Anandamide – this endocannabinoid makes us happy

anandamid

“Bliss” – this is the meaning of anandamide, the best known and scientifically first described endocannabinoid. It is one of the most important endocannabinoids for controlling the balance in our body, called homeostasis.

Humans – but also other mammals and insects – produce endogenous cannabinoids, so-called endocannabinoids. These activate the body’s endocannabinoid system (ECS), just as phytocannabinoids from the cannabis plant do.

Like the psychotropic tetrahydrocannabinol (THC), anandamide activates cannabinoid receptors and has numerous important functions for the body: Anandamide plays a role in the reward system and helps relieve pain and cramps. Anandamide even causes euphoric feelings in some endurance athletes – the so-called “runner’s high”.

Endocannabinoids activate other structures besides the endocannabinoid system, such as ion channels (e.g., TRPV1 channels) and other receptors, which are currently being explored.

Endurance sports and anandamide: Happy and pain-free

Some endurance athletes experience a runner’s high after longer training sessions. This state of consciousness triggered by sport is described as a euphoric feeling of happiness in which athletes feel no pain and can train endlessly. For a long time, scientists assumed that endorphins, the body’s own opioids, were behind this. However, preclinical studies on mice showed that endocannabinoids – and not endorphins – are mainly responsible for the runner’s high.

In a double-blind study published in 2020, a team of German researchers showed that the runner’s high also depends on endocannabinoids in humans. Of the participants, 63 experienced increased euphoria and were less anxious after 45 minutes of moderate-intensity running. Plasma levels of the endocannabinoids anandamide and 2-arachidonoylglycerol increased. In contrast, relaxed walking did not show this effect. To find out whether endorphins or endocannabioids caused the feeling of happiness, participants were administered the opioid antagonist naltrexone. Naltrexone blocks opioid receptors and thus abolishes the effects of any mood-enhancing endogenous opioids circulating in the blood. It was shown that euphoria occurs in runners despite naltrexone. This suggests that endocannabinoids are the main players in runner’s high [1].

Patients with chronic pain can also benefit from the pain-relieving effects of regular endurance exercise. In a study completed in 2013, Swedish researchers examined the effects of a 15-week exercise program in patients with fibromyalgia, a chronic muscle-fiber pain throughout the body. Fibromyalgia affects 2 to 4 percent of all people, with women more commonly affected. In addition to constant pain, many sufferers also struggle with depression, anxiety, stiffness, fatigue, sleep disturbances and cognitive impairment. The study involved 37 women with fibromyalgia and 33 healthy women. Participants took part in an exercise program twice a week for 15 weeks under physical therapy guidance. Before and after the start of training, levels of pain, depression, anxiety, fatigue, and muscle strength were measured. Blood samples were collected before and after the study and the endocannabinoids anandamide and 2-arachidonoylglycerol, as well as the endocannabinoid-like substances oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were measured.

The sports program showed significant effects on the endocannabinoid system in fibromyalgia patients: blood levels for anandamide increased significantly, while stearoylethanolamide decreased. Levels of pain and depressive symptoms also decreased, while the muscle strength of the patients increased. In contrast, stearoylethanolamide was elevated in healthy women after the exercise program. It is possible that the different stearoylethanolamide levels in fibromyalgia patients and healthy individuals indicate different metabolic processes in tissues such as muscle and brain. However, these findings need to be confirmed in future studies. An association between 2-arachidonoylglycerol and muscle strength in the hands and legs was shown. Significant changes in 2-AG levels were absent, but an inverse relationship was shown between 2-AG and magnitude of pain intensity, depression, general health, and fatigue. However, due to lack of statistical models, affected and healthy individuals could not be compared [2].

Discovery of anandamide

The cannabis plant contains over 100 different cannabinoids that interact with the endocannabinoid system. Cannabidiol (CBD), the most important non-psychotropic phytocannabinoid, was first isolated from the hemp plant in 1940. In 1963, the chemical structure of CBD was elucidated by chemist Raphael Mechoulam, who also deciphered the structure of tetrahydrocannabinol (THC) in 1964. The discovery of phytocannabinoids were the impetus for the study of the endocannabinoid system (ECS), consisting of cannabinoid receptors, endogenous cannabinoids, and enzymes that break down and metabolize them [3]. In 1990, the CB1 receptor was discovered, through which THC exerts its intoxicating effects [4]. The CB2 receptor was discovered in 1993 [3].

After that, science searched for endogenous substances that bind to cannabinoid receptors, the endocannabinoids. In 1992, the first endocannabinoid to be isolated was arachidonylethanolamide (AEA) from a pig brain. AEA was given the trivial name anandamide. The endocannabinoid is known after “ananda,” the Sanskrit word for “bliss,” borrowed from the euphoric effects of THC. Despite its completely different chemical structure compared to THC, anandamide has a cannabimimetic effect at the CB1 receptor, thus exerting cannabis-like effects [6]. In 1996, scientists detected small amounts of anandamide in chocolate [7]. However, a “chocolate addiction” cannot be explained in this way, since one would have to eat kilograms of chocolate for psychotropic effects. In addition to anandamide, other endocannabinoids and endocannabinoid-like substances have been discovered, all of which belong to the chemical class of N-acylethanolamines [6].

The endocannabinoid system regulates balance, the so called homeostasis, in many organ systems. Endocannabinoids such as anandamide control among others [8]:

  • Development of the nervous system
  • Synaptic transmission and memory
  • Stress, emotions and reward system [9]
  • Immune modulation
  • Hormone secretion
  • Food intake and energy balance
  • Motility and secretion in the digestive tract
  • Reproductive function
  • Bone mass

Endocannabinoids and endocannabinoid-like substances

Endocannabinoids are endogenous messenger substances with cannabis-like (cannabimimetic) effects. In contrast to many other messenger substances (e.g. glutamate, dopamine, serotonin [8]), endocannabinoids are not stored because of their fat-solubility, but are released from the cell membrane (N-arachidonyl-phosphatidylethanolamine or diacylglycerol) by fat-splitting enzymes (lipases) when required. Each cell of the body thus contains precursors for the biosynthesis of endocannabinoids. After they have done their job, endocannabinoids are rapidly deactivated by degrading enzymes (hydrolases). Known endocannabinoids are chemical derivatives (amides, esters, or ethers) of arachidonic acid. Arachidonic acid is an omega-6 fatty acid and precursor substance of various messenger substances such as prostaglandins and other eicosanoids (e.g. leukotrienes [10], thromboxanes [10], endocannabinoids) [6].

Anandamide and 2-arachidonoylglycerol (2-AG) are the two most important endocannabinoids [6]. More recently, scientists have discovered other endocannabinoids that modulate the endocannabinoid system in a variety of ways. O-arachidonylethanolamide (virodhamine), discovered in 2002, blocks CB1 receptors. This endocannabinoid was given the name virodhamine as a possible endogenous cannabinoid receptor antagonist, derived from “virodha,” which means “opposite” in Sanskrit. Also discovered in 2002 was N-arachidonyl dopamine (NADA), which activates TRPV1 channels (capsaicin receptors). These ion channels, found on peripheral sensory nerve fibers (C-fibers, A-fibers), respond to noxious stimuli such as protons (acidic pH), heat, and capsaicin, the pungent ingredient in chili peppers. TRPV1 channels have also been shown to exist in the central nervous system, but probably perform other tasks there. This suggests the existence of endogenous TRPV1 agonists in the brain [8,9].

In addition to arachidonic acid-derived endocannabinoids, there are N-acylethanolamines derived from various long-chain fatty acids. They occur in greater amounts than anandamide and do not act at cannabinoid receptors but activate other receptors such as PPAR-alpha receptors (peroxisome-activated receptor alpha). Various physiological effects include anti-inflammation and appetite reduction [6].

What is Anandamid?

Anandamide, an amide of arachidonic acid and ethanolamine. Despite chemical differences, endocannabinoids resemble cannabis phytocannabinoids and interact with cannabinoid receptors. Both THC and anandamide act as partial agonists at CB1 receptors, the receptor through which THC exerts psychotropic effects [6, 11].

Non-psychotropic CBD acts on CB1 receptors as a negative allosteric modulator, causing THC to bind more poorly. In this way, CBD has antipsychotropic effects and curbs side effects of THC [17]. However, most of the effects of CBD occur via other targets (e.g., TRPV1 channels, 5-HT1A, inhibition of FAAH) [12]. Thus, CBD indirectly activates the endocannabinoid system by blocking the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH). The subsequent increased levels of anandamide activate cannabinoid receptors [13].

2-Arachidonylglycerol, unlike anandamide, is a full agonist at CB1 and CB2 receptors, thus activating cannabinoid receptors more strongly than anandamide and THC. Tissue concentrations of this endocannabinoid are 100- to 1000-fold higher than anandamide, which is why 2-arachidonoylglycerol is probably the more important endocannabinoid.

Interaction of anandamide with the endocannabinoid system

Anandamide exerts numerous effects in the brain. In the hippocampus, it influences learning and memory. In the basal ganglia and hypothalamus, anandamide modulates locomotor activity, food intake and the reward system. Via the spinal cord and brain, it has an antinociceptive effect, counteracting pain. In peripheral tissues, anandamide exerts local effects. These include regulation of vascular tone (tension of blood vessels) and embryonic development [14].

Many effects of anandamide – analogous to THC – are mediated by activation of the inhibitory (inhibitory) G-protein-coupled cannabinoid receptors CB1 and CB2. Unlike many other neurotransmitters, which transmit signals from neuron to neuron, endocannabinoids act as retrograde messengers: the signal is transmitted from the downstream (postsynaptic) to the upstream (presynaptic) neuron. Endocannabinoids are produced on demand from membrane lipids when the nerve cell is overactive and reduce further release of the messenger in question via an inhibitory G protein. Cannabinoid receptors control the activity of various neurotransmitters, which can be inhibitory (e.g., gamma-aminobutyric acid) or stimulatory (e.g., glutamate) [9].

Pharmacological research suggests that other targets exist for cannabinoids: These include other G protein-coupled receptors (e.g., GPR118, GPR55, GPR119), peroxisome proliferator-activated receptors (PPARs), equilibrative nucleoside transporter 1 (ENT-1), subtypes of serotonin receptors, TRPV channels, and various voltage-gated ion channels [23].

Anandamide is involved in numerous processes in the body [9,14]:

Interaction of anandamide with ionic channels

Anandamide, like phytocannabinoids, can produce effects that are independent of CB1 and CB2 receptors. Several studies have shown that many ionic channels may be potential targets for anandamide. An American research team from the University of California, Davis published a review paper in 2021 on the effects of endocannabinoids, particularly anandamide, on ionic channels with a focus on potassium channels. Depending on the ionic channel, anandamide can produce inhibitory or stimulatory effects, resulting in many physiological and pathophysiological processes [14].

Anandamide and other endocannabinoids affect the following ionic channels, among others, as shown in preclinical studies in cell cultures and animals [14,15,16]:

Potassium channels are a group of over 70 different ionic channels found in almost every cell. Their roles include the regulation of neurotransmission, heart rate, muscle contraction, hormone release and cell survival. Therefore, potassium channels are an interesting approach to develop new therapies against cancer as well as metabolic, neurological and cardiovascular diseases [14].

TRPV1 channels are a family of non-selective ligand-gated cation channels with multiple physiological functions, including perception of temperature and osmotic pressure, sensory input (smell, taste, vision, hearing), and pain perception. Capsaicin, the pungent ingredient in chili peppers, activates TRPV1 channels and help with nerve pain. A study published in 1999 on isolated arteries showed that anandamide also activates TRPV1 channels, producing vasodilator (vasodilating) calcitonin gene-related peptide (CGRP). Thus, anandamide could activate vascular TRPV1 channels to dilate peripheral blood vessels. Anandamide and related lipids are thought to be endogenous TRPV1 agonists, affecting sensory neurons (e.g., nociception, vasodilation, neurogenic inflammation) [14].

Glycine receptors are ligand-gated ion channels activated by the inhibitory neurotransmitter glycine. They are found in brain regions involved in pain transmission and reward. It is possible that glycine receptors play a role in pain relief and in the pathophysiology of drug addiction. Recent studies demonstrated the importance of glycine receptors as targets of cannabinoids in the central nervous system. Anandamide selectively activated glycine receptors in preclinical studies: the studies were performed on rats on oocytes with recombinant glycine receptors and on the ventral tegmental area (VTA) – a part of the dopaminergic reward system [14].

The nicotinic acetylcholine receptor (nAChR) is involved in pain transmission and drug abuse as well as in neurodegenerative diseases (e.g., Alzheimer’s disease). The ligand-controlled ionic channel is activated by the neurotransmitter acetylcholine as well as by nicotine. Preclinical studies on clawed frog (Xenopus) oocytes with cloned nicotinic receptors showed that anandamide reduced effects triggered by nicotine. Pharmacological experiments with specific inhibitors showed direct activation of nicotinic acetylcholine receptors by anandamide, although the endocannabinoid system is not involved. Further research is needed to further understand interactions between cannabinoids and ionic channels. It may be possible in the future to develop cannabis-based drugs that target specific ionic channels [14].

Anandamid and the reward system

The happiness hormone dopamine is the central neurotransmitter in the brain’s mesolimbic reward system. It is vital because the organism is motivated to eat, for example, by rewarding feelings. The reward system encourages desirable behaviors by positively reinforcing them with feelings of pleasure. Drug use or even behaviors (e.g., gambling) upset the finely tuned reward system, resulting in neuroadaptation, an adjustment of dopaminergic information transmission. The maladaptive reward system becomes sensitized, i.e., reacts more strongly to the addictive substance. Affected individuals develop increasingly strong cravings, which can lead to addictive disorders. Thus, occasional use can lead to drug abuse and eventually to dependence [9].

Several brain regions belong to the reward system [9]:

  • Ventrales tegmental area (VTA)
  • Pars compacta of Substantia nigra
  • Nucleus accumbens
  • Other structures of the limbic system such as prefrontal cortex, amygdala, hippocampus

Various studies showed that anandamide is involved in the reward process. Thus, CB1 receptors are found in the VTA, nucleus accumbens as well as in cortex, amygdala and hippocampus. Anandamide modulates these cannabinoid receptors as “endogenous THC” and is also involved in other psychotropic substances – apart from cannabinoids. Even though intoxicating drugs can have completely different effects, they usually increase the release of dopamine and thus cause feelings of pleasure. This is just as true for “natural” rewards like delicious food. While most other neurotransmitter systems use only a single endogenous messenger, the endocannabinoid and endorphin systems – both involved in the reward system – have multiple endogenous ligands. Based on recent findings, researchers hypothesized that endocannabinoids modulate the activity of dopamine-producing neurons.

A possible therapeutic approach for drug use disorders may therefore be to specifically modulate anandamide levels in the brain. Anandamide, like THC, stimulates central CB1 receptors as a partial agonist and therefore acts similarly to phytocannabinoids. Since repeated stimulation of CB1 receptors can result in cannabis use disorder, scientists are trying to modulate anandamide levels: By inhibiting the enzyme FAAH, anandamide degradation is slowed. Increased endocannabinoid tone could also be achieved by inhibiting anandamide uptake into the cell membrane.

Italian and American scientists* highlighted the relationship between anandamide, FAAH inhibition, and addiction to nicotine, alcohol, opioids, and psychostimulants in a 2019 review [9].

  • Nicotine: Physical and psychological dependence makes it difficult to quit smoking. Animal studies demonstrated that increased levels of anandamide can assist in nicotine withdrawal: After administration of the FAAH inhibitor URB597, withdrawal symptoms such as anxiety were reduced. Anandamide also shifted the dose-response curve for rewarding feelings from nicotine to the right, thus decreasing feelings of reward. Studies in rodents and squirrel monkeys provided valuable results in the exploration of FAAH inhibitors as new drugs for tobacco dependence.
  • Alcohol: A 2007 study in rats found that AM404 (N-arachidonoylphenolamine) reduced alcohol consumption in the animals. Similar to nicotine-dependent mice, the FAAH inhibitor URB597 prevented withdrawal-induced anxiety in alcohol-dependent mice in a 2017 study. Deprived animals were found to have elevated levels of anandamide in several brain regions (including nucleus accumbens and amygdala), which may protect against withdrawal-related stress. Susceptibility to binge drinking may be related to polymorphisms (gene variants) of the FAAH gene that determine enzyme activity: People with certain gene variants have elevated levels of anandamide because FAAH functions more poorly. The human gene was inserted into knockout mice, causing the animals to consume more alcohol. So, in rodents, increased CB1 activity leads to increased alcohol consumption, while decreased activity reduced alcohol use. Gene studies in humans published in 2018 found an association between severity of alcohol dependence and the FAAH gene variant Pro129Thr: gene studies in Europeans and Americans found an increased occurrence of the Thr129-allele in alcohol-dependent individuals.
  • Opioids: Preclinical studies in rats revealed in a study published in 2005 that CB1 agonists, like THC, promote the reinforcing effects of heroin. CB1 and opioid receptors appear to interact with each other. In 2013, a study in morphine-dependent rats found that inhibition of the FAAH and MAGL enzymes reduced opioid withdrawal symptoms. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the combined FAAH/MAGL inhibitor SA-57 were studied: rats receiving a combination of FAAH inhibitor and MAGL inhibitor or the combined FAAH/MAGL inhibitor showed increased levels of anandamide. Treated rats showed fewer withdrawal symptoms such as jumping, head shaking, diarrhea, and weight loss. Drug-induced increases in anandamide levels could therefore be a therapeutic approach for opioid withdrawal symptoms.
  • Psychostimulants: While most drugs increase dopamine levels indirectly, psychostimulants act directly on dopaminergic neurons of the reward system. Psychostimulants block the re-uptake of monoamines such as dopamine into the presynaptic neuron. The increased levels of dopamine in the synaptic cleft lead to increased activation of dopaminergic neurons. Rewarding, motivational, and addictive effects of psychostimulants are related to the endocannabinoid system. Several research teams have demonstrated the absence of some acute and chronic effects of cocaine in CB1 knockout mice. The exact role of endocannabinoids in the initiation of chronic cocaine use is currently not fully understood. There is evidence that cocaine use releases endocannabinoids. In a study published in 2015 in mice, cocaine led to increased dopamine release in the nucleus accumbens. In mice given the FAAH inhibitor URB597, even a low dose of cocaine – which is not normally intoxicating yet – led to sensitization. Thus, cocaine-triggered increased levels of anandamide may be involved in neuroadaptation. In cell cultures and in mice, the FAAH inhibitor URB597 reduced cocaine-induced spasms and decreased activation and cell death of neurons in the hippocampus.

The review shows that anandamide can reinforce rewarding feelings during drug use but can also induce avoidance behavior (aversive behavior) or anxiety. Animal models did not show a clear abuse potential for THC and anandamide. Thus, much research is needed to accurately understand neurobiological effects of anandamide on the reward system. Anandamide is involved in the effects of a wide variety of drugs but may reduce the potential for dependence under certain conditions.

Inhibitors of anandamide degradation were shown to counteract some of the reinforcing effects of nicotine, alcohol, opiates, and psychostimulants. Anandamide could therefore provide support for substance use disorders. It is possible that the ameliorative effect occurs via interactions between different receptors (between CB1 and/or CB1 receptors and PPAR-alpha receptors). Blocked FAAH also increases OEA and PEA, which may also play a therapeutic role. Modulation of the endocannabinoid system may also be a therapeutic approach for pain and other brain disorders such as anxiety disorders and depression. However, therapeutic use needs to be explored in future clinical trials. Currently, studies are taking place on the use of cannabis-based medications in psychiatric disorders such as addiction.

Anandamide protects against cramps

Cannabinoids have anticonvulsant effects – for example, a finished drug containing CBD is approved for children with rare epilepsies. However, the antiepileptic mechanism of action is currently not fully understood. The endocannabinoid system (ECS) modulates excitability in the central nervous system. In fact, ECS and seizures are linked: Affected individuals have increased levels of anandamide and 2-AG after seizures. Altered numbers of cannabinoid receptors have also been found in epilepsy sufferers. The anticonvulsant effects of endocannabinoids are mediated via cannabinoid receptors, but also via other targets: Thus, the two non-psychotropic phytocannabinoids cannabidiol (CBD) and cannabidivarin (CBDV) have anticonvulsant effects, although they bind only very weakly to CB1 receptors.

American researchers from the University of Pennsylvania investigated the antiepileptic mechanism of action in fruit flies (Drosophila melanogaster) in a report published in 2020: Due to their short generation time, they are a popular model organism. Like mammals, fruit flies also have an endocannabinoid system consisting of endocannabinoids and enzymes such as FAAH. Fruit flies are ideal for studying cannabinoid receptor-independent effects because, unlike mammals, they do not have cannabinoid receptors. The scientists fed fruit flies different doses of anandamide solutions. The insects were then swirled around for ten seconds to induce convulsions. After one to two days, it was found that anandamide significantly protected the fruit flies from convulsions, and the effect was dose dependent. Experiments were also conducted with the endocannabinoids oleoylglycerol (2-OG), oleoylethanolamide (OEA), and 2-arachidonylglycerol (2-AG). Anticonvulsant effects were observed only for anandamide and 2-AG.

The research team also investigated the role of TRPV1 channels (capsaicin receptors) in the anticonvulsant effect of anandamide. It is known that the TRPV1 agonist capsaicin is effective in neuropathic pain. Pain relief seems paradoxical at first because capsaicin receptors are activated, which explains the initial burning pain when chili peppers are eaten. However, calcium influx into the nerve cell desensitizes TRPV1 channels in the long term, making them less sensitive [18]. This effect is used by physicians for the local therapy of neuropathic pain (e.g., post-zoster neuralgia) with high-dose capsaicin patches. The patch is applied to the painful skin area and removed after a maximum of one hour. Initially, there is reddening of the skin and even an increase in pain, which paradoxically means that sufferers need more painkillers. After a few days to weeks, however, the nociceptors become less sensitive, resulting in sustained pain relief for months [19]. The paradoxical analgesic effects of TRPV1 agonists such as capsaicin, CBD and non-cannabinoid TRPV1 agonists can thus be explained by desensitization [18].

The fruit fly experiments showed that blockade of TRPV1 channels by the antagonist capsazepine blocked the anticonvulsant effects of anandamide. The research team suggests that desensitization of TRPV1 channels, similar to that seen in pain, may explain the anticonvulsant effects of anandamide. Overall, the study provided further evidence that endocannabinoids also have anticonvulsant effects independent of cannabinoid receptors. In addition to anandamide, 2-AG and the degradation product arachidonic acid also showed anticonvulsant effects [18].

Conclusion

Anandamide plays a role in many physiological and pathological processes. The two endocannabinoids anandamide and 2-arachidonoylglycerol have analgesic, antianxiety, and neuroprotective effects [14]. However, further preclinical and clinical studies are needed to understand the effects of anandamide. Drug elevation of anandamide levels may have potential in drug addiction to, for example, tobacco, alcohol, opioids, and psychostimulants, according to preclinical studies [9]. Findings from fruit fly experiments showed that not only anandamide, but also the degradation product arachidonic acid has anticonvulsant effects through activation of TRPV1 channels [18]. Also being researched is the anti-inflammatory effect of anandamide for the treatment of vascular inflammation as the most important trigger of cardiovascular disease [20]. However, we do not have to wait for research results to benefit from the happiness messenger anandamide. Through regular endurance exercise, we can raise our endocannabinoid levels ourselves and take advantage of the euphoric and pain-relieving effects of anandamide. Not only healthy people benefit from this, but also chronic pain patients [1,2].

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About Minyi Lü

Minyi Lü leidet an chronischen Schmerzen aufgrund ihrer Fingerarthrose. Ihre Beschwerden behandelt sie seit 2017 sehr erfolgreich mit medizinischem Cannabis. Als Pharmazeutin im Praktikum bringt sie nun ihr Know-how ein, um über die neuesten wissenschaftlichen Erkenntnisse rund um Medizinalcannabis zu berichten.