt’ to the specific needs of the body. Ashwagandha has been referred to as ‘Indian Ginseng’, due to its ability to enhance mental stamina and boost resilience.

A systematic review of human trials using Ashwagandha (also called Withania somnifera, Sensoril™ and KSM-66™ — patented extracts); concluded that 

“All five studies concluded that Withania somnifera intervention resulted in greater score improvements (significantly in most cases) than placebo in outcomes on anxiety or stress scales…[However] current evidence should be received with caution because of an assortment of study methods and cases of potential bias.”

(Pratte et al., 2017)

Another study (n=64) measured the serum cortisol levels (a hormone often elevated during high levels of stress) in a group of chronically stressed people. They were given 300 mg of high strength Ashwagandha, two times per day, for 600mgs in total, for 60 days. 

“[Participants] exhibited a significant reduction (P<0.0001) in scores on all the stress-assessment scales on day 60, relative to the placebo group. The serum cortisol levels were substantially reduced (P=0.0006) in the Ashwagandha group, relative to the placebo group.”

(Chandrasekhar, Kapoor and Anishetty, 2017)


Rhodiola Rosea also was known as; Arctic root, Rose root/Rosenroot, Orpin Rose, or Golden root, is also adaptogenic. It has traditionally been used in Europe and Asia to reduce fatigue and improve vitality. It’s even said to have been used by the Vikings to preserve their physical strength during battle. Along with reducing fatigue, it’s been linked to; anxiety reduction, longevity, improved cognition and to be neuroprotective against toxins.

Ten participants with a diagnosis of GAD (Generalised Anxiety Disorder), were recruited from the UCLA Anxiety Disorders Program. Participants were given a total daily dose of 340 mg of Rhodiola extract for 10 weeks. They were assessed using; Hamilton Anxiety Rating Scale (HARS), the Four-Dimensional Anxiety and Depression Scale, and the Clinical Global Impressions of Severity/Improvement Scale. The results of the study achieved were; 

“Individuals treated with R. rosea showed significant decreases in mean HARS scores at endpoint (t=3.27, p=0.01).”

(Bystritsky A, 2008).

A Swedish study (n=60) examined the effects of 576 mg Rhodiola Rosea supplemented daily for 28 days, on patients with suffering from stress-related fatigue. They saw a significant improvement on questionnaire results related to the quality of life, depression, attention and fatigue. Along with this, they observed a drop in cortisol response to awakening stress. They concluded that 

“..repeated administration of Rhodiola extract SHR-5 exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome.”

(Olsson EM, 2009)


Magnesium is an essential dietary mineral and is the second most prevalent electrolyte in the body, after sodium. Magnesium is one of the most essential minerals to overall health, it is involved in over 300 biochemical functions in the body. These range from; regulating heartbeat rhythms to assisting neurotransmitter functions. Worryingly this is one of the leading nutrient deficiencies in adults with an estimated 80 per cent being deficient (Recommended Daily Intake of around 400mgs for men and 300mgs for women). Lowered levels of magnesium have been linked to a variety of issues, including mood disorders, such as anxiety.

A Russian study examined 62 patients with anxiety disorders and reviewed their blood samples. They noticed a high prevalence of low magnesium levels compared to the control. 

“..use of Magne B6 Forte [a magnesium, 100mgs and vitamin b6, 2mgs, supplement] (4 tablets/day, 30 days, then 2 tablets/day for 1 year) resulted in a significant increase in the Magnesium levels in the plasma and erythrocytes, the compensation of anxiety and depressive symptoms, improvement of sleep and general health of the patients, with the reduced consumption of antidepressants (by 30% on average).”

(Kopitsyna UE, 2015)

It’s worth noting that a recent study (n=91) suggests that fixing magnesium deficiency may take over 3 months to reach full effect: 

“Overall symptomatology, assessed through a magnesium status questionnaire, improved 28% over 30 days and 63% over 90 days.”

(Weiss, Brunk and Goodman, 2018)

Mice and rat studies suggest similar findings as to Russian research, but also show that even the gut microbiota can be affected by magnesium deficiency. 

“We demonstrated that the gut microbiota composition correlated significantly with the behaviour of unchallenged dietary mice. A magnesium-deficient diet altered the gut microbiota, and was associated with altered anxiety-like behaviour, measured by decreased latency to enter the lightbox.”

(Pyndt Jørgensen B, 2015)


Phenibut acts upon the central nervous system by binding to GABA-B receptors in the brain, which impedes the effects on the excitatory neurotransmitter glutamate, which has a calming effect on the central nervous system. It has been referred to as both a nootropic (nootropics are a group of supplements that are used to affect brain chemistry to produce a desired physiological and/or subjective feeling) and a tranquilliser. It is classified as a gabapentinoid. Gabapentinoids are a class of chemical compounds that are derivatives of gamma-aminobutyric acid, more commonly referred to as GABA. GABA is classed as an amino acid; “a carbon chain with an amine group at one end and then a carboxylic acid at the other, which block α2δ subunit-containing voltage-dependent calcium channels” (PsychonautWiki). Developed during the 1960s in the Soviet Union, Phenibut has been used to treat a range of illnesses from alcoholism to PTSD. It is still used clinically in Russia today but is classed as a nutritional supplement, or scheduled narcotic in some countries (Australia for one).

Aside from a vast array of anecdotal experiences found on many online forums, it’s been surprisingly hard to find studies which specifically examine the use of phenibut on anxiety (check out r/nootropics to see some of these). The best I could seem to find when it came to the anxiolytic effects of phenibut was 2 rodent studies.

Firstly, a study completed in 2009 by Cui et al. noted significant reductions in wakefulness time and slept latency in physically-stressed rats who were given baclofen (a pharmaceutical version of phenibut). It also pointed out that the effect of psychological stress on total REM sleep was also reversed.

Secondly, a study in 2007 by Lhullier et al. treated hyperactive rodents induced by cocaine administration (score!) with baclofen and examined the decrease in movement afterwards. Rodents with hyperactivity exhibited a significant dose-dependent reduction in movement activity after they were administered baclofen, as is evidenced by a decrease in the distance travelled.

[WARNING] Phenibut is a potent drug, and you can build up tolerance and addiction very quickly. As such, it should only be used once or twice per week max and never over 1g. [WARNING]


Selank is a neuropeptide, small protein-like molecules (peptides) used by neurons to communicate with each other. Selank is a synthetic derivative of the body’s naturally produced tetrapeptide called Tuftsin which is a hexapeptide with a wide range of uses. Selank was first synthesised in the late 1990s at the Institute of Molecular Genetics of the Russian Academy of Science.

Selank is employed as an anxiolytic in the therapy of anxiety and phobic disorders and shown to be of particular use in cases of GAD. Its action is compared to that of mild benzodiazepines but without the associated sedative effects. As a selective anxiolytic with a nootropic component and even antiviral properties, Selank is often used as a treatment for depression, fear and general anxiety. Selank has passed all phases of clinical trials and is now being prepared for registration and mass production. 

Dosages for subcutaneous injection seem to range from 250mcgs — 1mg. As for the nasal spray, it is generally available as a 0.15% spray, with 75 μg of Selank in each spray. The recommended dosage is 2 or 3 sprays per dose with 3 doses per day (for a total of around 675 mcgs per day).

It is postulated that Selank works via its ability to inhibit enkephalin hydrolysis. Enkephalin is implicated in the receptor-dependent modulation of adaptive behavioural responses to stressful or threatening environmental stimuli. A 2001 study performed by the Center of Mental Health, Russian Academy of Medical Sciences, Moscow: 

“..demonstrated a considerable shortening of enkephalin half-life and reduced total enkephalinase activity in the blood during generalised anxiety…Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which attenuates behavioural anxiety reactions and does not cause side effects typical of most anxiolytics, dose-dependently inhibited enzymatic hydrolysis of plasma enkephalin.”

(Zozulya AA 2001)

Selank has also been shown to work as an adjunct treatment with commonly used pharmaceutical anxiety treatments such as the use of benzodiazepines; 

“..combined treatment decreased the level of undesirable side-effects of phenazepam [a Russian benzodiazepine] (attention and memory, asthenia, sedation, increase in sleep duration, sexual disorders, anhedonia and orthostatic hypotension [low blood pressure when standing up]) during the course of treatment and after the tranquiliser withdrawal. Taken together, the therapeutic efficacy and reduction of side-effects had a positive impact on the quality-of-life of the patients treated.”

(Medvedev VE, 2018)

Interestingly Selank also demonstrates an ability to increase learning ability, peaking on the third day of administration, during times of stress; 

“..results obtained here with data on the anti-anxiety actions of Selank suggested the potential for its use in optimising mnestic functions in conditions of elevated emotional tension.”

(Kozlovskii & Danchev 2003)

Although it should be noted that this study was at significantly higher doses and in rats.


Cannabidiol (CBD) is a compound coming from cannabis plants. CBD binds to the same receptors as Tetrahydrocannabinol (THC is the main psychoactive part of marijuana) however, does not produce the high. Instead, it is proposed as a treatment for many health issues, including anxiety. CBD may boost signalling through serotonin receptors. It’s also been shown regular dosing may help the hippocampus regenerate neurons, which could be useful for treating anxiety or depression. Scans of patients suffering from depression and/or anxiety often show a reduced hippocampus. The hippocampus may be linked to emotional regulation, and successful treatment of depression is often associated with the birth of new neurons (neurogenesis) in the hippocampus. Finally, CBD has been shown to reduce chronic inflammation, which has also been linked to issues such as depression and anxiety.

A study (n=24) from Department of Neuroscience and Behavior, University of São Paulo examined the effect of administering 600mgs CBD and measured the levels of distress in people with Generalized Social Anxiety Disorder (GSAD) during a simulation public speaking test. The results were gauged by both subjective tests, along with health markers such as BP and heart rate. It was observed, 

“Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech.”

(Bergamaschi, M. M. 2011)

They also noted that with the use of CBD, the GSAD’s group response was similar to that of the healthy control.

A review of 40 CBD studies, including both rodent and human models, was conducted by Alexandre Rafael de Mello Schier and colleagues. Although they concluded more research into dosing and mechanisms involved were needed, they found 

“..studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with a social anxiety disorder”

(Schier, A. R. 2012)

The Stack 

So my stack looks like this; 

Morning = L-theanine x 200mgs, Ashwagandha 300mgs, Magnesium glycinate (for better bioavailability 200 mg), Rhodiola 450mgs, CBD 200mgs and NA Selank 500mcgs. 

Evening = 300mgs Ashwagandha and 200mgs of Magnesium.

I’ll be splitting those two and having evening doses to increase my sleep quality hopefully (and to potentially mitigate any GI issues the magnesium may cause). I may take these all at once if I believe I’m going to be having a particularly stressful event coming up.

Thus ends part 1 of this post. Part 2 will look at; exercise, meditation, strategies for developing an overall better mindset and the full list of references. 

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