The runner's high is a transient state of euphoria coupled with lessened feelings of anxiety and a higher pain threshold, which can come either from continuous moderate physical exertion over time or from short bursts of high-intensity exercise. The exact prevalence is unknown, but it seems to be a relatively rare phenomenon that not every athlete experiences. [1] The name comes from distance running, and it is alternatively called "rower's high" in rowing. [2] [3] [4] [5]
Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related pleasurable feelings, specifically phenethylamine (an endogenous psychostimulant), β-endorphin (an endogenous opioid), and anandamide (an endogenous cannabinoid). [6] [7] [8] [9] [10] However, more recent studies suggest that endorphins have a limited role in the feelings of euphoria specifically related to the runner's high due to their inability to cross the blood-brain barrier, placing more importance in the endocannabinoids instead, which can cross this barrier. [1] [4] [11] [12]
Endorphins are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogenous painkillers often produced in the brain and adrenal medulla during physical exercise or orgasm and inhibit pain, muscle cramps, and relieve stress.
Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.
Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands:
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
Euphoria is the experience of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and dancing, can induce a state of euphoria. Euphoria is also a symptom of certain neurological or neuropsychiatric disorders, such as mania. Romantic love and components of the human sexual response cycle are also associated with the induction of euphoria. Certain drugs, many of which are addictive, can cause euphoria, which at least partially motivates their recreational use.
2-Arachidonyl glyceryl ether is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. It is an ether formed from the alcohol analog of arachidonic acid and glycerol. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.
Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endogenous cannabinoids called endocannabinoids, a group of retrograde neurotransmitters that include lipids, such as anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).
N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.
An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,. The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan–bilaterian divergence, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, through which it exerts a variety of biological effects, some related to chronic inflammation and pain.
Abnormal cannabidiol (Abn-CBD) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive or sedative effects.
RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).
Hemopressin (Hp) is an alpha hemoglobin fragment with the sequence PVNFKFLSH, originally identified in extracts of rat brain using an enzyme capture technique. It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors. Longer forms of hemopressin containing 2-3 additional amino acids on the N-terminus have been identified in extracts of mouse brain. These longer hemopressin peptides, named RVD-Hpα and VD-Hpα, bind to CB1 receptors and were originally reported to be agonists. In addition to the Hp peptides from alpha hemoglobin, a related peptide from beta hemoglobin has been found in mouse brain extracts; this peptide, named VD-Hpβ, is also an agonist at CB1 cannabinoid receptors. Hemopressin is not an endogenous peptide but rather an extraction artefact. The only endogenous peptide found endogenously at physiological conditions is RVD-hemopressin (pepcan-12), which has more recently been shown to be a negative allosteric modulator of CB1 receptors and positive allosteric modulator of CB2 receptors. RVD-hemopressin (pepcan-12) is generated from a pro-peptide called pepcan-23 and these peptides are exclusively found in noradrenergic neurons in the brain and in the adrenal medulla.
The neurobiological effects of physical exercise involve possible interrelated effects on brain structure, brain function, and cognition. Research in humans has demonstrated that consistent aerobic exercise may induce improvements in certain cognitive functions, neuroplasticity and behavioral plasticity; some of these long-term effects may include increased neuron growth, increased neurological activity, improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory. The effects of exercise on cognition may affect academic performance in children and college students, improve adult productivity, preserve cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.
N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.
Cannabis consumption in pregnancy may or may not be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits. The American College of Obstetricians and Gynecologists recommended that cannabis use be stopped before and during pregnancy. There has not been any official link between birth defects and marijuana use. Cannabis is the most commonly used illicit substance among pregnant women.
The runner's high describes an euphoric state resulting from long-distance running.