Substance P is a neuropeptide (neurotransmitter) most known for its role in pain perception. It also has a wide range of effects in nausea, stress responses, emotional behavior, learning, and memory.
However, although substance P is important for survival, excess levels are harmful and can lead to a variety of diseases. Read more to learn about what conditions are associated with high and low levels of substance P and how to increase and decrease it.
What is Substance P?
Substance P was first isolated from horse brain and gut extracts in the 1930s as a mystery substance with strong blood pressure-lowering and smooth muscle contractile properties .
Because it was in powdered form, it was named substance P (“P” for powder) .
Today, it is fully recognized as a neurotransmitter that is widely dispersed throughout the body, with high levels in the brain, gut, and spinal cord [1, 2].
Because of its broad distribution in the body, substance P influences a diverse range of functions. It also amplifies or excites most cellular processes .
Substance P is involved in:
- Pain perception 
- Emotional behavior 
- Stress 
- Nausea and vomiting 
- Inflammation 
- Smooth muscle contraction 
- Saliva production 
- Blood cell formation 
- Wound healing 
- Allergy 
Most actions of Substance P’s binding to NK-1 (neurokinin receptor subtype) receptors mediate its actions. The receptors are found in a variety of cell types (e.g., neurons, muscle cells, immune cells) .
The cell quickly takes NK1 receptors back up after substance P binding. The cells remove and break down substance P, while NK-1 receptors are recycled to the cell membrane .
Substance P and the NK-1 receptor have been extensively researched for their role in a variety of diseases .
Drugs that block Nk1 receptors have been used to treat mood disorders (depression, anxiety, and stress), nausea from chemotherapy, rheumatoid arthritis, and inflammatory bowel disease [15, 16].
Substance P levels are increased in stressful or anxiety-provoking situations .
Stressful stimuli like heat and pain trigger the release of substance P from sensory nerve endings. The amount of its release is proportional to the intensity and frequency of stimulation .
Once released, substance P may have direct actions as a neurotransmitter or other functions on non-nerve cell targets .
It can also be cleared and inactivated by enzymes that break down proteins (e.g., NEP and ACE) [18, 19].
Roles of Substance P
1) Widens Blood Vessels
Substance P is a powerful vasodilator (widens blood vessels) of large blood vessels in animals and humans [20, 21].
It widens blood vessels by binding to NK1 receptors on the vessel wall and causing the release of nitric oxide .
Unlike other neurotransmitters, vasodilation caused by substance P declines during continuous injection. This is likely due to the rapid internalization of Nk1 receptors after activation .
2) Plays a Dual Role in Pain Management
Substance P helps transmit pain signals from different parts of the body to the spinal cord and brain (where the pain is perceived) [24, 25, 26].
Specifically, sensory nerve fibers (i.e., primary afferent nerve fibers) detect pain and release substance P, which in turn binds to Nk-1 receptors in the spinal cord. Nerve cells in the spinal cord then relay the pain information to the brain [27, 28].
Substance P also increases sensitivity to pain indirectly by its inflammatory effects (swelling, immune cell recruitment, vasodilation) .
Interestingly, in some studies, substance P has a pain-relieving effect. For example, in mice with acid-induced chronic muscle pain, substance P reduced pain by decreasing the detection of pain signals in muscle sensory neurons .
This dual role of substance P in pain management may explain why drugs that block Nk-1 receptors have been unsuccessful in relieving pain in clinical trials [25, 31, 32].
3) Increases Inflammation
Substance P is secreted by many inflammatory immune cells (i.e., macrophages, eosinophils, lymphocytes, and dendritic cells) and initiates the production of inflammatory cytokines (IL-1β, IL-6, and IL-8) [33, 34, 7].
In turn, most cytokines bind to substance P and NK-1 receptors .
Substance P causes brain inflammation, a local inflammatory response to some types of infection or injury .
All of these effects are mediated by the Nk-1 receptor [37, 38].
4) Improves Learning and Memory
Substance P has excitatory effects in the hippocampus or the memory center of the brain. It promotes long-term potentiation, which is associated with learning and the formation of memories [39, 40, 41].
Moreover, injection of substance P in parts of the brain that control motivation and reward facilitated learning and memory in rats [42, 43].
Substance P stimulated the growth of nerve stem cells of adult rats under both normal conditions and during injury. It may help with nerve cell formation after injury .
5) Causes Nausea
Substance P and its receptor are present in high levels in the Area Postrema (the vomiting center in the medulla) along with other neurotransmitters (e.g., choline, histamine, dopamine) .
It activates the NK-1 receptors. Applying substance P in the vomiting center of the brain causes dry heaving in ferrets [46, 47, 48].
Drugs that block Nk1 receptors can help treat nausea associated with chemotherapy .
6) Causes an Itching Sensation
Substance P (injected in the skin) causes an itch sensation in human skin by stimulating histamine release from mast cells .
Substance P also causes scratching behavior in mice but through mechanisms independent of histamine [50, 51].
7) Enhances Wound Healing
Substance P accelerated wound healing in the eyes (in rabbits) and spinal cord (in rats) by promoting a local inflammatory response essential for healing [52, 53, 54].
Conditions with Elevated Substance P
1) Causes Skin Disorders
Patients with eczema have higher blood levels of substance P .
Substance P causes mast cell accumulation and inflammation, which is involved in the development of eczema. Mast cells are white blood cells that play a role in allergic and inflammatory reactions .
Because of its role in inflammation and cell growth, substance P can contribute to psoriasis progression. Psoriasis skin and patches have an increased production of substance P and the Nk-1 receptor [56, 57, 58].
Substance P can cause pruritus, or itchy skin, in humans indirectly by stimulating histamine release from skin mast cells [59, 60].
There is a positive correlation between substance P levels and itchiness in disorders involving pruritus (e.g., contact dermatitis) [61, 62].
Aprepitant, a drug that blocks substance P receptors, was effective in treating chronic pruritus in one clinical study .
2) May Cause Stress, Anxiety, and Depression
Substance P and neurokinin 1 (NK1) receptors are abundant in brain areas involved in emotion and behavioral responses to stress [17, 64, 65].
The brain releases substance P during stressful situations at a rate proportional to the intensity and frequency of stimulation .
Also, direct injections of substance P in the brain induced a range of fear and anxiety-related behaviors in animals [17, 67, 5].
Depression and PTSD patients have markedly higher levels of substance P in their cerebrospinal fluid .
In a study (DB-RCT) of patients with major depression and anxiety, a drug that blocks NK1 receptors reduced symptoms of depression and anxiety .
3) May Cause Aggression
Substance P levels are directly associated with rage and aggression in mammals [70, 71, 72].
It also caused aggressive behavior in rats and cats. Although mechanisms remain unclear, Nk-1 receptors in the hypothalamus may be involved [73, 74, 70].
4) May Be a Factor in Fibromyalgia
Fibromyalgia patients have higher spinal fluid levels of substance P .
Chronic stress, a factor linked to fibromyalgia, increases substance P levels [76, 77].
5) May Contribute to Obesity
Substance P promotes appetite in mice. Drugs that block its receptor reduce weight gain and blood levels of insulin and leptin after a high-fat diet [78, 79].
Mice without Nk-1 receptors also have reduced weight gain and lower insulin levels .
6) May Promote Cancer Growth
Tumor cells have high levels of substance P and NK-1 receptors .
In cell-based studies, substance P promoted tumor cell growth, tumor cell migration (invasion, infiltration, and metastasis), and the formation of new blood vessels by binding to Nk-1 receptors .
In contrast, drugs that block Nk-1 receptors inhibited cancer cell growth, prevented cancer cell movement, and stopped the growth of new blood vessels .
7) May Be a Factor in Arthritis
Substance P blood levels are positively associated with chronic rheumatoid arthritis .
Higher levels are also linked to increased chronic pain intensity in arthritis patients .
Substance P release is enhanced in inflamed tissues, which may explain the increase in pain sensitivity .
8) May Be a Factor in Gut Disorders
Substance P and IBS
People with irritable bowel syndrome (IBS) have elevated substance P and mast cell levels [85, 86].
Substance P activates and induces the secretion of mast cells. Mast cell count is positively correlated with gut leakiness and inflammation, both key factors in IBS development [87, 88, 89, 90].
Substance P and IBD
Inflammatory bowel disease (IBD) patients have higher substance P and NK-1 receptor levels in their rectums and colons .
Substance P increases inflammatory cytokine production from pre-fat cells in the gut, which contributes towards IBD development .
9) Worsens Sickle Cell Disease Symptoms
Blood levels of substance P are elevated in patients with sickle cell disease and increase further during sickle cell crisis. A sickle cell crisis occurs when blood cells get stuck in small blood vessels and slow or block blood flow .
Substance P stimulates cytokines (TNF-α and IL-8) that promote the adherence of sickle red blood cells to the vessel wall, which raises the risk of a sickle cell crisis .
Also, the increased levels of substance P may partly account for the high pain sensitivity experienced in this disease .
10) Contributes to Cystitis
Patients with interstitial cystitis (inflammation of the bladder) have increased numbers of substance P positive nerve fibers and mast cells in the bladder .
Substance P triggers mast cell secretion, which promotes a local inflammatory response and contributes to bladder inflammation and pain .
11) Infections – HIV, Measles, RSV
The Nk-1 receptor and Substance P have specific effects in different types of infections .
Substance P and HIV
It has a bidirectional relationship with HIV. It can enhance HIV infection by:
- facilitating HIV entry into immune cells [96, 97].
- promoting HIV replication within immune cells [95, 98].
In turn, HIV increases the production of substance P in immune cells. This effect explains why HIV-infected men and women have higher blood substance P levels compared to healthy individuals [99, 100].
Substance P and Measles
Nk-1 receptors levels are higher during a measles virus (MV) infection, which facilitates measles viral entry and replication in cells. However, substance P blocks the entry of measles virus in cells, likely by displacing it from Nk-1 receptors [101, 102, 103, 104].
Substance P and RSV
Substance P production is higher in respiratory syncytial virus (RSV). Airways inside the lung are more susceptible to the inflammatory effects of substance P during RSV infection in rats [105, 106].
Conditions with Low Substance P
Alzheimer’s patients have lower substance P levels in their brain and spinal fluids .
Since substance P improved learning, memory, and the survival of neurons during injury in animal studies, its deficiency may contribute to Alzheimer’s development .
In a rat model of Alzheimer’s disease, substance P treatment recovered cognitive function by reducing the toxic effects of amyloid-β (Aβ) deposits on neurons .
2) Type 1 Diabetes
Substance P is decreased in the blood of type 1 diabetes patients, especially in those with diabetic neuropathy .
Injection of substance P in the pancreatic arteries of non-obese diabetic mice (genetically prone to develop type 1 diabetes) reversed abnormal insulin resistance, insulitis (inflammation of the hormonal tissue in the pancreas), and diabetes for weeks .
In contrast, substance P has a different effect on Type 2 diabetes. In cell-based studies, substance P promoted insulin resistance, likely a result of its inflammatory effects [111, 112, 113].
Normal Blood Levels of Substance P
Substance P levels in humans are highly variable and range from 12.25 to 397 pg/ml. These values depend on the sample preparation and method of measurement .
Factors that Decrease Substance P
Natural Substances That Lower Substance P
- Capsaicin: Capsaicin, an active component of chili peppers, makes the sensory receptors release substance P. Eventually, substance P becomes depleted and the nerve endings reduces its release. It also works by de-sensitizing sensory receptors on the skin, which helps reduce pain [115, 116].
- Internal opioids (e.g., enkephalin): These help decrease the release of substance P from sensory nerve endings [117, 118].
- Adenosine: It reduces substance P in the cerebrospinal fluid 
Drugs that Lower Substance P
- Nk-1 Receptor Blockers: These drugs work by preventing the binding of substance P to its main receptor, Nk-1. They have been successful in treating mood disorders, nausea from chemotherapy, itchiness, rheumatoid arthritis, and inflammatory bowel disease [15, 16, 120].
- Narcotics: Morphine inhibits substance P release from nerve endings .
Hormones that Lower Substance P
Lifestyle Factors that Lower Substance P
- Massage therapy: Substance P levels decreased after massage therapy in fibromyalgia patients .
Factors that Increase Substance P
Natural Substances That Increase Substance P
Drugs that Increase Substance P
- Muscarinic acetylcholine receptor activators: Anethole trithione, pilocarpine, and cevimeline elevate substance P levels in human saliva 
- THC increases the production of substance P 
Lifestyle Factors that Increase Substance P:
- Stress: Physical and emotional stressors stimulate the release of substance P from sensory nerves .
Genes that Increase Substance P
A polymorphism in the angiotensin-converting enzyme (ACE) (the enzyme that degrades substance P) gene is associated with substance P levels in parts of the brain. Individuals with the DD genotype have higher substance P levels .