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 1930’s as a mystery substance with strong blood pressure-lowering and smooth muscle contractile properties [R].

Because it was in powdered form, it was named substance P (“P” for powder) [R].

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 [R, R].

Substance P Function

Because of its broad distribution in the body, substance P influences a diverse range of functions. It also amplifies or excites most cellular processes [R].

Substance P is involved in:

  • Pain perception [R]
  • Emotional behavior [R]
  • Stress [R]
  • Nausea and vomiting [R]
  • Inflammation [R]
  • Smooth muscle contraction [R]
  • Saliva production [R]
  • Blood cell formation [R]
  • Wound healing [R]
  • Allergy [R]

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) [R].

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 [R].

Substance P and the NK-1 receptor have been extensively researched for their role in a variety of diseases [R].

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 [R, R].

Substance P Activation

Substance P levels are increased in stressful or anxiety-provoking situations [R].

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 [R].

Once released, substance P may have direct actions as a neurotransmitter or other functions on non-nerve cell targets [R].

It can also be cleared and inactivated by enzymes that break down proteins (e.g., NEP and ACE) [R, R].

Roles of Substance P

1) Substance P Widens Blood Vessels

Substance P is a powerful vasodilator (widens blood vessels) of large blood vessels in animals and humans [R, R].

It widens blood vessels by binding to NK1 receptors on the vessel wall and causing the release of nitric oxide [R].

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 [R].

2) Substance P 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) [R, R, R].

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 [R, R].

Substance P also increases sensitivity to pain indirectly by its inflammatory effects (swelling, immune cell recruitment, vasodilation) [R].

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 [R].

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 [R, R, R].

3) Substance P 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) [R, R, R].

In turn, most cytokines bind to substance P and NK-1 receptors [R].

Substance P causes brain inflammation, a local inflammatory response to some types of infection or injury [R].

All of these effects are mediated by the Nk-1 receptor [R, R].

4) Substance P 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 [R, R, R].

Moreover, injection of substance P in parts of the brain that control motivation and reward facilitated learning and memory in rats [R, R].

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 [R].

5) Substance P 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) [R].

It activates the NK-1 receptors. Applying substance P in the vomiting center of the brain causes dry heaving in ferrets [RR, R].

Drugs that block Nk1 receptors can help treat nausea associated with chemotherapy [R].

6) Substance P Causes an Itching Sensation

Substance P (injected in the skin) causes an itch sensation in human skin by stimulating histamine release from mast cells [R].

Substance P also causes scratching behavior in mice but through mechanisms independent of histamine [R, R].

7) Substance P 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 [R, R, R].

Conditions with Elevated Substance P

1) Substance P Causes Skin Disorders

Substance P and Eczema

Patients with eczema have higher blood levels of substance P [R].

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 [R].

Substance P and Psoriasis

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 [R, R, R].

Substance P and Pruritus

Substance P can cause pruritus, or itchy skin, in humans indirectly by stimulating histamine release from skin mast cells [R, R].

There is a positive correlation between substance P levels and itchiness in disorders involving pruritus (e.g., contact dermatitis) [R, R].

Aprepitant, a drug that blocks substance P receptors, was effective in treating chronic pruritus in in one clinical study [R].

2) Substance P 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 [R, R, R].

The brain releases substance P during stressful situations at a rate proportional to the intensity and frequency of stimulation [R].

Also, direct injections of substance P in the brain induced a range of fear and anxiety-related behaviors in animals [R, R, R].

Depression and PTSD patients have markedly higher levels of substance P in their cerebrospinal fluid [R].

In a study (DB-RCT) of patients with major depression and anxiety, a drug that blocks NK1 receptors reduced symptoms of depression and anxiety [R].

3) Substance P May Cause Aggression

Substance P levels are directly associated with rage and aggression in mammals [R, R, R].

It also caused aggressive behavior in rats and cats. Although mechanisms remain unclear, Nk-1 receptors in the hypothalamus may be involved [R, R, R].

4) Substance P May Be a Factor in Fibromyalgia

Fibromyalgia patients have higher spinal fluid levels of substance P [R].

Chronic stress, a factor linked to fibromyalgia, increases substance P levels [R, R].

4) Substance P 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 [R, R].

Mice without Nk-1 receptors also have reduced weight gain and lower insulin levels [R].

5) Substance P May Promote Cancer Growth

Tumor cells have high levels of substance P and NK-1 receptors [R].

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 [R].

In contrast, drugs that block Nk-1 receptors inhibited cancer cell growth, prevented cancer cell movement, and stopped the growth of new blood vessels [R].

6) Substance P May Be a Factor in Arthritis

Substance P blood levels are positively associated with chronic rheumatoid arthritis [R].

Higher levels are also linked to increased chronic pain intensity in arthritis patients [R].

Substance P release is enhanced in inflamed tissues, which may explain the increase in pain sensitivity [R].

7) Substance P 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 [R, R].

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 [R, RR, R].

Substance P and IBD

Inflammatory bowel disease (IBD) patients have higher substance P and NK-1 receptor levels in their rectums and colons [R].

Substance P increases inflammatory cytokine production from pre-fat cells in the gut, which contributes towards IBD development [R].

8) Substance P 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 [R].

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 [R].

Also, the increased levels of substance P may partly account for the high pain sensitivity experienced in this disease [R].

9) Substance P 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 [R].

Substance P triggers mast cell secretion, which promotes a local inflammatory response and contributes to bladder inflammation and pain[R].

10) Substance P and Infections – HIV, Measles, RSV

The Nk-1 receptor and Substance P have specific effects in different types of injections [R].

Substance P and HIV

It has a bidirectional relationship with HIV. It can enhance HIV infection by:

  • facilitating HIV entry into immune cells [R, R]
  • promoting HIV replication within immune cells [R, R]

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 [R, R].

Substance P and Measles

Nk-1 receptors levels are higher during 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 [R, RR, R].

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 [R, R].

Conditions with Low Substance P

1) Substance P and Alzheimer’s

Alzheimer‘s patients have lower substance P levels in their brain and spinal fluids [R].

Since substance P improved learning, memory, and the survival of neurons during injury in animal studies, its deficiency may contribute to Alzheimer’s development [R].

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 [R].

2) Substance P and Type 1 Diabetes

Substance P is decreased in the blood of type 1 diabetes patients, especially in those with diabetic neuropathy [R].

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 [R].

In contrast, substance P has a different effect in Type 2 diabetes. In cell-based studies, substance P promoted insulin resistance, likely a result of its inflammatory effects [R, R, R].

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 [R].

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 [R, R, R].
  • Internal opioids (e.g., enkephalin): These help decrease the release of substance P from sensory nerve endings [R, R].
  • Adenosine: It reduces substance P in the cerebrospinal fluid [R]

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 [R, R, R].
  • Narcotics: Morphine inhibits substance P release from nerve endings [R].

Hormones that Lower Substance P

Lifestyle Factors that Lower Substance P

  • Massage therapy: Substance P levels decreased after massage therapy in fibromyalgia patients [R].

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 [R]
  • THC increases the production of substance P [R]

Lifestyle Factors that Increase Substance P:

  • Stress: Physical and emotional stressors stimulate the release of substance P from sensory nerves [R].

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 [R].

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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5 COMMENTS

  • Jim

    The Potassium connection is interesting. I think I might need to watch my potassium supplementation.
    But this
    “Natural Substances That Lower Substance P

    Capsaicin: Capsaicin, an active component of chili peppers, depletes substance P from nerve endings. It also works by de-sensitizing sensory receptors on the skin, which helps reduce pain [R, R].”
    –and yes I realize it’s from references–

    seems to contradict the reference about potassium:
    https://www.ncbi.nlm.nih.gov/pubmed/16696851
    Substance P release evoked by capsaicin or potassium from rat cultured dorsal root ganglion neurons is conversely modulated with bradykinin.

    1. Helen

      We added a clarification to the post. Check this doi: 10.13140/2.1.4232.6721 for more information.

  • al darfco

    Potassium bicarbonate such as used in club soda is a much better form of potassium to take for supplementation.

  • Jeff

    Potassium itself is caustic and will cause gut irritation. This is why supplements are limited to 99 mg per pill usually – it can burn through the stomach lining if too much is taken without sufficie t fluid.

  • Rob White

    Fascinating. I have Interstitial cystitis and Find that high potassium foods really aggravate the pain and dysfunction, so it was interesting to read that potassium increases pain chemical signalling

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