What is Pregnenolone?

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Pregnenolone or “PREG” is a “parent hormone” produced by mammals and invertebrates, meaning that all other important hormones in the body are made from this primary hormone.

PREG is created in the body from cholesterol and is found in relatively high concentrations in the brain, hence its known term as a “neurosteroid.”

However, it is not biologically active.

When it gets converted to steroid hormones, those molecules are the ones that are active at their respective receptor sites in the body.

The first step is the conversion of cholesterol to pregnenolone sulfate by the enzyme sulfotransferase.

Pregnenolone is then converted to progesterone by the enzyme 3beta-hydroxysteroid dehydrogenase.

Progesterone is then converted to testosterone and estrogen.

Testosterone is converted to dihydrotestosterone (DHT).

I should note that synthesizing these and other steroid hormones in mammals is much more complicated than the simplified description above, but you get the idea!

The image below gives us an idea of the complexity, multiple metabolic pathways, and breadth of this process:

Pregnenolone acts as an endocannabinoid, similar to cannabidiol (CBD) in how it works.

Due to this mode of action, there is potential for its application in managing mood and pain.

It may have the potential to help with memory loss.

Some evidence suggests that it could support myelinization in the nerves, potentially slowing neural degeneration associated with multiple sclerosis.

Additionally, pregnenolone exerts its own effect as “an anti-inflammatory molecule to maintain immune system homeostasis in various inflammatory conditions.”

It is made from three sources in the body: the gonads (or sex organs), the adrenal glands, and the brain.

It has a variety of functions, including cognitive and memory enhancement, managing the body’s stress response system, and anti-inflammatory effects.

Clinical trials do show that pregnenolone levels decline with age.

Pregnenolone is also being studied for its potential to treat many conditions such as memory impairments such as Alzheimer’s disease, anxiety, depression, and chronic pain.

Monique Vallee states in her review article that strong clinical evidence suggests that PREG may have therapeutic benefits in managing these medical problems and that this precursor hormone may be a natural biomarker for brain disorders.

How long does Pregnenolone take to work?

There is no clear consensus on when people start seeing any benefit from taking PREG.

Some clinicians have anecdotally settled on their own prescribing patterns and claim that 30 mg to 90 mg of pregnenolone taken daily will suffice for most people.

They also claim that people start seeing improvement in memory within 2-3 weeks.

As a healthcare practitioner, I urge all readers to exercise caution with these statements.

The reason is that these providers are adding PREG to their patients’ established regimens of FDA-approved prescription medications such as donepezil (Aricept) and memantine (Namenda).

So, one possibility is that any improvement in memory seen in these patients is most likely due to the donepezil and/or memantine instead of the PREG.

However, another possibility is that PREG works by affording additive or synergistic pharmacological effects when given concomitantly with the prescription agents mentioned above.

So, while I am not completely convinced that PREG is solely responsible for improving memory, I am cautiously optimistic about its potential role when given with other cognitive enhancers.

More research is needed, but I am keeping an open mind about PREG’s use in people suffering from dementia.

Health Benefits of Pregnenolone

Role in Anxiety and Depression

Studies suggest that PREG may play a role in regulating anxiety and depression.

In one study, people taking PREG subjectively reported a reduction in depression ratings.

In that study, investigators discovered an interesting finding in a subgroup of study participants that seems to add additional evidence to the thought that pregnenolone is involved in the body’s stress response system.

They found that PREG seemed to reverse the sedating effects of a single dose of a commonly prescribed benzodiazepine, diazepam (Valium).

This finding suggests that PREG may play a possible role in reversing the sedative-hypnotic effects of benzodiazepines, especially if they are dosed inappropriately.

PREG may possibly play an important therapeutic role in managing bipolar depression (BPD).

In a randomized controlled trial, Brown and colleagues investigated the role of PREG in 80 adults with bipolar disorder who were in a depressed mood state.

The participants were split evenly between taking PREG or a placebo as add-on therapy to prescription medications indicated for bipolar depression.

In the group taking PREG, participants’ doses were slowly increased to 500 mg per day. Commonly used clinical scales for assessing depressive state in BPD were used to assess the study participants.

The authors found that depression remission rates were more pronounced (61%) in the group taking PREG than those in the placebo group (37%). Study participants tolerated PREG well.

These results led the study investigators to conclude that PREG may improve BPD-associated depressive symptoms with minimal side effects.

Role in Memory and Cognitive Health

PREG may play a role in improving memory and cognitive function by increasing acetylcholine levels and modulating GABA (the main inhibitory neurotransmitter in the brain).

In a study by the Veterans Administration, the administration of PREG to male mice improved their memory response to a “footshock” experiment.

The PREG-administered mice showed a greater propensity to avoid a mild electric shock to their feet than their friends who had not been administered PREG!

However, studies involving PREG use in humans yielded mixed results regarding memory function (Disclaimer – No humans were given electric shocks or harmed in any way!)

In one 12-week clinical trial involving twelve study participants with autism spectrum disorder, PREG use yielded a statistically significant improvement in irritability.

Role in Management of Psychosis

In a 2011 report published in the journal Neuroscience, the authors found clinical evidence that PREG may be a viable therapeutic agent for managing schizophrenia.

They reviewed several animal and human studies and found that PREG may help patients suffering from schizophrenia by positively affecting steroid hormones in the brain.

The investigators also found evidence that PREG may increase levels of gamma-aminobutyric acid (GABA) in the brain.

GABA is the main inhibitory neurotransmitter in the brain, the chemical that calms you down and naturally fights agitation.

Role in Neuroprotective Functions

PREG may play an integral role in protecting the central nervous system.

For example, in Alzheimer’s Disease, PREG may reduce the number of amyloid plaques, beta-amyloid 42 proteins, and neurofibrillary tangles in the brain, the primary toxins responsible for the progression of this particular type of dementia.

Studies suggest that the brain’s response to the presence of these toxins is to increase the production of PREG endogenously.

Interestingly, PREG levels in the brains of individuals with Parkinson’s Disease (PD) are lower than usual.

This may suggest that there may be some clinical significance between endogenous pregnenolone levels and Parkinson’s disease development.

However, we have to exercise caution here and not jump to the conclusion that lower PREG levels are the cause of PD and that the disease can be reversed by simply supplementing with PREG.

The studies merely indicate that further research needs to be conducted to explore the possibility of a potential causal relationship between lower PREG levels and PD.

Role in Chronic Pain

Promising recent research suggests that PREG may indeed help ease pain.

The Veterans Administration conducted a double-blind placebo-controlled study in 2020 that explored the potential therapeutic effects of PREG on 94 vets suffering from chronic low back pain.

The veterans were randomly assigned to either supplemental pregnenolone or placebo for a 4-week period.

Pregnenolone and placebo were given at fixed, escalating doses according to the following schedule: 100 mg for one week, 300 mg for one week, and 500 mg for two weeks.

The veterans experienced significant pain scores and mobility improvements at the end of the 4-week schedule.

Furthermore, side effects were experienced minimally.

Based on these significantly positive results, the study investigators concluded that “Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain . . .”

Role in Management of Drug Addiction

There is mixed scientific evidence regarding the key role of pregnenolone supplements in countering drug addiction.

Several articles have been written about the potential role of PREG in countering the reward pathway seen in cannabis use by blocking dopamine release.

Based on this assertion, some scientists and proponents suggest long-term PREG use to combat drug addiction.

Other investigators have issued strong caution about pursuing this route of treatment.

They contend that blocking dopamine release in the long term could lead to a “hypodopaminergic” state, resulting in “aberrant substance and non-substance (behavioral) addictions.”

Based on these concerns, I would caution anyone contemplating using PREG to combat drug addiction to consult their healthcare providers first.

While there may be some potential short-term benefits to using PREG, the long-term adverse effects remain to be seen, and if they do manifest, they could be extremely dangerous.

Further research is needed to ascertain PREG’s safety and efficacy in drug addiction fully.

 

Side effects of Pregnenolone

PREG is generally tolerated well and is not associated with severe side effects. In the autism spectrum study discussed above, episodes of tiredness and diarrhea that could have been related to pregnenolone were reported.

Some other side effects that have been noted with PREG use are:

• Insomnia
• Headache
• Mood changes
• Irregular heart rhythm
• Anxiety
• Restlessness
• Agitation
• Hair loss
• acne
• sweating
• muscle pain
• Appetite changes
• Diarrhea
• Constipation
• Tremor

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The company clearly displays certificates of analyses and third-party test results for all its products on its website.

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Warnings

Additionally, concurrent use of PREG may be dangerous if you have hormone-sensitive medical conditions such as breast cancer, prostate cancer, uterine fibroids, or endometriosis.

Overall, research is still lacking about the safety of the long-term use of pregnenolone.

Since PREG is sold as a dietary supplement in the US, the manufacturers are not required by the FDA to submit the samples for bioequivalence, potency, and safety.

In other words, you never really know what you are getting in each tablet or capsule of the product.

As a healthcare professional, I have to insert my word of caution here:

NEVER start self-treating any perceived or clinically diagnosed medical condition with pregnenolone supplementation or any other dietary supplements without consulting your licensed medical provider first.

Avoiding or delaying standard medical care can be very dangerous for you!

Drug Interactions With Pregnenolone

There are moderate interactions between PREG and several medications, especially hormones:

Pregnenolone interactions with Estrogens

Since PREG is the precursor to endogenous estrogen production, taking it concurrently with prescription estrogens may raise levels in the body to unsafe levels.

Examples of estrogen medications are:

• estradiol
• ethinyl estradiol
• conjugated equine estrogens (Premarin)
• and any other medications containing estrogen

Pregnenolone interactions with Progesterone

As with estrogens, taking PREG with progestins can also cause progesterone levels in the body to rise to unsafe levels.

Some examples of medications containing progestins are:

• norethindrone
• levonorgestrel (Plan B)
• medroxyprogesterone (Depo-Provera)
• etonogestrel (Nexplanon)

Pregnenolone interactions with Testosterone

PREG is made into testosterone in the body, and like the interactions above, taking it with doctor-prescribed testosterone can temporarily increase testosterone levels in the body.

This can then cause an unintended secondary problem because since a negative feedback loop regulates endogenous testosterone production, production of testosterone may then decrease

Side effects of too much testosterone (men and women) include:

Increased secondary sexual characteristics (body and facial hair)

• Anxiety
• Headache
• Breast swelling (gynecomastia)
• Male-pattern baldness
• Increased or decreased libido (interest in sex)

Pregnenolone interactions with Benzodiazepines

PREG may decrease the sedating effects of benzodiazepines such as lorazepam, alprazolam, diazepam, and others.

This could lead to a potentially life-threatening situation because the individual thinks they need to take more of the benzo to realize its therapeutic effect, leading to a likely case of benzodiazepine overdose.

 

Summary

• Pregnenolone (PREG) is a naturally-occurring steroid hormone precursor made from cholesterol
• Scientific studies suggest that several potential health benefits of pregnenolone exist
• Role in anxiety and mood/depression
• Role in memory
• Role in neuroprotective functions
• Role in chronic pain
• Role in psychosis-related symptoms
• Role in drug addiction
• Pregnenolone side effects are generally mild
• Pregnenolone does have clinically significant interactions with hormone-based medications
• Always seek professional medical advice before beginning pregnenolone supplementation