Hydrogen Sulfide and Major Depression: Last one in is a rotten egg

There is a common notion that Major Depression is due to a “chemical imbalance.” Cells in the brain called neurons communicate with one another with substances called neurotransmitters. Many are under the impression that the chemical imbalance of Major Depression is a lack of the “happy” neurotransmitter, serotonin, or not enough of the “reward” neurotransmitter, dopamine. However, no one or two neurotransmitters are responsible for experiencing happiness and contentment or, conversely, depression. Moreover, both increased and decreased activities of certain neurotransmitters, including serotonin, have been associated with anxiety and depression. Indeed, serotonin is a neurotransmitter that activates 14 different subtypes of receptors. It has widespread and varied influences across neural networks in the brain. Its role in depression depends on where and how it acts, not just on how much is present.

There are dozens, perhaps hundreds, of different neurotransmitters in the brain, and only subtle differences between neurotransmitters in the brain and chemicals that many other types of cells in the body release to communicate with one another and maintain an overall balance of functions in the body. Many of those substances, some referred to as hormones and others as cytokines, circulate through the body and enter the brain as bridges of communication between the body and the central nervous system. It is the coordinated activity of hundreds of such substances, made in the brain or transported into the brain, that alter physiological states and moods in responses to environmental and internal demands and changes.

Historically, there have been only a few different classes of neurotransmitters in the brain. The best-known class of neurotransmitter consists of the monoamines. These neurotransmitters are derived from amino acids, which are the chemical building blocks of proteins. Monoamines in the human brain include serotonin, dopamine, norepinephrine, epinephrine, histamine, and the so-called trace monoamines phenethylamine, tyramine, synephrine, and octopamine. (In case you are wondering, octopamine was first identified in octopus salivary glands, and it serves as a major neurotransmitter in the brains of cephalopods.) Closely related neurotransmitters are actual amino acids, including glutamate, GABA and glycine. Acetylcholine, neither a monoamine nor amino acid but a unique, small molecule derived from the nutrient choline, was one of the first neurotransmitters to be discovered. Other types of neurotransmitters are the peptides, which are short chains of amino acids. Two well-known peptide neurotransmitters are the so-called “love hormone” oxytocin and the “endogenous morphine” peptides, known as endorphins.  Some neurotransmitters, such as cannabinoids, and neuromodulators such as prostaglandins, are derived from fat molecules. Some steroids, which are large, multi-ringed molecules, can also act as neurotransmitters and neuromodulators.

Some of the most recently identified neurotransmitters are, surprisingly, small gas molecules. These neurotransmitters, referred to as gasotransmitters, include nitrous oxide, also known as laughing gas; carbon monoxide, a gas that is deadly if inhaled in sufficient concentrations; and the newest addition, hydrogen sulfide, the gas that helps create the stench of rotten eggs. Given the moniker, laughing gas, it should not come as a surprise that nitrous oxide can affect mood and may have antidepressant properties. Contrary to what one might expect from a potentially deadly gas, minute quantities of carbon monoxide appear to interact with dopamine and other neurotransmitters in the brain to improve mood and help resist inflammation and stress. Although hydrogen sulfide can be deadly in high concentrations, growing evidence suggests that it may also play an important role in mood stabilization.

Several recent studies have shown that people suffering Major Depression have lower levels of hydrogen sulfide in their blood than do individuals who are not depressed. Reduced levels of hydrogen sulfide are also seen in people suffering Bipolar Disorder during the depressed phases of their illness. The more severe the depression, the lower are the blood levels of hydrogen sulfide. On the other hand, studies in laboratory animals have suggested that increasing levels of hydrogen sulfide levels can alleviate depression-like symptoms. For example, artificially increasing levels of the stress hormone, corticosterone, in rodents can cause depression-like behaviors in those animals. However, treatment with the chemical sodium hydrosulfide, which acts to increase levels of hydrogen sulfide in the body, prevented the emergence of those behaviors. Indeed, administration of sodium hydrosulfide was more effective than treatment with the commonly used human antidepressant, Zoloft. In another study, rats subjected to inescapable foot-shock, which is used as an animal model of PTSD, exhibited both depression-like behaviors and reduced levels of hydrogen sulfide in the hippocampus. The hippocampus is a part of the brain that connects memory and awareness of changes in the environment with emotional responses. When animals that received shocks  were subsequently administered sodium hydrosulfide, those depression-like symptoms significantly decreased. Neurochemical studies have provided insight into how hydrogen sulfide might offer protection from the symptoms of Major Depression. Among its complex actions in the brain are stimulating brain-derived neurotrophic factor, inhibiting the key enzyme glycogen synthase kinase-3β, modulating the enzyme known as the mammalian target of rapamycin, enhancing the actions of insulin, stimulating energy-producing mitochondria, dampening stress responses, reducing neuroinflammation, and acting as an anti-oxidant. All of those effects are also produced, directly or indirectly, by antidepressant medications.

Consistent with the above findings, several natural sources of hydrogen sulfide, most notably garlic and onions, have long been used by herbalists and practitioners of folk medicine to promote health and well-being. Both plants are rich in sulfur-containing compounds, such as alliins and cysteine derivatives, that generate hydrogen sulfide. A recent Chinese study found that high consumption of garlic is associated with reduced incidence of Major Depression. Another study found garlic useful in reducing the severity of Premenstrual Dysphoric Disorder. Recently published studies have also confirmed old folk beliefs in the ability of onion juice to relieve insomnia. Those findings in humans are supported by a plethora of studies showing the abilities of extracts of garlic and onion to reduce the emergence of anxiety and depression-like behaviors in animal models. More powerful, concentrated sources of hydrogen sulfide are available over-the-counter or on the internet. Purified extracts of garlic, high in sulfur-rich allicin, are one such source, as well as N-acetylcysteine, or NAC. NAC has found use in medicine as an antidote for Tylenol overdose. However, a number of papers have shown NAC to beneficial effects on anxiety, depression, and compulsive behaviors. One mechanism of NAC action is likely generation of the potent antioxidant substance, glutathione. However, NAC also increases hydrogen sulfide in the body.    Sulphoraphane, yet another source of hydrogen sulfide, is found in cruciferous vegetables, such as broccoli, Brussel sprouts, kale, and cabbage. It can also be purchased in pure form in health food stores or on the internet.    Sulphoraphane has been found in both human and animal studies to hold promise in treatment of anxiety and Major Depression.  It is unlikely that deficits in hydrogen sulfide are solely responsible for human mood disorders. However, restoring normal levels of this gasotransmitter may help, or even be essential, in their treatment. Thus, one might say the last one on the hydrogen sulfide bandwagon may be both a sad and a rotten egg.