Economic bubble

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Economic_bubble

An economic bubble (also called a speculative bubble or a financial bubble) is a period when current asset prices greatly exceed their intrinsic valuation, being the valuation that the underlying long-term fundamentals justify. Bubbles can be caused by overly optimistic projections about the scale and sustainability of growth (e.g. dot-com bubble), and/or by the belief that intrinsic valuation is no longer relevant when making an investment (e.g. Tulip mania). They have appeared in most asset classes, including equities (e.g. Roaring Twenties), commodities (e.g. Uranium bubble), real estate (e.g. 2000s US housing bubble), and even esoteric assets (e.g. Cryptocurrency bubble). Bubbles usually form as a result of either excess liquidity in markets, and/or changed investor psychology. Large multi-asset bubbles (e.g. 1980s Japanese asset bubble and the 2020–21 Everything bubble), are attributed to central banking liquidity (e.g. overuse of the Fed put).

In the early stages of a bubble, many investors do not recognise the bubble for what it is. People notice the prices are going up and often think it is justified. Therefore bubbles are often conclusively identified only in retrospect, after the bubble has already popped and prices have crashed.

Origin of term

Jan Brueghel the Younger's A Satire of Tulip Mania (ca. 1640)

 

A card from the South Sea Bubble

The term "bubble", in reference to financial crisis, originated in the 1711–1720 British South Sea Bubble, and originally referred to the companies themselves, and their inflated stock, rather than to the crisis itself. This was one of the earliest modern financial crises; other episodes were referred to as "manias", as in the Dutch tulip mania. The metaphor indicated that the prices of the stock were inflated and fragile – expanded based on nothing but air, and vulnerable to a sudden burst, as in fact occurred.

Some later commentators have extended the metaphor to emphasize the suddenness, suggesting that economic bubbles end "All at once, and nothing first, / Just as bubbles do when they burst," though theories of financial crises such as debt deflation and the Financial Instability Hypothesis suggest instead that bubbles burst progressively, with the most vulnerable (most highly-leveraged) assets failing first, and then the collapse spreading throughout the economy.

Types

There are different types of bubbles, with economists primarily interested in two major types of bubbles:

Equity bubble

An equity bubble is characterised by tangible investments and the unsustainable desire to satisfy a legitimate market in high demand. These kind of bubbles are characterised by easy liquidity, tangible and real assets, and an actual innovation that boosts confidence. Three instances of an equity bubble are the Tulip Mania, Bitcoin, and the dot-com bubble.

Debt bubble

A debt bubble^[4] is characterised by intangible or credit based investments with little ability to satisfy growing demand in a non-existent market. These bubbles are not backed by real assets and are based on frivolous lending in the hope of returning a profit or security. These bubbles usually end in debt deflation causing bank runs or a currency crisis when the government can no longer maintain the fiat currency. Examples are the Roaring Twenties stock market bubble (which caused the Great Depression) and the United States housing bubble (which caused the Great Recession).

Impact

The impact of economic bubbles is debated within and between schools of economic thought; they are not generally considered beneficial, but it is debated how harmful their formation and bursting is.

Within mainstream economics, many believe that bubbles cannot be identified in advance, cannot be prevented from forming, that attempts to "prick" the bubble may cause financial crisis, and that instead authorities should wait for bubbles to burst of their own accord, dealing with the aftermath via monetary policy and fiscal policy.

Political economist Robert E. Wright argues that bubbles can be identified before the fact with high confidence.

In addition, the crash which usually follows an economic bubble can destroy a large amount of wealth and cause continuing economic malaise; this view is particularly associated with the debt-deflation theory of Irving Fisher, and elaborated within Post-Keynesian economics.

A protracted period of low risk premiums can simply prolong the downturn in asset price deflation, as was the case of the Great Depression in the 1930s for much of the world and the 1990s for Japan. Not only can the aftermath of a crash devastate the economy of a nation, but its effects can also reverberate beyond its borders.

Effect upon spending

Another important aspect of economic bubbles is their impact on spending habits. Market participants with overvalued assets tend to spend more because they "feel" richer (the wealth effect). Many observers quote the housing market in the United Kingdom, Australia, New Zealand, Spain and parts of the United States in recent times, as an example of this effect. When the bubble inevitably bursts, those who hold on to these overvalued assets usually experience a feeling of reduced wealth and tend to cut discretionary spending at the same time, hindering economic growth or, worse, exacerbating the economic slowdown.

In an economy with a central bank, the bank may therefore attempt to keep an eye on asset price appreciation and take measures to curb high levels of speculative activity in financial assets. This is usually done by increasing the interest rate (that is, the cost of borrowing money). Historically, this is not the only approach taken by central banks. It has been argued that they should stay out of it and let the bubble, if it is one, take its course.

Causes

It has also been variously suggested that bubbles may be rational, intrinsic, and contagious. To date, there is no widely accepted theory to explain their occurrence. Recent computer-generated agency models suggest excessive leverage could be a key factor in causing financial bubbles.

Puzzlingly for some, bubbles occur even in highly predictable experimental markets, where uncertainty is eliminated and market participants should be able to calculate the intrinsic value of the assets simply by examining the expected stream of dividends. Nevertheless, bubbles have been observed repeatedly in experimental markets, even with participants such as business students, managers, and professional traders. Experimental bubbles have proven robust to a variety of conditions, including short-selling, margin buying, and insider trading.

While there is no clear agreement on what causes bubbles, there is evidence to suggest that they are not caused by bounded rationality or assumptions about the irrationality of others, as assumed by greater fool theory. It has also been shown that bubbles appear even when market participants are well capable of pricing assets correctly. Further, it has been shown that bubbles appear even when speculation is not possible or when over-confidence is absent.

More recent theories of asset bubble formation suggest that they are likely sociologically-driven events, thus explanations that merely involve fundamental factors or snippets of human behavior are incomplete at best. For instance, qualitative researchers Preston Teeter and Jorgen Sandberg argue that market speculation is driven by culturally-situated narratives that are deeply embedded in and supported by the prevailing institutions of the time. They cite factors such as bubbles forming during periods of innovation, easy credit, loose regulations, and internationalized investment as reasons why narratives play such an influential role in the growth of asset bubbles.

Liquidity

One possible cause of bubbles is excessive monetary liquidity in the financial system, inducing lax or inappropriate standards of lending by the banks, which makes markets vulnerable to volatile asset price inflation caused by short-term, leveraged speculation. For example, Axel A. Weber, the former president of the Deutsche Bundesbank, has argued that "The past has shown that an overly generous provision of liquidity in global financial markets in connection with a very low level of interest rates promotes the formation of asset-price bubbles."

According to the explanation, excessive monetary liquidity (easy credit, large disposable incomes) potentially occurs while fractional reserve banks are implementing expansionary monetary policy (i.e. lowering of interest rates and flushing the financial system with money supply); this explanation may differ in certain details according to economic philosophy. Those who believe the money supply is controlled exogenously by a central bank may attribute an 'expansionary monetary policy' to that bank and (should one exist) a governing body or institution; others who believe that the money supply is created endogenously by the banking sector may attribute such a 'policy' to the behavior of the financial sector itself, and view the state as a passive or reactive factor. This may determine how central or relatively minor/inconsequential policies like fractional reserve banking and the central bank's efforts to raise or lower short-term interest rates are to one's view on the creation, inflation and ultimate implosion of an economic bubble. Explanations focusing on interest rates tend to take on a common form, however: when interest rates are set excessively low (regardless of the mechanism by which that is accomplished) investors tend to avoid putting their capital into savings accounts. Instead, investors tend to leverage their capital by borrowing from banks and invest the leveraged capital in financial assets such as stocks and real estate. Risky leveraged behavior like speculation and Ponzi schemes can lead to an increasingly fragile economy, and may also be part of what pushes asset prices artificially upward until the bubble pops.

But these [ongoing economic crises] aren’t just a series of unrelated accidents. Instead, what we’re seeing is what happens when too much money is chasing too few investment opportunities.

Paul Krugman

Simply put, economic bubbles often occur when too much money is chasing too few assets, causing both good assets and bad assets to appreciate excessively beyond their fundamentals to an unsustainable level. Once the bubble bursts, the fall in prices causes the collapse of unsustainable investment schemes (especially speculative and/or Ponzi investments, but not exclusively so), which leads to a crisis of consumer (and investor) confidence that may result in a financial panic and/or financial crisis. If there is a monetary authority like a central bank, it may take measures to soak up the liquidity in the financial system in an attempt to prevent a collapse of its currency. This may involve actions like bailouts of the financial system, but also others that reverse the trend of monetary accommodation, commonly termed forms of 'contractionary monetary policy'.

These measures may include raising interest rates, which tends to make investors become more risk averse and thus avoid leveraged capital because the costs of borrowing may become too expensive. There may also be countermeasures taken pre-emptively during periods of strong economic growth, such as increasing capital reserve requirements and implementing regulation that checks and/or prevents processes leading to over-expansion and excessive leveraging of debt. Ideally, such countermeasures lessen the impact of a downturn by strengthening financial institutions while the economy is strong.

Advocates of perspectives stressing the role of credit money in an economy often refer to (such) bubbles as "credit bubbles", and look at such measures of financial leverage as debt-to-GDP ratios to identify bubbles. Typically the collapse of any economic bubble results in an economic contraction termed (if less severe) a recession or (if more severe) a depression; what economic policies to follow in reaction to such a contraction is a hotly debated perennial topic of political economy.

Psychology

Greater fool theory

Main article: Greater fool theory

Greater fool theory states that bubbles are driven by the behavior of perennially optimistic market participants (the fools) who buy overvalued assets in anticipation of selling it to other speculators (the greater fools) at a much higher price. According to this explanation, the bubbles continue as long as the fools can find greater fools to pay up for the overvalued asset. The bubbles will end only when the greater fool becomes the greatest fool who pays the top price for the overvalued asset and can no longer find another buyer to pay for it at a higher price. This theory is popular among laity but has not yet been fully confirmed by empirical research.

Extrapolation

The term "bubble" should indicate a price that no reasonable future outcome can justify.

Clifford Asness

Extrapolation is projecting historical data into the future on the same basis; if prices have risen at a certain rate in the past, they will continue to rise at that rate forever. The argument is that investors tend to extrapolate past extraordinary returns on investment of certain assets into the future, causing them to overbid those risky assets in order to attempt to continue to capture those same rates of return.

Overbidding on certain assets will at some point result in uneconomic rates of return for investors; only then the asset price deflation will begin. When investors feel that they are no longer well compensated for holding those risky assets, they will start to demand higher rates of return on their investments.

Herding

Another related explanation used in behavioral finance lies in herd behavior, the fact that investors tend to buy or sell in the direction of the market trend. This is sometimes helped by technical analysis that tries precisely to detect those trends and follow them, which creates a self-fulfilling prophecy.

Investment managers, such as stock mutual fund managers, are compensated and retained in part due to their performance relative to peers. Taking a conservative or contrarian position as a bubble builds results in performance unfavorable to peers. This may cause customers to go elsewhere and can affect the investment manager's own employment or compensation. The typical short-term focus of U.S. equity markets exacerbates the risk for investment managers that do not participate during the building phase of a bubble, particularly one that builds over a longer period of time. In attempting to maximize returns for clients and maintain their employment, they may rationally participate in a bubble they believe to be forming, as the likely shorter-term benefits of doing so outweigh the likely longer-term risks.

Moral hazard

Moral hazard is the prospect that a party insulated from risk may behave differently from the way it would behave if it were fully exposed to the risk. A person's belief that they are responsible for the consequences of their own actions is an essential aspect of rational behavior. An investor must balance the possibility of making a return on their investment with the risk of making a loss – the risk-return relationship. A moral hazard can occur when this relationship is interfered with, often via government policy.

A recent example is the Troubled Asset Relief Program (TARP), signed into law by U.S. President George W. Bush on 3 October 2008 to provide a government bailout for many financial and non-financial institutions who speculated in high-risk financial instruments during the housing boom condemned by a 2005 story in The Economist titled "The worldwide rise in house prices is the biggest bubble in history". A historical example was intervention by the Dutch Parliament during the great Tulip Mania of 1637.

Other causes of perceived insulation from risk may derive from a given entity's predominance in a market relative to other players, and not from state intervention or market regulation. A firm – or several large firms acting in concert (see cartel, oligopoly and collusion) – with very large holdings and capital reserves could instigate a market bubble by investing heavily in a given asset, creating a relative scarcity which drives up that asset's price. Because of the signaling power of the large firm or group of colluding firms, the firm's smaller competitors will follow suit, similarly investing in the asset due to its price gains.

However, in relation to the party instigating the bubble, these smaller competitors are insufficiently leveraged to withstand a similarly rapid decline in the asset's price. When the large firm, cartel or de facto collusive body perceives a maximal peak has been reached in the traded asset's price, it can then proceed to rapidly sell or "dump" its holdings of this asset on the market, precipitating a price decline that forces its competitors into insolvency, bankruptcy or foreclosure.

The large firm or cartel – which has intentionally leveraged itself to withstand the price decline it engineered – can then acquire the capital of its failing or devalued competitors at a low price as well as capture a greater market share (e.g., via a merger or acquisition which expands the dominant firm's distribution chain). If the bubble-instigating party is itself a lending institution, it can combine its knowledge of its borrowers' leveraging positions with publicly available information on their stock holdings, and strategically shield or expose them to default.

Other

Some regard bubbles as related to inflation and thus believe that the causes of inflation are also the causes of bubbles. Others take the view that there is a "fundamental value" to an asset, and that bubbles represent a rise over that fundamental value, which must eventually return to that fundamental value. There are chaotic theories of bubbles which assert that bubbles come from particular "critical" states in the market based on the communication of economic factors. Finally, others regard bubbles as necessary consequences of irrationally valuing assets solely based upon their returns in the recent past without resorting to a rigorous analysis based on their underlying "fundamentals".

Stages

According to the economist Charles P. Kindleberger, the basic structure of a speculative bubble can be divided into five phases:

• Substitution: increase in the value of an asset
• Takeoff: speculative purchases (buy now to sell in the future at a higher price and obtain a profit)
• Exuberance: a state of unsustainable euphoria.
• Critical stage: begin to shorten the buyers, some begin to sell.
• Pop (crash): prices plummet

Identification

CAPE based on data from economist Robert Shiller's website, as of 8/4/2015. The 26.45 measure was 93rd percentile, meaning 93% of the time investors paid less for stocks overall relative to earnings.

Economic or asset price bubbles are often characterized by one or more of the following:

1. Unusual changes in single measures, or relationships among measures (e.g., ratios) relative to their historical levels. For example, in the housing bubble of the 2000s, the housing prices were unusually high relative to income. For stocks, the price to earnings ratio provides a measure of stock prices relative to corporate earnings; higher readings indicate investors are paying more for each dollar of earnings.
2. Elevated usage of debt (leverage) to purchase assets, such as purchasing stocks on margin or homes with a lower down payment.
3. Higher risk lending and borrowing behavior, such as originating loans to borrowers with lower credit quality scores (e.g., subprime borrowers), combined with adjustable rate mortgages and "interest-only" loans.
4. Rationalizing borrowing, lending, and purchase decisions based on expected future price increases rather than the ability of the borrower to repay.
5. Rationalizing asset prices by increasingly weaker arguments, such as "this time it's different" or "housing prices only go up."
6. A high presence of marketing or media coverage related to the asset.
7. Incentives that place the consequences of bad behavior by one economic actor upon another, such as the origination of mortgages to those with limited ability to repay because the mortgage could be sold or securitized, moving the consequences from the originator to the investor.
8. International trade (current account) imbalances, resulting in an excess of savings over investments, increasing the volatility of capital flow among countries. For example, the flow of savings from Asia to the U.S. was one of the drivers of the 2000s housing bubble.
9. A lower interest rate environment, which encourages lending and borrowing.

Notable asset bubbles

Commodities

Bitcoin price gain/loss 2011, 2013

• Tulip mania (Dutch) (1634–1637)
• Comic book speculation bubble (1985-1993)
• Silver Thursday 1980
• Uranium bubble of 2007
• Cryptocurrency bubble (2016–2017, 2021–)

Equities

Private securities

• South Sea Company (British) (1720)
• Mississippi Company (France) (1720)
• Canal Mania (UK) (1790s–1810s)
• Railway Mania (UK) (1840s)

Quoted securities

• Roaring Twenties stock-market bubble (US) (1921–1929)
• Poseidon bubble (Australia) (1969–1970)
• Chinese stock bubble of 2007 (2003–2007)
• Dot-com bubble (US) (1996–2000)

Real estate

• Florida building bubble (US) (1922–1926)
• 2000s Property bubbles:
  • Australian property bubble
  • Irish property bubble
  • New Zealand property bubble
  • Spanish property bubble
  • Romanian property bubble
  • United States housing bubble (US) (2002–2006)

Debt

• Corporate debt bubble (2010–)

Multi-asset/Broad-based

• Japanese asset price bubble (1986–1991)
• 1997 Asian financial crisis (1997)
• Everything bubble (2020–2021)

Notable periods post asset bubbles

• Panic of 1837
• Great Depression (1929–1934)
• Lost Decade (Japan) (1990–2013)
• Early 2000s recession (2002–2003)
• Great Recession (2008–2012)

Cancer and nausea

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cancer_and_nausea 

 

A painting from 1681 depicting a person affected by nausea and vomiting

Cancer and nausea are associated in about fifty percent of people affected by cancer. This may be as a result of the cancer itself, or as an effect of the treatment such as chemotherapy, radiation therapy, or other medication such as opiates used for pain relief. About 70 to 80% of people undergoing chemotherapy experience nausea or vomiting. Nausea and vomiting may also occur in people not receiving treatment, often as a result of the disease involving the gastrointestinal tract, electrolyte imbalance, or as a result of anxiety. Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs and may result in patients delaying or refusing further radiotherapy or chemotherapy.

The strategies of management or therapy of nausea and vomiting depend on the underlying causes. Medical treatments or conditions associated with a high risk of nausea and/or vomiting include chemotherapy, radiotherapy and malignant bowel obstruction. Anticipatory nausea and vomiting may also occur. Nausea and vomiting may lead to further medical conditions and complications including: dehydration, electrolyte imbalance, malnutrition, and a decrease in quality of life.

Nausea may be defined as an unpleasant sensation of the need to vomit. It may be accompanied by symptoms such as salivation, feeling faint, and a fast heart rate. Vomiting is the forceful ejection of stomach contents through the mouth. Although nausea and vomiting are closely related, some patients experience one symptom without the other and it may be easier to eliminate vomiting than nausea. The vomiting reflex (also called emesis) is thought to have evolved in many animal species as a protective mechanism against ingested toxins. In humans, the vomiting response may be preceded by an unpleasant sensation termed nausea, but nausea may also occur without vomiting. The central nervous system is the primary site where a number of emetic stimuli (input) are received, processed and efferent signals (output) are generated as a response and sent to various effector organs or tissues, leading to processes that eventually end in vomiting. The detection of emetic stimuli, the central processing by the brain and the resulting response by organs and tissues that lead to nausea and vomiting are referred to as the emetic pathway or emetic arch.

Causes

Some medical conditions that arise as a result of cancer or as a complication of its treatment are known to be associated with a high risk of nausea and/or vomiting. These include malignant bowel obstruction (MBO), chemotherapy-induced nausea and vomiting (CINV), anticipatory nausea and vomiting (ANV), and radiotherapy-induced nausea and vomiting (RINV).

Malignant bowel obstruction

Main article: Bowel obstruction

Malignant bowel obstruction (MBO) of the gastrointestinal tract is a common complication of advanced cancer, especially in patients with bowel or gynaecological cancer. These include colorectal cancer, ovarian cancer, breast cancer, and melanoma. Three percent of all advanced cancers lead to malignant bowel obstruction and 25 to 50 percent of patients with ovarian cancer experience at least one episode of malignant bowel obstruction. The mechanisms of action that may lead to nausea in MBO include mechanical compression of the gut, motility disorders, gastrointestinal secretion accumulation, decreased gastrointestinal absorption, and inflammation. Bowel obstruction and the resulting nausea may also occur as a result of anti-cancer therapy such as radiation, or adhesion after surgery. Impaired gastric emptying as a result of bowel obstruction may not respond to drugs alone, and surgical intervention is sometimes the only means of symptom relief. Some constipating drugs used in cancer therapy such as opioids may cause a slowing of peristalsis of the gut, which may lead to a functional bowel obstruction.

Chemotherapy

Main article: Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side effects of chemotherapy and is associated with a significant deterioration in quality of life. CINV is classified into three categories:

• early onset (occurring within 24 hours of initial exposure to chemotherapy)
• delayed onset (occurring 24 hours to several days after treatment)
• anticipatory (triggered by taste, odor, sight, thoughts, or anxiety)

Risk factors that predict the occurrence and severity of CINV include sex and age, with females, younger people and people who have a high pretreatment expectation of nausea being at a higher risk, while people with a history of high alcohol consumption being at a lower risk. Other person-related variables, such as chemotherapy dose, rate and route of administration, hydration status, prior history of CINV, emesis during pregnancy or motion sickness, tumour burden, concomitant medication and medical conditions also play a role in the degree of CINV experienced by a person. By far the most important factor which determines the degree of CINV is the emetogenic potential of the chemotherapeutic agents used. Chemotherapeutic agents are classified into four groups according to their degree of emetogenicity: high, moderate, low and minimal.

Chemotherapeutic agents associated with vomiting

Association with vomiting	Examples
Highly emetogenic (>90%) Intravenous agents	Cisplatin, Mechlorethamine, Streptozotocin, Cyclophosphamide > 1500 mg/m2, Carmustine, Dacarbazine, Anthracycline
Highly emetogenic (>90%) oral agents	Hexamethylmelamine, Procarbazine
Moderately emetogenic (30-90%) intravenous agents	Oxaliplatin, Cytarabine > 1g/m2, Carboplatin, Ifosfamide, Cyclophosphamide < 1500 mg/m2, Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Irinotecan, Azacitidine, Bendamustine, Clofarabine, Alemtuzumab
Moderately emetogenic (30-90%) oral agents	Cyclophosphamide, Temozolomide, Vinorelbine, Imatinib

The European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) in 2010 as well as the American Society of Clinical Oncology (ASCO) (2011) recommend a prophylaxis to prevent acute vomiting and nausea following chemotherapy with high emetic risk drugs by using a three-drug regimen including a 5-HT3 receptor antagonist, dexamethasone and aprepitant (a neurokinin-1 antagonist) given before chemotherapy.

Anticipatory

A common consequence of cancer treatment is the development of anticipatory nausea and vomiting (ANV). This kind of nausea is usually elicited by the re-exposure of the patients to the clinical context they need to attend to be treated. Approximately 20% of people undergoing chemotherapy are reported to develop anticipatory nausea and vomiting. Once developed, ANV is difficult to control by pharmacological means. Benzodiazepines are the only drugs that have been found to reduce the occurrence of ANV but their efficacy decreases with time. Recently, clinical trials suggests that cannabidiolic acid suppresses conditioned gaping (ANV) in shrews. Because ANV is widely believed to be a learned response, the best approach is to avoid the development of ANV by adequate prophylaxis and treatment of acute vomiting and nausea from the first exposure to therapy. Behavioral treatment techniques, such as systematic desensitization, progressive muscle relaxation and hypnosis have been shown to be effective against ANV.

Radiation therapy

The incidence and severity of radiation therapy-induced nausea and vomiting (RINV) depends on a number of factors including therapy related factors such as irradiated site, single and total dose, fractionation, irradiated volume and radiotherapy techniques. Also involved are person related factors such as gender, general health of the person, age, concurrent or recent chemotherapy, alcohol consumption, previous experience of nausea, vomiting, anxiety as well as the tumor stage. The emetogenic potential of radiotherapy is classified into high, moderate, low and minimal risk depending on the site of irradiation:

• High risk: total body irradiation (TBI) is associated with a high risk of RINV
• Moderate risk: radiation of the upper abdomen, half body irradiation and upper body irradiation
• Low risk: radiation of the cranium, spine, head and neck, lower thorax region and pelvis
• Minimal risk: radiation of extremities and breast

Pathophysiology

Nausea and vomiting may have a number of causes in people with cancer. While more than one cause may exist in the same person stimulating symptoms via more than one pathway, the actual cause of nausea and vomiting may be unknown in some people. The underlying causes of nausea and vomiting may in some cases not be directly related to the cancer. The causes may be categorized as disease-related and treatment-related.

The stimuli which lead to emesis are received and processed in the brain. It is thought that a number of loosely organized neuronal networks within the medulla oblongata probably interact to coordinate the emetic reflex. Some of the brain stem nuclei which have been identified as important in the coordination of the emetic reflex include the parvicellular reticular formation, the Bötzinger complex and the nucleus tractus solitarii. The nuclei coordinating emesis had formerly been referred to as the vomiting complex, but it is no longer thought to represent a single anatomical structure.

Efferent outputs which transmit the information from the brain leading to the motoric response of retching and vomiting include vagal efferents to the esophagus, stomach and intestine as well as spinal somatomotor neurones to the abdominal muscles and phrenic motor neurones (C3–C5) to the diaphragm. Autonomic efferents also supply the heart and airways (vagus), salivary glands (chorda tympani) and skin and are responsible for many of the prodromal signs such as salivation and skin pallor.

Nausea and vomiting may be initiated by various stimuli, through different neuronal pathways. A stimulus may act on more than one pathway. Stimuli and pathways include:

• Toxic substances in the gastrointestinal tract: toxic substances (including drugs which are used in the treatment of cancer) in the lumen of the gastrointestinal tract stimulate vagal afferent nerves in the gut mucosa which communicate to the nucleus tractus solitarii and the area postrema to initiate vomiting and nausea. A number of receptors on the terminal ends of the vagal afferent nerves have been identified as being involved in this process, including the 5-hydroxytryptamine3 (5-HT3), neurokinin-1, and cholecystokinin-1 receptors. Various local mediators located in enterochromaffin cells of the gut mucosa play a role in stimulating these receptors. Of these 5-hydroxytryptamine seems to play the dominating role. This pathway has been postulated to be the mechanism by which some anti-cancer drugs such as cisplatin induce emesis.
• Toxic substances in the blood: toxic substances which have been absorbed into the blood (including cytostatics) or endogenous toxic (waste) material released by body or cancer cells into the blood can be detected directly in the area postrema of the brain and trigger the emetic reflex. The area postrema is a structure located on the floor of the fourth ventricle around which the blood–brain barrier is permeable, thus allowing for the detection of humoral or pharmacological stimuli in the blood or cerebrospinal fluid. This structure contains receptors which form a chemoreceptor trigger zone. Some of the receptors and neurotransmitters involved in the regulation of this emetic pathway include dopamine type D2, serotonin types 2–4 (5HT2–4), histamine type 1(H1), and acetylcholine (muscarinic receptors type 1 to 5, M1–5). Some other receptors such as substance P, cannabinoid type 1 (CB1) and the endogenous opioids may also be involved.
• Pathological conditions of the gastrointestinal tract: diseases and pathological conditions of the GIT may also lead to nausea and vomiting through direct or indirect stimulation of the above named pathways. Such conditions may include malignant bowel obstruction, hypertrophic pyloric stenosis and gastritis. Pathological conditions in other organs which are linked to the above named emetic pathways may also lead to nausea and vomiting, such as the myocardial infarction (through stimulation of cardiac vagal afferents) and kidney failure.
• Stimulation of the central nervous system: certain stimuli of the central nervous system may induce the emetic reflex. These include fear, anticipation, brain trauma and increased intra-cranial pressure. Of particular relevance to cancer patients in this regard are the stimuli of fear and anticipation. Evidence suggests that cancer patients may develop the side effects of nausea and vomiting in anticipation of chemotherapy. In some patients, re-exposure to cues such as smell, sounds or sight associated with the clinic or previous treatment may evoke anticipatory nausea and vomiting.
• Pathological conditions of the vestibular system: a disturbance of the vestibular system such as in motion sickness or Ménière's disease can induce the emetic reflex. Such disturbances of the vestibular system could also be cancer related such as in cerebral or vestibular secondaries (metastasis), or cancer treatment related such as the use of opioids.

Management

The strategies of management or prevention of nausea and vomiting depend on the underlying causes, whether they are reversible or treatable, stage of the illness, the person's prognosis and other person specific factors. Anti emetic drugs are chosen according to previous effectiveness and side effects.

Medication

Drugs that are used in the prophylaxis and therapy of nausea and vomiting in cancer include:

• 5-HT3 antagonists: 5-HT3 antagonists produce their anti emetic effect by blocking of the amplifying effect of serotonin on peripheral and central 5-HT3 receptors located on the various vagal afferent nerve endings and the chemoreceptor trigger zone. They are effective in the treatment and prophylaxis of CINV as well as in malignant bowel obstruction and kidney failure which are associated with elevated serotonin levels. These substances include Dolasetron, Granisetron, Ondansetron, Palonosetron, and Tropisetron. They are often used in combination with other anti emetic drugs in people with high risk of emesis or nausea and are recommended as the most effective anti emetics in the prophylaxis of acute CINV.
• Corticosteroids: such as Dexamethasone are used in the treatment of emesis as a result of chemotherapy, malignant bowel obstruction, raised intracranial pressure and in the chronic nausea of advanced cancer, though their exact mode of action remain unclear. Dexamethason is recommended for use in the acute prevention of highly, moderately, and low emetogenic chemotherapy and in combination with aprepitant for the prevention of delayed emesis in highly emetogenic chemotherapy.
• NK1 receptor antagonists: such as Aprepitant block the NK1 receptor in the brainstem and gastrointestinal tract. Their antiemetic activity when added to a 5-HT3 receptor antagonist plus dexametasone has been shown in several phase II double-blind studies.
• Cannabinoids: are a useful adjunct to modern anti emetic therapy in selected patients. They show a combination of weak anti emetic efficacy with potentially beneficial side effects such as sedation and euphoria. However, their usefulness is generally limited by the high incidence of toxic effects, such as dizziness, dysphoria, and hallucinations. Some studies have shown that cannabinoids are slightly better than conventional anti emetics such as metoclopramide, phenothiazines and haloperidol in the prevention of nausea and vomiting. Cannabinoids are an option in affected people who are intolerant or refractory to 5-HT3 antagonists or steroids and aprepitant as well as in refractory nausea and vomiting and rescue anti emetic therapy.
• Prokinetic agents such as Metoclopramide
• Dopamine receptor antagonists such as Phenothiazines (Prochlorperazine and chlorpromazine), haloperidol, olanzapine, and Levomepromazine, block D2 receptors found in the chemoreceptor trigger zone
• Antihistaminic agents like Promethazine block H1 receptors in the vomiting center of the medulla, the vestibular nucleus, and the chemoreceptor trigger zone
• Anticholinergic agents such as Scopolamine (Hyoscine) are used as anti emetics as they relax smooth muscle and reduce gastrointestinal secretions by blockade of muscarinic receptors. They may be useful in the management of terminal bowel obstruction
• Somatostatin analoga such as Octreotide are used for the palliation of malignant bowel obstruction, especially when there is high output vomiting not responding to other measures
• Cannabidiol is used as a palliative treatment (non-curative symptomatic treatment) and improves numerous symptoms that frequently appear during chemotherapy like nausea, vomiting, loss of appetite, physical pain or insomnia. Due to the large number of cannabinoid receptors ( CB1 and CB2 ) distributed throughout the gastrointestinal tract ( GI ), these substances can help to control and treat many GI diseases where vomiting and nausea are frequent.

Other measures

Other non-drug measures may include:

• Diet: Small palatable meals are normally tolerated better than big meals in people affected by nausea and vomiting in cancer. Carbohydrate meals are better tolerated than spicy, fatty and sweet foods. Cool, fizzy drinks are found to be more palatable than still or hot drinks.
• The avoidance of environmental stimuli, such as sights, sounds, or smells that may initiate nausea.
• Behavioral approaches, such as distraction, relaxation training and Cognitive behavioural therapy may also be useful.
• Alternative medicine: Acupuncture and ginger have been shown to have some anti emetic effects on chemotherapy-induced emesis and anticipatory nausea, but have not been evaluated in the nausea of far advanced disease.

Palliative surgery

Palliative care is the active care of people with advanced, progressive illness such as cancer. The World Health Organization (WHO) defines it as an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems (such as nausea or vomiting), physical, psychosocial, and spiritual.

Sometimes it is possible or necessary to provide relief for cancer caused nausea and vomiting through palliative surgical intervention. Surgery is however not routinely carried out when there are poor prognostic criteria for surgical intervention such as intra-abdominal carcinomatosis, poor performance status and massive ascites. The surgical approach proves beneficial in affected people with operable lesions, a life expectancy greater than 2 months and good performance status. Often a malignant bowel obstruction is the cause of the symptoms in which case the purpose of palliative surgery is to relieve the symptoms of bowel obstruction by means of several procedures including:

• Stoma formation
• Bypass of the obstruction
• Resection of bowel segments
• Placement of stents.
• Percutaneous endoscopic gastrostomy (PEG) tube placement to enable gastric venting.
• Gastric venting through a nasogastric tube is a semi-invasive possibility for palliation of nausea and vomiting due to gastrointestinal obstruction in people with abdominal malignancies who decline surgery or where surgery may not be indicated. However nasogastric tubes are not recommended to be used over a long period of time because of the high risk of displacement, poor tolerance, restrictions in daily routine activities, coughing, clearing pulmonary secretions and can be cosmetically unacceptable and confining. Complications of nasogastric tubes include aspiration, hemorrhage, gastric erosion, necrosis, sinusitis and otitis.

Epidemiology

12.7 million new cancer cases and 7.6 million cancer deaths were estimated worldwide in 2008.

• Nausea or vomiting occur in 50 to 70% of people with advanced cancer.
• 50 to 80% of people undergoing radiotherapy experience nausea and/or vomiting, depending on the site of irradiation.
• Anticipatory nausea and vomiting is experienced by approximately 20 to 30% of people undergoing chemotherapy.
• Chemotherapy-induced nausea and vomiting resulting from treatment with highly emetogenic cytotoxic drugs can be prevented or effectively treated in 70 to 80% of affected people.

Cannabinoid

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cannabinoid

Cannabinoids (/kəˈnæbənɔɪdzˌ ˈkænəbənɔɪdz/) are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary intoxicating 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 (i.e., THCA, CBDA, CBCA and their common precursor CBGA) 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.

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC, but endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.

Uses

Medical uses include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain. Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".

Cannabinoid receptors

Before the 1980s, cannabinoids were speculated to produce their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals. Two known cannabinoid receptors are termed CB₁ and CB₂, with mounting evidence of more. The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.

The Endocannabinoid System (ECS) regulates many functions of the human body. 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.

Cannabinoid receptor type 1

Main article: Cannabinoid receptor type 1

CB₁ receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB₁ receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.

Cannabinoid receptor type 2

Main article: Cannabinoid receptor type 2

CB₂ receptors are predominantly found in the immune system, or immune-derived cells with varying expression patterns. While found only in the peripheral nervous system, a report does indicate that CB₂ is expressed by a subpopulation of microglia in the human cerebellum. CB₂ receptors appear to be responsible for immunomodulatory and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.

Phytocannabinoids

See also: Comparison of phytocannabinoids

 

The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden trichomes.

 

Cannabis indica plant

The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 113 different cannabinoids have been isolated from the Cannabis plant. To the right, the main classes of cannabinoids from Cannabis are shown.

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized. The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

Well known cannabinoids

The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).

Tetrahydrocannabinol

Main article: Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and Delta-8-Tetrahydrocannabinol (Δ⁸-THC), through intracellular CB₁ activation, induce anandamide and 2-arachidonoylglycerol synthesis produced naturally in the body and brain. These cannabinoids produce the effects associated with cannabis by binding to the CB₁ cannabinoid receptors in the brain.

Cannabidiol

Main article: Cannabidiol

Cannabidiol (CBD) is mildly psychotropic. Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis. Cannabidiol has little affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists. It was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiol has also been shown to act as a 5-HT_1A receptor agonist. CBD can interfere with the uptake of adenosine, which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.

CBD shares a precursor with THC and is the main cannabinoid in CBD-dominant Cannabis strains. CBD has been shown to play a role in preventing the short-term memory loss associated with THC.

There is tentative evidence that CBD has an anti-psychotic effect, but research in this area is limited.

Cannabinol

Main article: Cannabinol

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of neurotransmission (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated from cannabis extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940, followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds in vivo. Although CBN shares the same mechanism of action as other more well-known phytocannabinoids (e.g., delta-9 tetrahydrocannabinol or D9THC), it has a lower affinity for CB1 receptors, meaning that much higher doses of CBN are required in order to experience physiologic effects (e.g., mild sedation) associated with CB1R agonism. Although scientific reports are conflicting, the majority of findings suggest that CBN has a slightly higher affinity for CB2 as compared to CB1. Although CBN has been marketed as a sleep aid in recent years, there is a lack of scientific evidence to support these claims, warranting skepticism on the part of consumers.

Biosynthesis

Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is an analogous pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.

Double bond position

In addition, each of the compounds above may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ⁹-THC, while the minor form is called Δ⁸-THC. Under the alternate terpene numbering system, these same compounds are called Δ¹-THC and Δ⁶-THC, respectively.

Length

Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side chain are named using the suffix varin and are designated THCV, CBDV, or CBNV, while those with the heptyl side chain are named using the suffix phorol and are designated THCP and CBDP.

Cannabinoids in other plants

Phytocannabinoids are known to occur in several plant species besides cannabis. These include Echinacea purpurea, Echinacea angustifolia, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata. The best-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) from Echinacea species, most notably the cis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide. At least 25 different alkylamides have been identified, and some of them have shown affinities to the CB₂-receptor. In some Echinacea species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers. Yangonin found in the Kava plant has significant affinity to the CB1 receptor. Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors. A widespread dietary terpene, beta-caryophyllene, a component from the essential oil of cannabis and other medicinal plants, has also been identified as a selective agonist of peripheral CB₂-receptors, in vivo. Black truffles contain anandamide. Perrottetinene, a moderately psychoactive cannabinoid, has been isolated from different Radula varieties.

Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents.

Cannabis plant profile

Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called hemp) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content or for a specific chemical balance.

Quantitative analysis of a plant's cannabinoid profile is often determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

Pharmacology

Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.

Some is also stored in fat in addition to being metabolized in the liver. Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based "drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues.

Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, called terpenes. This interaction would lead to the entourage effect.

Cannabinoid-based pharmaceuticals

Nabiximols (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. Also included are minor cannabinoids and terpenoids, ethanol and propylene glycol excipients, and peppermint flavoring. The drug, made by GW Pharmaceuticals, was first approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis, making it the first cannabis-based medicine. It is marketed by Bayer in Canada. Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval. In 2007, it was approved for treatment of cancer pain. In Phase III trials, the most common adverse effects were dizziness, drowsiness and disorientation; 12% of subjects stopped taking the drug because of the side effects.

Dronabinol (brand name Marinol) is a THC drug used to treat poor appetite, nausea, and sleep apnea. It is approved by the FDA for treating HIV/AIDS induced anorexia and chemotherapy induced nausea and vomiting.

The CBD drug Epidiolex has been approved by the Food and Drug Administration for treatment of two rare and severe forms of epilepsy,^[59] Dravet and Lennox-Gastaut syndromes.

Separation

Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other distillation techniques. Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.

History

The first discovery of an individual cannabinoid was made, when British chemist Robert S. Cahn reported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940.

Two years later, in 1942, American chemist, Roger Adams, made history when he discovered Cannabidiol (CBD). Progressing from Adams research, in 1963 Israeli professor Raphael Mechoulam later identified the stereochemistry of CBD. The following year, in 1964, Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).

Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the Cannabis plant from the precursor CBG.

Endocannabinoids

Further information on the functions and regulation of the endocannabinoids: Endocannabinoid system

Anandamide, an endogenous ligand of CB₁ and CB₂

Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous ligand for the receptors.

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Main article: Arachidonoylethanolamine

Anandamide was the first such compound identified as arachidonoyl ethanolamine. The name is derived from the Sanskrit word for bliss and -amide. It has a pharmacology similar to THC, although its structure is quite different. Anandamide binds to the central (CB₁) and, to a lesser extent, peripheral (CB₂) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB₁ receptor. 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.

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology. All of these compounds are members of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and anorexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds and in molluscs.

2-Arachidonoylglycerol (2-AG)

Main article: 2-Arachidonoylglycerol

Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB₁ and CB₂ receptors with similar affinity, acting as a full agonist at both. 2-AG is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo. In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.

2-Arachidonyl glyceryl ether (noladin ether)

Main article: 2-Arachidonyl glyceryl ether

In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain. Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. It binds to the CB₁ cannabinoid receptor (K_i = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB₁ receptor, and only weakly to the CB₂ receptor.

N-Arachidonoyl dopamine (NADA)

Main article: N-Arachidonoyl dopamine

Discovered in 2000, NADA preferentially binds to the CB₁ receptor. Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.

Virodhamine (OAE)

Main article: Virodhamine

A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB₂ and a partial agonist at CB₁, it behaves as a CB₁ antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.

Lysophosphatidylinositol (LPI)

Lysophosphatidylinositol is the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.

Function

Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters such as dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use.

As hydrophobic molecules, endocannabinoids cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

The endocannabinoid 2-AG has been found in bovine and human maternal milk.

A review by Matties et al. (1994) summed up the phenomenon of gustatory enhancement by certain cannabinoids. The sweet receptor (Tlc1) is stimulated by indirectly increasing its expression and suppressing the activity of leptin, the Tlc1 antagonist. It is proposed that the competition of leptin and cannabinoids for Tlc1 is implicated in energy homeostasis.

Retrograde signal

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid-mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

"Runner's high"

The runner's high, the feeling of euphoria that sometimes accompanies aerobic exercise, has often been attributed to the release of endorphins, but newer research suggests that it might be due to endocannabinoids instead.

Synthetic cannabinoids

Main article: Synthetic cannabinoid

Historically, laboratory synthesis of cannabinoids was often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.

When synthetic cannabinoids are used recreationally, they present significant health dangers to users. In the period of 2012 through 2014, over 10,000 contacts to poison control centers in the United States were related to use of synthetic cannabinoids.

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

• Dronabinol (Marinol), is Δ⁹-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
• Nabilone (Cesamet, Canemes), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
• Rimonabant (SR141716), a selective cannabinoid (CB₁) receptor inverse agonist once used as an anti-obesity drug under the proprietary name Acomplia. It was also used for smoking cessation

Other notable synthetic cannabinoids include:

• JWH-018, a potent synthetic cannabinoid agonist discovered by John W. Huffman at Clemson University. It was often sold in legal smoke blends collectively known as "spice". Several countries and states have moved to ban it legally.
• JWH-073
• CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC.
• Dimethylheptylpyran
• HU-210, about 100 times as potent as THC
• HU-211, a synthetic cannabinoid derived drug that acts on NMDA instead of endocannabinoid system
• HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
• SR144528, a CB₂ receptor antagonist/ inverse agonist
• WIN 55,212-2, a potent cannabinoid receptor agonist
• JWH-133, a potent selective CB₂ receptor agonist
• Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine
• AM-2201, a potent cannabinoid receptor agonist

Recently, the term "neocannabinoid" has been introduced to distinguish these designer drugs from synthetic phytocannabinoids (THC or CBD obtained by chemical synthesis) or synthetic endocannabinoids.