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) .
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 .
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 .
Roles of Substance P
1) Widens Blood Vessels
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
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 .
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 .
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].
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
Drugs that block Nk1 receptors can help treat nausea associated with chemotherapy .
6) Causes an Itching Sensation
7) Enhances Wound Healing
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].
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
The brain releases substance P during stressful situations at a rate proportional to the intensity and frequency of stimulation .
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
4) May Be a Factor in Fibromyalgia
Fibromyalgia patients have higher spinal fluid levels of substance P .
5) May Contribute to Obesity
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
Substance P and IBD
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 .
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
Conditions with Low Substance P
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 .
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 .
Want More Targeted Ways to Combat Inflammation?
If you’re interested in natural and more targeted ways of lowering your inflammation, we at SelfHacked recommend checking out this inflammation wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help reduce inflammation levels. The recommendations are personalized based on your genes.
SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thank you for your support.