For a long time, scientists believed that no part of the human brain could regenerate. What have we learned since our technology improved? This article explores whether new research offers hope for brain injury and goes over various factors that may either shrink or grow the brain.
Neurogenesis & Brain Health
Of Jellyfish and Men
“Once again, a flurry of new research is suggesting neurogenesis may be more common than previously thought.”
Comb jellyfish can regrow their rudimentary brains [1]. But in most mammals (including humans), neurogenesis largely ceases in adulthood. It has been observed in a few places, including the hippocampus, a relatively ancient part of the brain many animals share. In comparison, only humans have a developed neocortex [2].
The party line in neuroscience has been observational. First, we believed no part of the human brain could regenerate. And we’ve added exceptions as our technology has improved.
Who’s to say we won’t find more exceptions?
Nothing in neuroscience is absolute because the brain is still a black box.
How Much Do We Know?
When we sleep, the hippocampus reactivates and connects with various brain regions, including the cortex – the brain’s “crust” or outer layer – all the while emitting delta brainwaves. Scientists think that this may explain, in part, how our memories stabilize while we’re asleep. A study published in Science in 2019 suggests just this [3].
One part of the cortex is called the occipital cortex is smaller than a speck of dust and it revealed cell types we had never seen before. Nor do we know exactly how memories are stored, though various scientific theories have been proposed [3].
An older but widely accepted working theory stands on long-term potentiation (LTP): neurons that fire together wire together. But that’s more a description than an explanation. We don’t know what induces LTP. When scientists temporarily block certain kinases to prevent neuronal connection (reconsolidation), it often reverts back [4].
So, researchers emphasize that the brain is more than its connectome (set of neuronal connections). But exactly what–that’s a focus of ongoing research.
Brain Injury Findings
Does new research give hope to people struggling with brain injury? Perhaps, but it’s still too early to say. Research findings are mostly limited to animal experiments.
Further studies need to clarify the relevance of neurogenesis after traumatic brain injury in humans. Until then, people with brain injury shouldn’t keep their hopes too high.
For example, induction of adult neurogenesis has been observed in normally non-neurogenic regions of the brain in response to injury and death of neurons – in animals [5].
Scientists say that upon injury in the non-neurogenic regions, there have been reports of local precursor cells generating new neurons and migrating from the neurogenic to the non-neurogenic region [5].
This has been suggested to occur in the neocortex [6], striatum, and hippocampus as a result of ischemic brain injury in rats [7, 8].
Neurons that were being generated in the subventricular zone were able to migrate to the injured striatum and differentiate into mature neurons in these animal experiments. Scientists have hypothesized that these migrated and matured cells may help repair neurological deficits, but this remains unproven [9].
Another study suggested that mice, in response to cortical lesions, may produce new neurons in the ventricular areas. The new neurons then migrated and populated to the cortical areas [10].
The authors mention that the migration and differentiation of neurons to nonneurogenic regions suggests the brain might have much more potent regenerative capabilities than previously imagined. How and whether this is relevant in humans is still highly uncertain [10].
Further studies need to clarify the relevance of neurogenesis after traumatic brain injury in humans.
Caveats & Limitations
This post explores associations between neurogenesis and aspects of health.
The majority of studies we discuss deal with associations only, which means that a cause-and-effect relationship hasn’t been established.
For example, just because memory and learning have been linked with neurogenesis doesn’t mean that increasing neurogenesis will improve these processes, unless clinical data about a direct link are available. However, data are lacking to make such claims.
Additionally, even if a study did find that neurogenesis contributes to brain recovery after TBI, neurogenesis is unlikely to be the only contributing factor. Complex processes like post-stroke or post-TBI recovery always involve multiple possible factors – including symptom severity, therapeutic modalities, brain chemistry, environment, health status, and genetics – that may vary from one person to another.
When to See a Doctor
If your goal is to increase neurogenesis to improve your neurological issues – including those of traumatic brain injury – it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.
Your doctor should diagnose and treat the condition causing your symptoms.
The existing evidence does not suggest that reduced neurogenesis causes any disease.
Additionally, changes in brain chemistry are not something that people can change on their own with the approaches listed below. Instead, the factors listed here are meant to reduce daily stress and support overall mental health and well-being.
Therefore, you may try the additional strategies listed below if you and your doctor determine that they could be appropriate. None of these strategies should ever be done in place of what your doctor recommends or prescribes.
Additional Precautions
We’re providing a summary of the existing research below, which should guide further investigational efforts.
The studies listed in the sections below were mostly done in animals and should not be interpreted as supportive of health benefits in humans.
Factors to Avoid that May “Shrink” the Brain
It’s always a good idea to avoid unhealthy habits – such as smoking, fast food, overeating, being under a lot of stress, and drinking too much – that can bring your body and mind out of balance. Look to get regular exercise, enough nutrients, sleep, and keep a healthy circadian rhythm.
Alcohol
Avoid in excess. Drinking 3-4 drinks a day (rather, having an alcohol percentage of .08%) could reduce the number of cells produced in the hippocampus by 40% in one human study [11].
Stress
Scientists think that brief stress might support hippocampal neurogenesis by increasing cell proliferation [12], but what is more common in modern society is chronic stress. Studies suggest that chronic stress leads to atrophy of the hippocampus and loss of neurons [13].
Neurotoxins
Exposure to neurotoxins in the form of mold, biotoxins, certain chemicals, and some infections is hypothesized to cause atrophy in the caudate nucleus, as seen in NeuroQuant (an MRI software program) [14].
Mice became anxious and forgetful after inhaling mold spores, which correlated with a decrease of new brain cells in the hippocampus as compared to the control mice [15].
Some neurotoxins are also thought to promote neurodegenerative disease and halt neurogenesis over the long term, though more research is needed [16].
What May “Grow” the Brain
Most current methods that are being investigated for promoting neurogenesis largely focus on modulating the expression of BDNF, NGF, and GDNF.
Here’s a breakdown of the main lifestyle, dietary, and other factors that may help “grow” the brain.
Lifestyles that Promote Neurogenesis
1. Exercise and Enriched Environment
An enriched environment consists of many components including expanded learning opportunities, increased social interaction, more physical activity, and larger housing. All of these things are hypothesized to increase neurogenesis, but they’re also good for overall health [17].
In one study, regularly running nearly doubled the number of surviving newborn neuronal cells in amounts similar to other enriched conditions [17].
Scientists suspect that sustained exercise may be one of the most effective ways to increase neurogenesis. It’s thought to stimulate BDNF, GDNF, and improve memory. The effects of interval exercise are seen as minor, but more research is needed [18, 19, 20].
Some evidence suggests different mechanisms behind these approaches. An enriched environment seems to increase the survival rate of new cells, while voluntary exercise increases the level of proliferation of progenitor cells – at least in animals [21].
For example, running outside (sustained exercise in an enriched environment) while making more friends (social enrichment) and not taking yourself too seriously (decreased chronic stress) are all lifestyle changes that support general wellbeing. They might also promote neurogenesis, but this is still being researched.
2. Sunlight
Moderate sunlight exposure is good for overall health, research suggests [22].
Some scientists hypothesize that sunlight may increase BDNF. Bright light might also support neurogenesis in the adult rat brain and is being investigated in animal models of anxiety and depression [23].
3. Sleep
The ways in which sleep disruption inhibits neurogenesis is not fully understood, but they seem to be very important.
Disruptions of sleep over 24 hours appear to inhibit cell proliferation and in some cases neurogenesis [24].
Short-term sleep deprivation (less than one day) has little effect on neurogenesis [25].
However, chronic sleep deprivation seems to reduce neurogenesis by increasing levels of stress hormones [26].
Researchers consider that adequate sleep increases neurogenesis by lowering TNF-α and stress hormones [26].
4. Sexual Activity
Sexual activity can help relieve stress, but animal studies suggest it may also increase neurogenesis. Acute sexual experience increased cell proliferation in the dentate gyrus of adult male rats despite elevations in glucocorticoid levels, stress hormones [27].
But chronic sexual experience no longer increased these stress hormones, while continuing to promote neurogenesis, enhanced cell proliferation, and the number of dendritic spines in the dentate gyrus of adult male rats. It also reduced anxiety in the animals [27].
Diet and Foods that Promote Neurogenesis
5. DHA (Docosahexaenoic acid)
DHA is an omega 3 fatty acid found throughout the body. It makes up to 97% of the omega-3 fats in the brain and up to 93% of the Omega-3 fats in the retina. Studies suggest it’s important for brain and eye health and cognition (28).
It’s found in fish oil, salmon, and other seafood.
DHA increased the formation of new connections in the hippocampus in gerbils [29].
Increased hippocampal neurogenesis via omega-3 fatty acids has been proposed as a way to prevent PTSD, but this hasn’t been proven in humans. More research is needed [30].
We have a bunch of recipes for salmon in the lectin avoidance cookbook.
6. Ketogenic diet
Research suggests that ketones may be an alternative fuel for both the normal and injured brain [31].
According to some estimates, ketones might provide up to 70% of the brain’s energy needs in certain circumstances [32].
One group of researchers found that a ketogenic diet increased neurogenesis in mice with epilepsy [33].
However, another study reported that a ketogenic diet had no effect on neurogenesis in adult rats [34].
BHB Ketones
Ketones (BHB) are hypothesized to increase BDNF, which is thought to be one way by which exercise might increase BDNF (through BHB) [35].
Cell studies are looking to determine if ketones (BHB) are more energy efficient than glucose and if they can stimulate new mitochondria [36].
MCT Oil
MCTs – fats from coconut oil and other sources – increased ketone levels in one small human study, which was associated with greater improvement in paragraph recall relative to placebo across all subjects [37].
In one study of 152 people with Alzheimer’s disease, those who received an MCT supplement for 90 days had higher ketone levels and improved brain function compared to a control group. These findings need to be replicated in larger trials [38].
Interestingly, on cognitive testing, MCT seemed to improve performance in APOEε4-negative but not APOE ε4-positive subjects. Larger, better-designed studies are needed [39].
Additional Research
A ketogenic diet is being researched in animals with Alzheimer’s. Plus, ketones are being investigated for protecting brain cells by reducing reactive oxygen species [40, 41, 42, 43, 44].
Feeding older and obese rats a ketogenic diet seems to improve brain function, as well as cerebral hypoxia in animals. These findings can’t be translated to humans [45, 46, 47].
Scientists are also exploring whether ketones can affect the following pathways in animals or cells:
- Protect against glutamate-mediated damage through reducing the formation of reactive oxidant species, by oxidizing coenzyme Q and increasing reduced of glutathione [48, 49].
- Enhance the conversion of glutamate to GABA [50, 51] and increasing blood flow to the brain [52].
Human data are lacking.
Bottom Line
Additional research is needed to determine whether – and what type of – ketogenic diets affect neurogenesis, particularly in humans.
7. Cutting Down on Sugar & Getting More Fruits and Veggies
Sugar may decrease neurogenesis due to its deleterious effect on glucose metabolism. Some researchers think that raw fruits and vegetables may have the ability to modulate this effect, though proper clinical trials have yet to be carried out [53].
Still, it would be prudent to eat sugar only in the company of flavonoid and polyphenol-rich foods, such as in whole fruits and veggies.
Plus, blueberries and flavonoid-rich foods are hypothesized to promote BDNF, a neurotrophin that’s thought to support neurogenesis [54].
8. Intermittent Fasting and Caloric Restriction
According to one hypothesis that has yet to be proven, fasting might help protect the brain from oxidative stress and injury. Scientists think it may result in an increase of BDNF [55], antioxidants and DNA-repair enzymes through SIRT1 [56, 57, 58].
Calorie restriction appears to increase the expression of several nerve growth factors including BDNF and GDNF in the hippocampus and basal ganglia [59]. It also improved memory function in rats. Still, the effects of fasting or caloric restriction on neurogenesis in humans remain unexplored.
Supplements that May Increase Neurogenesis
Speak with your doctor before taking any supplements. Make sure to let them know about any prescription or over-the-counter medication you may be taking, including vitamins and herbal supplements.
Remember that dietary supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.
9. Ginseng
Rg3 is a ginsenoside compound found in Panax ginseng. It is hypothesized to decrease excitotoxic and oxidative stress in the brain while promoting neurogenesis, based on animal experiments. This has yet to be proven in humans, though [60, 61, 62].
10. Uridine
Uridine is an important ingredient in mother’s milk. It’s also found in some foods like nutritional yeast, certain mushrooms and vegetables, and organ meats.
Scientists hypothesize that it contributes to the generation of new synapses in infants, but human studies haven’t confirmed it yet [63].
Uridine-5’-monophosphate (UMP) increased new synapses in an animal study [29].
UMP is also being studied for leading the growth of existing neurons in cell studies, possibly through increasing NGF [64, 65].
11. Resveratrol
In animals and cells, resveratrol appeared to increase the birth of new neurons [66].
Scientists hypothesize it might increases angiogenesis (the formation of new blood vessels) and levels of growth factors that are associated with neurogenesis. Theoretically, these changes may lead to improved learning and memory [67].
On the other hand, resveratrol research in humans seemed to come to a halt after scientists were faced with this compound’s poor bioavailability. Efforts attempting to improve resveratrol’s bioavailability are underway.
12. Phosphatidylcholine
Phosphatidylcholine a key lipid component of cell membranes. It prevented the decrease of hippocampal neurogenesis by lowering TNF-alpha in mice, but human studies are lacking [68].
13. Curcumin
Long-term curcumin use increased neurogenesis in chronically-stressed mice. The authors said that it also prevented the decrease in serotonin receptors and BDNF in the hippocampus due to stress [69].
In healthy mice, curcumin increased the number of new cells in the hippocampus [70].
Still, its effects on neurogenesis in humans remain unexplored.
Other Therapies Researched for Promoting Neurogenesis
14. Transcranial Magnetic Stimulation
Transcranial Magnetic Stimulation (TMS) is a noninvasive way to stimulate parts of the brain with a magnetic field generator [71].
Repetitive transcranial magnetic stimulation (rTMS) is approved for certain forms of treatment-resistant depression in Canada [72].
Among its many proposed mechanisms, some scientists have hypothesized that it might promote hippocampal neurogenesis and synaptic plasticity. This has been confirmed in animals but is still an area of research in humans [73].
15. Transcranial Direct Stimulation
Transcranial Direct Stimulation (tDCS) has been suggested to increase homeostatic neuroplasticity in animals. Some scientists say this might speak to its long-term effects, but this is uncertain and unproven in humans [74].
Drug-Related Pathways that May Increase Neurogenesis
The following factors are highly experimental. Evidence is lacking to support their use for neurogenesis. No drug has ever been approved by the FDA for the purpose of increasing neurogenesis.
Thus, we bring up these factors solely for informational purposes. Do not take any drug without a doctor’s recommendation.
Approved Medication
SSRIs
Selective serotonin reuptake inhibitors (SSRI) like fluoxetine and sertraline have been suggested to increase neurogenesis [75, 76].
Some evidence shows increased hippocampal neurogenesis is required to produce positive results from antidepressants, but this is still a matter of debate [77, 78].
Unapproved Drugs
The following section deals with scientific findings behind unapproved drugs like pregnenolone. Another section summarizes experimental research about the effects of psychedelics like ayahuasca on mood and neurogenesis in the brain. Our aim is to discuss research findings.
We strictly advise against taking these substances under any circumstances.
Psychedelics like psilocybin and ibogaine are illegal. They are classified as Schedule I drugs, which means that they have no medical uses and a high potential for abuse and harm. Having possession of these substances can result in criminal prosecution.
The FDA recently approved a trial with a psilocybin-based drug in people with depression under a Breakthrough Therapy Designation. However, until the results are published and carefully reviewed by regulatory bodies,psilocybin remains classified as an illegal drug.
Synthetic Nootropics
Synthetic nootropics like piracetam, other racetams, semax, and similar compounds are all classified as unapproved new drugs by the FDA. That means that they are being illegally produced and marketed and have a high potential for harm.
Nonetheless, researchers have been interested in the effects of some of these compounds.
One research team is investigating whether noopept can increase the expression of NGF and BDNF in the hippocampus. Several members of the racetams family have been suggested to increase neurogenesis, though the findings have been inconclusive and proper human data are lacking [79, 80].
Another controversial nootropic hypothesized to promote BDNF is Selank, a drug with a questionable safety profile that’s not approved for use in the US [81].
Another investigational “neurogenic” compound is NSI-189 [82, 83]. It is currently under phase 2 clinical trials for the treatment of age-related decline in cognitive ability and depression [84].
Cerebrolysin
Cerebrolysin is a mixture of peptides derived from the brain of pigs. It is not approved for medical use in the United States. Currently, it is undergoing phase 2 trials for Alzheimer’s disease.
In a mouse model of Alzheimer’s, cerebrolysin restored neurogenesis and decreased cell death in the hippocampus [85].
Similar effects were observed in the subventricular zone (part of the brain) in mice after stroke [86].
It’s impossible to draw any conclusions about its effects until the results of clinical trials are out.
Illegal Substances
Ibogaine
Folklore describes the discovery of Ibogaine:
“Deep in the African forest, there was a porcupine happily munching on the root of an Iboga plant before a shaman found it and slew it for dinner. He brought it back to his wife to prepare and then left to continue the hunt. The shaman didn’t make it home in time for dinner, and so the wife began to eat. Soon after she experienced 2 full days of visions. After the horror faded she arrived with such mystical clarity that bewildered all people of the land. The shaman returned to the chewed root the porcupine left behind and gathered its magical bark.”
There started the Iboga Bwiti tradition, at least this is what fable tells us. Although interesting, this story is more of a myth than an actual account of ibogaine’s effects [87].
Ibogaine is a naturally occurring psychoactive substance found in plants in the Apocynaceae family. It has been used for spiritual exploration [88].
Scientists are investigating whether it can increase the levels of GDNF in cells. GDNF is a compound that increases neurogenesis in the hippocampus in mice [89, 90].
Additionally, ibogaine use carries many dangers and serious risks [91]. Derivatives of ibogaine without psychedelic properties are under development, but no proper clinical trials have been published to date [92, 88].
Psilocybin
Psilocybin is a compound with hallucinogenic and euphoric effects that is produced by more than 180 species of mushrooms. Low doses of psilocybin increased the birth of new neurons in the hippocampus in mice [93].
