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I believe that the use of ketogenic diets as a treatment for substance use disorders may be woefully underutilized by individuals and treatment centers. I think this is a potential problem. Are there profound psychosocial factors that drive substance use disorders? Absolutely. Am I suggesting that psychotherapy and social support are not needed? No. I think they can be invaluable. But clinical psychologists and psychiatrists, and quite frankly, all the other people running treatment centers for addiction recovery, really need to understand how ketogenic diets could improve the chances that people can recover from substance use disorders.

There is some very good science showing how ketogenic diets can help with recovery from addiction. So, this article is written not only for the clinical psychologist, addiction specialist, or other allied mental health professional looking to enhance the biological pillar of their biopsychosocial model of practice. It’s not even written just for an MD or other prescriber of the many medications we use to help people reduce cravings or manage withdrawal effects as part of their recovery. This article is also written for the person suffering from substance abuse disorder and the people who love them.

We are going to learn about pathological changes in the brain that we see in substance use disorders, how ketogenic diets can be a treatment, and some exciting clinical trials that, at the time of this writing, are recruiting participants. Finally, we will also introduce some potential issues that, while not in the literature at this time, will need to be further studied as ketogenic diets as a treatment for substance use disorder become more known and accessible.

Restoring Brain Energy: Ketogenic Diets and Substance Use Disorders

Acute alcohol intake is known to shift the way the brain uses fuel. There is a shift from glucose to acetate, an alcohol metabolite. In those with Alcohol Use Disorder, this shift persists beyond the intoxication period and becomes an accepted fuel source that the brain expects and is adapted for. In Alcohol Use Disorder (AUD), there is a chronic and persistent state of low brain glucose and high acetate metabolism. This is not new information. We have known that glucose metabolism is impaired in alcohol use disorder since 1966 when Roach and their colleagues published their initial suggestion that impaired glucose metabolism may be an underlying cause of alcoholism.

When someone is going through alcohol withdrawals and stops alcohol use, the brain stops getting the fuel it is expecting and equipped to handle.

Thus, we hypothesize that a paradoxical energy-deficit state in the brain emerges during alcohol detoxification when acetate levels in plasma decrease and that this contributes to withdrawal symptoms and neurotoxicity in patients with AUD

Wiers, C. E., Vendruscolo, L. F., Van der Veen, J. W., Manza, P., Shokri-Kojori, E., Kroll, D. S., … & Volkow, N. D. (2021). Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents. Science Advances7(15), eabf6780.

Why doesn’t the alcoholic brain just seamlessly switch back to glucose metabolism? The researchers do not say, but I would suspect that that machinery is either downregulated or damaged due to the high levels of oxidative stress that occur in an environment of substance use disorders.

We don’t just see this impairment in glucose metabolism in alcohol use. It is also an issue in opioid use.

Morphine treatment can down-regulate the expression level of certain metabolic enzymes, including PDH, LDH, and NADH, and thus impairs the energy metabolism. 

Jiang, X., Li, J., & Ma, L. (2007). Metabolic enzymes link morphine withdrawal with metabolic disorder. Cell Research17(9), 741-743. Jiang, X., Li, J. & Ma, L. Metabolic enzymes link morphine withdrawal with metabolic disorder. Cell Res 17, 741–743 (2007).

Morphine treatment, for example, can down-regulate the expression level of certain metabolic enzymes, including PDH, LDH (lactate dehydrogenase), and NADH. This down-regulation can impair the energy metabolism of glucose in the brain. PDH, in particular, is crucial for converting pyruvate into acetyl-CoA, and disruption in its activity can negatively impact energy production from glucose.

Methamphetamine users who have since become abstinent also show areas of brain hypometabolism.

In conclusion, we report that abstinent MA users have decreased rCMRglc in frontal white matter and impaired frontal executive functions…

Kim, S., Lyoo, I., Hwang, J. et al. Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users. Neuropsychopharmacol 30, 1383–1391 (2005).

Ketone bodies, including beta-hydroxybutyrate and acetoacetate, are unique in their ability to cross the blood-brain barrier and be utilized by brain cells. They have the ability to bypass broken glucose uptake machinery. Once in the brain, ketones are converted into acetyl-CoA, which then enters the citric acid cycle to produce ATP, which is energy the brain can then use. You may have heard that the brain needs a lot of energy, and that is absolutely true. It requires huge amounts of energy just to maintain brain function. Ketones are an absolute rescue source for areas of the brain that have become hypometabolic in substance use disorders and can no longer utilize glucose efficiently.

These results suggest that ketones are actually the preferred energy substrate for the brain because they enter the brain in proportion to their plasma concentration irrespective of glucose availability; if the energy needs of the brain are being increasingly met by ketones, glucose uptake decreases accordingly.

Cunnane, S. C., Courchesne-Loyer, A., Vandenberghe, C., St-Pierre, V., Fortier, M., Hennebelle, M., … & Castellano, C. A. (2016). Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Frontiers in molecular neuroscience, 53.

Given the success of ketogenic diets in addressing brain hypometabolism in neurodegenerative diseases, it is reasonable to consider their potential benefits in substance use disorders (SUDs). The neurological impacts of SUDs share similarities with those seen in mental illness and neurological disorders, (which also respond well to ketogenic diets) and suggest that ketogenic diets could offer a novel approach to support brain energy metabolism.

By shifting the brain’s primary energy source in this way, ketogenic diets appear to alleviate the energy deficit in the brain that emerges during alcohol detoxification. What does this mean for people trying to recover? In alcohol use disorder, we know it means there is a reduction in withdrawal symptoms and cravings.

A very important factor in treatment.

And with other SUDs showing areas of brain hypometabolism, I bet it makes you wonder how a ketogenic diet could help them, too.

Neuroinflammation in Substance Use: How the Ketogenic Diet Offers Relief

Neuroinflammation plays a crucial role in the development and progression of substance use disorders (SUDs) with serious impacts on cognitive function and driving pathogenic changes in brain structures. In people with substance use disorders, certain parts of the immune system can become overactive and cause inflammation in the brain. This inflammation can then increase the levels of specific signals in the body that contribute to inflammation, such as TNF-α, IL-1, and IL-6.

This is important for treatment because inflammation in the brain can have a significant impact on how the brain functions, and this can affect a person’s thoughts, feelings, and behaviors. For people with substance use disorders, this inflammation can contribute to cravings and make it harder to stop using substances. It can also affect memory, decision-making, and emotional regulation, making it more challenging to cope with stress and other triggers that can lead to relapse. Brain inflammation can make the journey to recovery more difficult by affecting a person’s ability to think clearly, make good decisions, and manage cravings and emotions.

In other words, this disruption of signals coming from unchecked brain inflammation affects how the brain functions and contributes to the symptoms and progression of substance use disorders. Inflammatory cytokines of the type we see in these disorders can result in persistent changes in basal ganglia and dopamine (DA) function, characterized by a lack of pleasure, fatigue, and psychomotor slowing. It can also be instrumental in leading to reduced neural responses to hedonic rewards, decreased DA metabolites, increased reuptake, and decreased turnover of presynaptic DA. These inflammatory responses may contribute to drug-induced rewards and drug relapse.

The basal ganglia and dopamine (DA) are crucial parts of the brain’s reward system, which is responsible for the feeling of pleasure and motivation.

When these areas are affected by inflammation, it can disrupt the normal functioning of the reward system. They lead to a lack of pleasure from activities that were once enjoyable (anhedonia), and the fatigue experienced further reduces a person’s motivation to engage in pleasurable activities. We have all seen ourselves or others with SUD suffer in this way when they attempt to stop use.

I don’t want you to think that the suffering that goes on with substance use disorders is all about dopamine. It is important to understand that the basal ganglia are also involved in cognition and emotion. Inflammation can potentially affect these processes, contributing to the cognitive deficits and emotional dysregulation we see in those suffering from these disorders.

I don’t want to leave you with the impression that Alcohol Use Disorder is the only Substance Use Disorder that contributes to chronic neuroinflammation. Brains with other substance use disorders (SUDs) besides alcohol use disorder (AUD) can also show signs of inflammation. Many substances of abuse, such as opioids, cocaine, and methamphetamine, are shown in the research literature to increase neuroinflammation.

Luckily, a ketogenic diet (KD) has been shown to play a neuroprotective role in SUDs by reducing neuroinflammation.

Individuals with AUD who adhered to a ketogenic diet (KD) – a diet high in fats and low in carbohydrates – exhibited lower levels of these inflammatory markers compared to those who followed a standard American diet (SA). This indicates that the KD may be effective in mitigating brain inflammation.

Besides being energy substrates, KBs are also active as intracellular signaling mediators, which participate in intracellular signaling cascades and regulate neuroinflammation directly or indirectly, especially βHB

Jiang, Z., Yin, X., Wang, M., Chen, T., Wang, Y., Gao, Z., & Wang, Z. (2022). Effects of ketogenic diet on neuroinflammation in neurodegenerative diseases. Aging and disease13(4), 1146.

Metabolism is a messy process. Especially if you are relying on fuels like glucose. Ketogenic diets shift metabolism from relying on glucose to using ketones as a primary energy source, which means a reduction in the production of pro-inflammatory mediators and a much-needed increase in the production of anti-inflammatory mediators. Ketone metabolism is “cleaner,” makes less of a ROS mess, and creates less damage for a struggling brain to deal with.

Ketogenic diets also have direct anti-inflammatory effects that are really powerful. They do this by modulating various inflammatory signaling pathways. One example is the ability of the diet to inhibit the NF-κB pathway and reduce the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are involved in the inflammatory response.

βHB can bind to HCA2 to further inhibit the production of pro-inflammatory cytokines and enzymes via the NF-κB pathway in activated primary microglia pretreated with βHB and stimulated with lipopolysaccharide (LPS)

Jiang, Z., Yin, X., Wang, M., Chen, T., Wang, Y., Gao, Z., & Wang, Z. (2022). Effects of ketogenic diet on neuroinflammation in neurodegenerative diseases. Aging and disease13(4), 1146.

The gut microbiome also plays a crucial role in controlling inflammation. Certain gut bacteria can produce metabolites that have anti-inflammatory effects, while others can produce metabolites that have pro-inflammatory effects. The ketogenic diet is quite frankly famous for its ability to alter the composition of the gut microbiome, influencing the production of these metabolites and subsequently modulating inflammation. The diet has been shown to increase the abundance of beneficial bacteria that produce short-chain fatty acids (SCFAs) to help produce anti-inflammatory effects.

Reductions in inflammation have a direct bearing on the level of oxidative stress a brain must endure, which brings us to the next section of this article. If you are a little confused about the difference between inflammation and oxidative stress and how they are related, I highly recommend this article to help clear it up before you move on with your reading of his post.

Combating Oxidative Stress and Mitochondrial Dysfunction: The Protective Role of the Ketogenic Diet in Substance Use Disorders

Oxidative stress occurs when there is an imbalance between the production of ROS and the body’s ability to detoxify these harmful molecules. The balance between the production of reactive oxygen species (ROS) and the body’s ability to handle the damage they cause is called oxidative stress.

Do we see oxidative stress in substance use disorders? You bet we do!

Our analysis showed that persons with SUD show higher oxidant markers and lower antioxidant markers than healthy controls.

Viola, T. W., Orso, R., Florian, L. F., Garcia, M. G., Gomes, M. G. S., Mardini, E. M., … & Grassi‐Oliveira, R. (2023). Effects of substance use disorder on oxidative and antioxidative stress markers: A systematic review and meta‐analysis. Addiction Biology28(1), e13254.

As if that wasn’t impressive enough, the ketogenic diet has been shown to increase the production of glutathione. Glutathione is a very powerful antioxidant created by your body that ensures you have a cellular defense against oxidative stress.

Neurotransmitters and Reward Systems in SUDs: The Balancing Act of the Ketogenic Diet

Substance use disorders (SUDs) are complex conditions that involve an interplay of genetic, environmental, and neurobiological factors. We know that the brain’s reward system plays a role in the development and maintenance of SUDs. Neurotransmitters (NTs) are chemical messengers that transmit signals that drive the reward system in the brain, and alterations in those systems can contribute to the development of SUDs.

Addiction is the key process that underlies substance use disorders, and research using animal models and humans has revealed important insights into the neural circuits and molecules that mediate addiction.

Kalin, N. H. (2020). Substance use disorders and addiction: mechanisms, trends, and treatment implications. American Journal of Psychiatry177(11), 1015-1018.

We already discussed Dopamine (DA) in other areas of this article, but I bring it up again in a discussion of its role in the early stages of addiction because it is critical in the acute rewarding effects of substances. As substance use progresses, glutamatergic projections become more prominent. Glutamate, the primary excitatory NT in the brain, is involved in neuroplasticity changes that diminish the value of natural rewards, decrease cognitive control, and promote compulsive drug-seeking behaviors. Dysregulation of glutamate homeostasis is a key neurometabolic feature of SUDs.

A certain amount of glutamate is supposed to be processed into the inhibitory transmitter GABA, but alterations in GABAergic systems often seen in SUD can lead to increased anxiety and stress, exacerbating the disorder. This disruption of the overall level of inhibitory activity in the brain, crucial for maintaining a balance between excitation and inhibition, contributes to disordered substance use. Additional NT systems, such as serotonin, epinephrine, and norepinephrine, are also disrupted in SUDs, leading to increased stress and anxiety and contributing to the cycle of addiction.

Once again, the ketogenic diet’s multiple effects can offer hope. By modulating the levels of these NTs and stabilizing brain energy metabolism, the ketogenic diet can help restore balance in the brain’s reward circuitry and reduce cravings for substances of abuse. For instance, the diet has been shown to increase GABA function, which can help alleviate anxiety and stress and improve mood. It has also been shown to modulate glutamate, serotonin, and dopamine levels, which might stabilize mood and reduce the emotional dysregulation often seen in SUDs.

How does it do this? We don’t totally know, but we do know that ketogenic diets have an impact on the brain’s electrical control in neurons, which is directly related to the functioning of neurotransmitter systems. Electrical control in neurons is essential for normal brain function and is generated by ion channels and synaptic receptors. These electrical activities are fundamental processes that enable the release and reception of neurotransmitters at synapses.

For example, when an action potential reaches a synapse, it triggers the release of neurotransmitters, which then bind to synaptic receptors on the postsynaptic neuron. This binding leads to changes in the membrane potential and further electrical signaling. The proper functioning of this system is crucial for the brain’s reward circuitry, which is often dysregulated in SUDs.

The diet affects electrical regulators in the brain, including ATP-sensitive K+ channels, voltage-dependent Ca2+ channels, AMPA-type glutamate receptors, and adenosine A1 receptors, among others. Don’t let all these fancy terms you may or may not know distract you. These are powerful regulators that work together to elicit neuronal inhibition and improve the fluidity of cell membranes, leading to more efficient neurotransmitter signaling. This is one of the ways the effects of ketogenic diets are directly related to the functioning of neurotransmitter systems, helping to ensure the proper release and reception of neurotransmitters at synapses.

So, when I tell you that the ketogenic diet offers a multifaceted approach to addressing the NT imbalances and dysfunctions seen in SUDs, you wouldn’t, at this point, be surprised. The growing body of evidence supporting the benefits of the ketogenic diet in treating other neurological and psychiatric conditions further underscores its potential in addressing the complex interplay of NT dysfunctions in SUDs.


If you, or someone you love, would like to participate in clinical trials that are recruiting those here:

But don’t feel like you have to wait for a clinical trial to benefit. You can hopefully find a treatment center near you (or not so near you) using ketogenic diets for Substance Use Disorder (SUD), or you can pull together your own treatment team from existing ketogenic metabolic therapy practitioners, mental health professionals, and a medical professional that can help with prescriptions.


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