Before an important talk or podcast, Dr. Rhonda Patrick drinks exogenous ketone esters. Why?

With Dr. Patrick describing the main benefit as feeling "less anxious and more in the present", there's something worth unpacking here.

Can ketones help with anxiety? What's the state of the current research & potential mechanisms of action?

H.V.M.N. co-founder, Geoffrey Woo, details it all in a video below.

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Transcription

Overview

Are ketone esters the perfect fuel before a big talk or meeting to calm the nerves? Can ketone esters help with anxiety? This is what we'll be exploring today.

Before talking about ketones, let's first define the target: Anxiety. Anxiety is formally defined as "a feeling of apprehension and fear, characterized by physical symptoms such as palpitations, sweating, and feelings of stress."

Some anxiety is a positive, preferable response. When you're under a threat, the right level of stress or anxiety response is a beneficial effect. For example, in prehistoric times, when a saber tooth tiger was chasing a caveman or cavewoman, a spike in anxiety and stress probably makes that cave person more survivable. That anxiety is a survival response. However, you don't want to be overly stressed and overly anxious. It can start backfiring and detracting from overall performance when one is so overly stimulated that you cannot even respond and start freezing. The Yerkes Dodson curve from psychology defines this.

Stress on the x axis. Performance on the y axis. Low stress is low performance, high stress is low performance. The "right" level of stress means optimal performance. You want to be in the happy medium of being stimulated yet calm.

So...can ketone esters be useful for anxiety? What's the evidence ?

The notion of ketones reducing anxiety is plausible, so let's start unpacking the literature on the potential mechanisms of action of how ketones can impact anxiety.

Proposed Mechanisms of Action

First, ketones reduce neuroinflammationYoum2015, specifically the NLRP3 inflammasome, which is a protein responsible for the activation of inflammatory responses in the body. An inflamed brain is no good - chronic brain inflammation is linked to depression and a number of neurological disorders.

Ketones in animal and cell studies impact glutamate and gamma-aminobutyric acid (GABA) balanceDaikhin1998. Glutamate is a precursor to GABA, and GABA is the key neurotransmitter that controls and reduces excitability for brain cells. Not to be overly reductive here, but data suggests that ketones ultimately upregulates GABA production. This could potentially result in a more relaxed brain state.

A study looking at ketogenic diet in rats demonstrated an upregulation of both ATP and adenosine in specific regions in the brain.Masino2009 ATP is energy and adenosine is relating to promotion of sleep and suppression of arousal.

There’s also the possibility that ketones modulate the autonomic nervous system, specifically through the GPR41 receptor. The autonomic nervous system controls the body's automatic processes such as your heartbeat, blood flow, breathing, even your metabolism. This makes sense as typically in a ketogenic state, the body is in a low-carbohydrate state, so maintenance of energy homeostasis is important. Ketones could be a key signal into autonomic nervous system to control energy, and therefore might play a role in anxiety.

Thus, a lot of supportive evidence on the mechanisms of action for how ketone esters could impact anxiety. The brain is very complicated and it's still much to be learned here. But the bottom line is that there's potentially a role of ketones in impacting key neurotransmitters like GABA and adenosine, which control excitability and arousal of the brain.

Another interesting mechanism of action relates to blood sugar control. Acute hyperglycemia is when the blood glucose level is too high because the body isn't properly using or doesn't make the hormone insulin. This is linked to impaired cognitive function and a deteriorated mood state. This has been shown in a study in a group of people with type 2 diabetesKivimaki2009. Speed of information processing, working memory, and some aspects of attention were impaired during acute hyperglycemia. Subjects were significantly more dysphoric during hyperglycemia, with reduced energetic arousal and increased sadness and anxiety. Ketone ester suppresses high blood sugar. Thus, in the case for people with high blood sugar and anxiety from that, ketone ester could potentially be helpful.

Current Research

We have a number of anecdotal reports from folks like Rhonda and many of our own customers, plus the mechanisms we just went through. The mechanisms we went over directionally point to the potential of application in humans, but we still do lack robust formal studies in humans. However, there does exist a couple promising animal studies with exogenous ketones have shown the ability of ketones to reduce anxiety-related behaviors.

Let's take a look at two of these studies.

One study demonstrated the anxiolytic (reduction of anxiety) effect with ketone ester supplementation in ratsAri2016. Anxiolytic effect was assessed by where the rats spent time in a maze.

Those with ketone ester spent less time in closed arms of the maze, making more entries and spending more time in the open arms of the maze. They also traveled more distance in the open arms and delayed entrance into the closed arms. This is all to say they spent less time hiding and more time exploring. This signals that perhaps their little rat brains were less anxious to explore new areas. You can imagine that if this same effect was applied to a human and a real-world situation, this could mean a wealth of positive benefits: Moving through a crowded conference quickly & purposefully to make connections in the industry, etcetera.

Another study demonstrated that beta-hydroxybutyrate (the ketone body in H.V.M.N. Ketone) attenuated stress-induced, depressive-like behaviors in rodent brainsYamanashi2017.

The mice moved around more and were quicker to feed compared to control.

Despite limited human data, rodent models are promising. Because of how we know ketones interact with the brain, it’s not a far jump to see how ketones can help reduce feelings of stress or anxiety.

Like Rhonda, I personally also like to drink H.V.M.N. Ketone Ester before a public talk, an important business meeting, or a podcast. In 10-15 minutes, I feel like it keys me into a flow state. My verbal fluidity increases and more a focused calm settles in.

Ultimately, there's much research to be done to better understand ketosis, ketones, and anxiety. No formal human studies, but a couple promising animal studies and directional mechanistic explanations from cellular / animal work. Stay tuned as scientists further investigate.