Chapter 16

CONTRIBUTING CAUSE

Drugs and Alcohol

It’s well known that drugs and alcohol can lead to mental disorders, and that people with mental disorders are more likely to use drugs and alcohol. Think of the young man smoking too much marijuana who ends up with schizophrenia. Or the alcoholic who develops dementia. Or the cocaine addict with bipolar disorder. Most people think these are just the results of toxic drugs on the brain. Or that maybe these people were predisposed to mental illness and the drugs pushed them over the edge. Both assertions are true. But exactly how do they cause mental illness? Up until now, no one could say for sure. The brain energy theory offers clear answers: drugs and alcohol converge on metabolism and mitochondria.

Most drugs fit into one of two categories—they either stimulate or inhibit cells. This includes alcohol, tobacco, marijuana, cocaine, amphetamines, and opiates. Some drugs work on specific cells in the brain or body, while others have broader effects on different types of cells. For example, alcohol and marijuana, which I’ll focus on soon, both have broad effects throughout the body. They act through receptors mostly found on the surfaces of cells, which then impact the mitochondria within those cells. However, mitochondria also have their own receptors for marijuana, nicotine, alcohol, and Valium right on their membranes. These drugs directly impact mitochondria.

Drugs and alcohol form a feedback loop with metabolism and mitochondria. People can enter this feedback loop in different ways, but once they get in, it can be difficult to get out.

Some people start using drugs or alcohol due to peer pressure or other social influences. They can be perfectly happy and metabolically healthy when they begin. Using excessive amounts of drugs and alcohol over time, however, impairs metabolism and mitochondrial function. Once impaired, people can get to a point in which they “need” the substances to feel normal. Notice that I used the word “normal” and not “good.” Initially, when people begin using drugs and alcohol, they often feel good. This reinforces the behavior. People like feeling good. But over time, the brain adapts to these substances and tries to counteract them. As the brain changes, people can begin to feel “bad” when they aren’t using the substance. This leads to a vicious cycle in which they now need the substance just to feel normal. They often can’t get the same high that they once got. When they try to go without the substance, they suffer in some way. This usually drives them to use again. And now they are trapped.

Other people get into drugs and alcohol because they are already metabolically compromised. They already suffer from depression, anxiety, insecurity, psychosis, or something distressing. They are looking to feel better. If their symptoms are bad enough, they will try anything. As a broad overview, if they suffer from symptoms of underactive cells, such as some of the symptoms of depression, taking something that is stimulating will make them feel better. If they suffer from symptoms of overactive or hyperexcitable brain cells, such as anxiety or psychosis, taking something that is sedating and inhibits cell activity can make them feel better. If the substance works well, they can get hooked. In some ways, who can blame them? They just want to feel better. Sometimes, people don’t necessarily feel “better” with substances; they just feel “different”—numb or out of it. For some, this can be preferable to the way they feel otherwise. In any case, this is probably why all mental disorders are associated with higher rates of substance use disorders.

Drugs and alcohol can have immediate effects on mitochondrial function that can result in symptoms of many psychiatric disorders. Different drugs can quickly produce hallucinations, delusions, manic symptoms, depressive symptoms, cognitive impairment, and other symptoms. I can’t review all of this in one chapter, but I’ll share some highlights of how alcohol and marijuana can impact mitochondria.

Alcohol

Alcohol has profound effects on metabolism and mitochondria. When consumed in excess, it’s known to be toxic to the liver and brain. Mitochondria play a primary role in this toxicity. I’ll walk you through some of the science.

When people drink alcohol, the liver does most of the processing. An enzyme called alcohol dehydrogenase (ADH) converts it into acetaldehyde, a toxic molecule to cells. Another enzyme, cytochrome P450 2E1 (CYP2E1), can also make this conversion. CYP2E1 happens to be located directly on mitochondria or the endoplasmic reticulum. Yet another enzyme, aldehyde dehydrogenase (ALDH), then converts acetaldehyde into a less toxic molecule, acetate. ALDH comes in two forms: one that ends up in the cytoplasm and another that ends up inside mitochondria. Acetate then gets used by mitochondria as a fuel source. As you can see, mitochondria are playing a role in all of this.

If people binge drink, these enzyme systems back up, and acetaldehyde levels rise. The first signs of problems are with mitochondria. They swell up, have trouble producing ATP, and create more ROS. Numerous studies have documented mitochondrial impairment, and even destruction, from large doses of alcohol.¹ This is likely the cause of death in alcohol poisoning.

Chronic alcohol consumption leads to chronic oxidative stress, a sign of mitochondrial impairment. This leads to inflammation, which only makes the problems worse. All of this is occurring throughout the body, but particularly in the liver and brain.

Even short periods of heavy alcohol use can have lasting effects. Researchers looked at adolescent rats exposed to two weeks of binge drinking and the effects on mitochondria in their brains over time.² They found that binge drinking immediately impaired mitochondrial function, not surprising after what I just shared with you. However, the effects in the hippocampus lasted into adulthood, with reduced levels of mitochondrial proteins, reduced ATP production, and problems managing calcium.

Dr. Nora Volkow, the director of the National Institute on Drug Abuse, has been studying the connections between addiction and metabolism for years now and is a pioneer in this field. She and others have discovered some surprising findings in chronic alcoholics. When people drink alcohol, their brains use less glucose as an energy source and instead use acetate from alcohol.³ Over time, alcoholics develop a problem with brain glucose metabolism. Their brain cells become energy deprived when they are sober.⁴ When they drink alcohol again, acetate fuels these struggling brain cells and provides relief. This brain energy deficit may be one of the reasons that alcoholics have trouble staying away from alcohol. Volkow and others set out to see if they could help these struggling brain cells with something other than alcohol. They turned to the ketogenic diet.

They recruited thirty-three people with alcohol use disorder and admitted them to a detox unit.⁵ Half of them got a ketogenic diet and the other half got the standard American diet for twelve weeks. The researchers detoxed participants using standard protocols and conducted a variety of blood tests and brain scans looking at brain metabolism in targeted regions. They found that people who got the ketogenic diet needed less detox medication and had fewer withdrawal symptoms. They also reported fewer cravings for alcohol. Brain scans showed improved brain metabolism and reduced levels of brain inflammation compared to those on the standard American diet. This pilot study demonstrated that a dietary intervention, seemingly unrelated to alcoholism, could make a big difference in the brains, and symptoms, of real people. This is how science can change the mental health field.

I want to point out one caution. As part of this work, the researchers tested what impact the diet might have on blood alcohol levels if a person were to drink. They tested rats on the ketogenic diet and found that their blood alcohol levels increased fivefold compared to rats on a normal diet, even though they all got the same amount of alcohol. This means that if people with alcohol use disorder were to try the ketogenic diet on their own, it could be dangerous if they drink. They could get much more intoxicated than usual. I don’t mean to imply that interventions like this can’t be used, but issues like this need to be considered, and people need to develop a safe way to manage these risks.

Marijuana

Marijuana is increasingly popular. Many people tout it as a “cure-all” for whatever ails you. It is thought to be good for seizures, pain disorders, nausea, anxiety, PTSD, and OCD. And yet, it can also cause mental symptoms, including learning and memory impairment, a lack of motivation, and possibly psychotic disorders.⁶

The brain energy theory offers a straightforward way to understand all these observations. They all relate to metabolism and mitochondria. The symptoms that improve are due to hyperexcitability. Any substance that reduces mitochondrial function in the correct cells could reduce these symptoms. However, such a substance could also cause symptoms if it impairs mitochondrial function too much. Is there any evidence that marijuana impacts mitochondria in these ways? Well, by now, you know I wouldn’t ask that question if the answer wasn’t a resounding yes.

Marijuana affects the endocannabinoid system in the human body. Receptors for cannabinoids are found throughout the body, but they are highly concentrated in the brain. There are primarily two types of receptors—CB1 and CB2. These are located on cell membranes, but CB1 receptors are also located directly on mitochondria. Because there are different types of receptors located on a wide variety of cells throughout the body, it’s not fair to say there is one universal effect on all cells. However, the predominant theme in neurons is that marijuana slows the function of mitochondria through CB1 receptors.⁷ Brain imaging studies of almost eight hundred adolescents, some who used marijuana and others who didn’t, showed that the regions of the brain highest in CB1 receptors showed “accelerated age-related cortical thinning” in the marijuana users, meaning that marijuana’s effects on these mitochondrial receptors was likely the cause of these brain areas getting thinner.⁸

A mouse study published in Nature found that mitochondria in astrocytes have a direct role in mediating the effects of marijuana—they control the amount of glucose and lactate (energy sources) going to neurons.⁹ This, in turn, has direct effects on social behaviors. All of this is mediated through the CB1 receptors on mitochondria. When these receptors were activated by THC (the active ingredient in marijuana), it led to a reduction in both mitochondrial function and energy sources going to neurons. It also led to social withdrawal behaviors. When the researchers removed mitochondrial CB1 receptors, THC no longer had the same effects. The mitochondria weren’t impacted in the same ways; the energy sources going to neurons weren’t reduced; and the social withdrawal behaviors didn’t occur, even though the mice were still being exposed to marijuana, and CB2 receptors were available on cells.

Another study from Nature tried to determine what causes the memory impairment from marijuana use. The researchers were ultimately hoping to better understand how memory works. The CB1 receptors on mitochondria again play a key role. The researchers found that marijuana’s effect on CB1 receptors directly impacted mitochondrial movement, synapse function, and memory formation. When they deleted the CB1 receptors, marijuana no longer had any of these effects, and memory wasn’t impaired. These researchers concluded: “By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.”¹⁰ In other words, brain energy and mitochondria play a primary role in our ability to remember.

There are many other addictive substances that impact metabolism and mitochondria, but I hope these two examples give you an idea of how substance use fits into the theory of brain energy.

Drug and Alcohol Treatment

Drug and alcohol treatment programs play a powerful role in improving mental and metabolic health. Reducing or stopping the use of substances that impair mitochondrial function is critically important.

Entire books are written on this topic. I won’t try to review their conclusions here. Numerous strategies are available, including inpatient detox, residential programs, outpatient therapy, group therapy, medication-assisted treatments, twelve-step programs, and halfway houses.

Interestingly, a new area of research is on the use of psychedelics as a treatment for some psychiatric disorders. I’ll get to that in Chapter 18.

Summing Up