- 1 Mental Landscape
- 2 What is a Drug?
- 3 Evidence of Drug Use
- 4 Finding and Consuming Drugs
- 5 Geographical Review of Drug Use
- 6 Evolutionary Theory
- 7 The Impact of Restriction
- 8 The Future Potential
- 9 Use or Abuse?
- 10 Stigma or Acceptance?
- 11 References
The legal classification of drugs creates an artificial separation between intoxicants which are deemed acceptable for everyday consumption and those which are demonized for their use. Legal, and taxable, substances such chocolate, coffee, alcohol and tobacco have mind altering properties in some cases similar to stronger narcotics but are consumed in much lower doses – coffee is the most popular drink worldwide and over 400 billion cups are consumed each year.
The desire to feel different seems universal to the human experience and there is wide ranging use of locally derived plants and mushrooms throughout the globe. Determination to seek out and consume these magical ingredients may have conferred evolutionary or community benefits to traditional communities around the world.
Speaking to God
In many tribal traditions the ability to communicate with spirits and other entities was a prized skill and much respect was given to the shaman or priest who could facilitate this kind of interaction. Achieving altered states of perception can be attained in a variety of ways: prolonged fasting; deep meditation; sleep deprivation; dehydration; repetitive movements such as dancing and whirling to get into a trance; endurance of pain and the use of psychedelic substances.
Typically the ingestion of psychedelics is a much quicker route of ascension to these desired experiences. The speed and relative ease with which psychedelics work facilitates the experience of altered conscious states allowing more individuals to have a personal experience of the divine. Psychedelic drug use is the preferred method of divine communication for many traditional people.
The majority of religions require communication between humans and spiritual beings in the non-physical realm and typically require changes in consciousness. Unfortunately, the use of traditional drugs has been tightly controlled by religious organizations, and now the government, who would rather maintain control of consciousness and limit the general population’s ability to have direct discussions with the divine.
Mind altering substances have the potential to radically alter perceptions of reality through various mechanisms which typically involve stimulating endogenous receptors in the brain and body. This means their use has the potential for both long term damage and addiction, especially for chemically enhanced or synthetically produced versions of natural substances because they are much stronger.
Addictive potential and inappropriate use has driven the use of many substances underground into a black market which lacks the quality control and community support of traditional drug consumption. By comparison the ritualistic use of psychedelics as a tool for communication, rite of passage and healing substance can have profound positive benefits for the individual and their community.
Recent research into the therapeutic benefits of a variety of illicit substances is uncovering a huge potential to treat a range of psychiatric and physical conditions. Understanding the traditional and cultural use of these favoured substances could highlight further ways in which modern man could benefit from ancient understanding.
What is a Drug?
Pharmacologically, a drug can be defined as any chemical substance which has the ability to cross the blood brain barrier (or impact substances that cross it) and cause changes in behavior, which can lead to addiction. From a legal perspective drugs are defined by their ability to cause harm and in most countries legislation divides them into different categories with varying penalties for their consumption or distribution, however, the reality of the reasons drugs have been made, and remain, illegal is not so clear cut.
A relatively recent scientific review of drug classifications in the UK proposed significant changes to the ways in which drugs have been categorized. The review proposed a more transparent evidence-based scale of harm and highlighted issues with the current system – which is based on historical events, financial benefits from taxation and political fear of change.[ii] Unfortunately the review was met with significant opposition from all major political parties and the work was essentially ignored.
Evidence of Drug Use
Modern drug use is quite different from the traditional reasons for consuming mind altering substances. Traditional drugs were likely discovered by foraging hunter-gatherers who experimented with the effects of psychoactive plants and mushrooms to achieve desired changes in consciousness.[iii]
Sadly, advances in chemistry found methods to purify the active substances contained in ancient drugs and the resulting chemicals are far stronger. Out of their traditional cultural context and with far greater effects these substances have marred the reputation of many potentially valuable substances.
The desire and ability to deliberately alter states of mind has played a significant role in societies all over the world since the dawn of time. An analysis of 488 societies (representing 57% of ethnographic societies worldwide) found that 90% had deliberately produced Altered States of Consciousness (ASC) in their core belief systems.[iv]Evidence suggests there are biological drives and significant social development associated with experiencing altered states, specifically in the development of symbology (and with it language).[v]
Finding and Consuming Drugs
The psychoactive activity of plants and mushrooms is a result of a class of organic molecules called alkaloids – found in different strengths in roots, leaves, seeds, bark or flowers. Consumption is via a variety of methods including smoking, snuffing (nasal use), swallowing (like a food substance) infusion (into a drink) or absorption through the skin (often using wounds or burns).
There are approximately 120 known psychoactive plants, a number comparable to the variation in plants we consume for food, of which there are only 150 in modern regular use.[vi] Many plants require elaborate processing or mixing with other substances to gain their full, and safe, psychoactive potential. The effort and elaborate processes required to prepare the substance for use demonstrates the degree of devotion to their effective use.
Geographical Review of Drug Use
The discovery of prehistoric art on the surface of rocks and in caves suggest mind altering substances have been part of our cultural foundation for a very long time and may even have played a part in our mental development.[vii]
The use of traditional drugs throughout the ancient world highlights the similarities in effects that dissimilar cultures were trying to achieve.The history of psychoactive drugs is tied to the ethnography of consciousness itself and they were often a highly valued commodity used as medicines, symbols and sacraments.[viii]
Proportionally there seem to be a larger number of psychoactive substances used in this continent than other places on earth. The landmass and vegetation is comparable to that of Africa yet the pursuance of altered states through psychoactive substances is much higher.South American native religions, Amazonian Cultures, Central American Cultures, Mexican subcultures, the Aztec, Maya and Inca all evolved ritualistic consumption of psychoactive substances.[ix]
Native Mexican cultures (Chichimeca,Huichol, Tarahumara, Toltec and others) consume the fresh or sundried flesh of the small button-style peyote cactus to reach altered states. Containing mescaline the cactus is consumed in long ceremonies over multiple days (which typically include dancing) designed to facilitate direct communication with spirit. Spanish invaders deemed the sacred plant Satanic and its use went underground but the cactus remains the official sacrament of the Native American Church and is believed to have been used for over 4,000 years.[x]
This woody vine has a long history of use in Central Mexico and is a species of Morning Glory. Believed to be a visionary plant of the Aztecs the seeds are crushed to prepare a drink. The active ingredient is LSA (similar to LSD) and the ‘trip’ typically includes heightened visual perception and acute awareness.[xi]
San Pedro Cactus
The San Pedro cults of the Northern Andes and Peru use this columnar mescaline containing healing cactus to diagnose and treat illness. Shaman and their patients consume the cactus, as a tea taken either orally or nasally, and the patient is ‘read’ to understand the cause of the illness. After diagnosis patients are required to travel high into the mountains to bathe in healing waters found in sacred lakes. The cactus is also used for inducing shamanic trances and enhances connection with other times and realities.[xii]
Native to Oaxaca, Mexico, Mazatec shamans use this herb, related to mint, to facilitate visions, to cure or divine (including finding lost objects). High doses of 50-100 leaves are taken orally and kept in the mouth while chewing to induce visionary states. Lower doses are consumed to manage chronic medical conditions such as headache or rheumatism – the plant is also thought to have antidepressant effects.[xiii]
Anadenanthera peregrine is a snuff found in Orinoco Venezuela. It is made by roasting and grinding seeds into a fine powder and mixed with ash made form specific leaves. The hallucinogenic powder has a long traditional use and is entrenched in the culture of Amazonian ethnic groups.[xiv] The visionary snuff has been used for over 4,000 years and is used to heal. Containing DMT (the most potent psychoactive) the mixture is often combined with the Banisteriopsiscaapi vine like Ayuhasca. Traditional use is guided by a shaman who accompanies the experience with song and music. [xv]
This is a mixture of barks and vines which together have a powerful hallucinogenic effect. Shamans brew traditional concoctions containing several active ingredients and potentiating herbs. The hallucinogenic effects come from the DMT and an inhibitor which prevents the breakdown of the active ingredients ensuring they can reach the brain. DMT is produced endogenously in the brain at both birth and death and during sleep, from the pineal gland, and has strong associations with visionary states and crossing into other worlds. The toxicity is low, although it often induces vomiting as a purging effect and its therapeutic potential to treat depression and other mental illnesses is currently being investigated.[xvi]
Found in the mountains of the Andes this plant enhances endurance and respiration, specifically at high altitudes where there is less oxygen. The sacred leaf is integral to activities involving manual labour and is also used ritualistically to mark rites of passage and various ceremonies when the leaves are used to bless crops and for healing and divination. Once chewed the leaves remain potent and are disposed of ritualistically to preserve the land’s fertility and security. [xvii]
The exact origin of many psychoactive substances is not fully understood due to the rapid way they spread once trading routes were established. Indian Vedic texts include descriptions of a hugely influential substance called Soma which was squeezed from a plant, however, the exact nature of this substance has been lost to time and may have been purposefully wiped out to prevent the over popularization of its use.
The cultivation and use of Cannabis is thought to have started in China in around 3000 BC and it is recognised as the most extensively used illicit substance on earth.[xviii]Cannabis, or hemp, is known for its relatively mild psychoactive effect, heightening of senses and huge variety of practical uses for making cloth, rope and paper. Medicinally Cannabis was used to treat a wide variety of illnesses and the female, psychoactive, plant was used to treat conditions which resulting from a lack of yin (female) energy such as: menstruation, gout, rheumatism, malaria, beri-beri, constipation, and absentmindedness.[xix] Cannabis was to reduce the pain from surgery and as mild analgesic – prepared with wine using cannabis resin (the sticky residue scraped from the plant).[xx]
Cannabis rapidly travelled into other cultures and in India became known as ‘bhang’ also appearing in the ancient spiritual texts the Vedas.
This powerful pain killing drug is harvested from the opium poppy Papaversomniferum, and thought to be originally cultivated in Persia and Mesopotamia (although some research indicates it may actually be European in origin). Evidence of its use dates back to 4,000 BC and it is referenced in Sumarian texts where it is referred to as the ‘Plant of Joy’.
This nut and leaf of this plant are referenced in traditional Indian medical texts from the healing science of Ayurveda. In both Indian and Chinese folk medicine the leaves are recorded for their detoxifying, antioxidant and antimutagenic properties. Modern science has identified other beneficial properties including cardiovascular protection, anticancer and anti-inflammatory effects. The leaf was typically chewed by itself but more modern usage involves wrapping the leaves with other substances such as tobacco, slaked lime and herbal flavourings to make a ‘Quid’. The use of the nut and leaf was widespread in ancient times and specifically the nut was known for its aphrodisiacal properties. [xxv]
Amanita muscaria is a mushroom found in the Siberian peninsula which is consumed by shaman after toasting or mixing with reindeer milk into a beverage. The psychoactive substances found in the mushroom can remain active after ingestion and the urine of shaman, or reindeer that have also chosen to consume the mushroom, is also imbibed to produce altered states. The red and white spotted mushroom has been widely used in ancient and modern mushroom symbolism and now represents the archetypal mushroom. Evidence of the mushrooms use, from archaeological finds and linguistic studies, dates is use back some 3,000 to 6,000 years and it is reputed to be one of the earliest entheogens used by man. [xxvi]
Several tribal groups use psychoactive drugs and physical methods to achieve altered states. Ritualistically plants were commonly used to mark rites of passage, such as transition into adulthood.
This leaf of this flowering herb found in the Horn of Africa is traditionally chewed for long periods of time to release a very small amount of the active ingredient, cathinone, which is an amphetamine like stimulant.[xxvii]The use of the leaf dates back thousands of years and it causes a mild euphoria and excitement similar to the consumption of strong coffee.[xxviii] Modern fears about the potential of this drug to be popularised and enhanced into a stronger substance have led to restrictions in its use and a change in legal status in many countries where it is traditionally consumed.
Tabernantheiboga is a psychotropic shrub native to West African rainforests taken in high doses to induce visions. The roots of the plant contain a variety of active substances, including ibogaine. The bitter bark of the root is where the highest concentration of ibogaine is found and when consumed causes local anaesthesia in the mouth. Rituals and tribal dances of the Bwiti religion involve consuming the plant in moderate doses and larger doses are taken for significant rites of passage such as entering the religion during the transition into adulthood. The substance is used for healing, to induce visions for spiritual enlightenment and solve problems – driving the stability of family and community structure.[xxix]
Egyptian priests used this medicinal and spiritual sacrament for over 3,000 years to bring on feelings of tranquillity and gentle euphoria. The mild psychoactive effects of the water-lilly (due to its apomorphine content) create an expanded state of consciousness useful for mediation and magical rituals, enabling its consumers to enter trance-like dreamy states. [xxx] The flowers steeped in wine are also used as an aphrodisiac and were consumed in large gatherings and used to treat impotence -the lilly is featured in tomb frescos and erotic cartoons.[xxxi]
Pagans have a deep and spiritual connection with nature and relied on the medicinal and magical properties of plants, herbs and mushrooms to heal and divine. Persecution of the wise-women who held this ancient knowledge by Christians has led to significant bias in appreciation for their knowledge and skills in herbalism – the witches were feared for their power and as much as possible eradicated losing much of their ancient wisdom.
Atropa belladonna was one of the many mind altering substances used ritualistically by Pagans. Typically it was absorbed through the walls of the vagina (as the membranes are very thin and easily allow substances to cross) and applied to a broom which a witch would ‘ride’. This method of application, and the ensuing effects, is what has given rise to the traditional ‘witch on a broomstick’ imagery.
The substance was typically mixed with other potent herbs to make a ‘flying ointment’ used to access altered states and visions – the ‘flying’ was not literal but mental as they traversed cerebral landscapes to access hidden knowledge and for spiritual communion.
Hyoscyamusniger is another ancient drug used as both a poison and an intoxicating narcotic and was also a key component of witches flying ointments. The psychotropic effects include excitement, rage, confusion, hallucinations and delirium, flying sensations and erotic hallucinations and typically the experience will not be remembered the next day.[xxxiii]
The use of mind altering drugs has been associated with key progressions in human development, specifically catapulting our evolution in the arenas of art and music as they bypass our adaptive information processing systems – allowing us to perceive things differently and think outside of the box.[xxxiv]
There even seems to be a symbiotic relationship between man and the substances he consumes – the evolution of man and psychotropic substances goes hand in hand and mammalian ability to metabolize and effectively use these drugs is symbiotic with the plants adaptions to produce chemicals which directly influence our neurology.[xxxv]
The ancient consumption of medicinal drugs and mind altering substances offers multiple benefits related to:
- Increased endurance – essential for survival in difficult conditions and climates
- Problem solving – receiving guidance from higher powers and creating community conensus
- Intoxication – for relaxation, entertainment and community bonding experiences
- Aphrodisiacs – to ensure the survival of the community and promote sexual satisfaction
- Medicinal – to diagnoses and treat states of disease both physically and energetically
Modern man has the same requirements and still relies on coffee, alcohol, narcotics and pharmaceuticals to achieve many of the same goals – but often with more side effects and greater potential for abuse.
The Impact of Restriction
Sadly restriction of these ancient drugs and medicines means they get stronger as criminal gangs try and reduce their risk and increase profit by trading the smallest quantities (physically) for the most amount of money. Processed crack cocaine, for example, is much more profitable, due to its addictive nature, than bales of coca leaves.
The prohibition of drugs has created a black market; much like the prohibition of alcohol did in America, and has created criminals who are simply meeting the demand for our basic human desires to experience alternative states of conscious reality. The taboo surrounding drug use also prevents addicts seeking help and removes society’s ability to support those experiencing problems.
Many of the medicinal benefits of psychoactive substances have been ignored due to restrictions in their supply and scientific study. The blanket disapproval has hindered the development of novel therapeutic approaches to treat a variety of diseases and mental conditions.
The Future Potential
Fortunately the veil has lifted and there is currently a selection of scientific and clinical trials reviewing the potential of many ancient and sacred herbs and modern psychedelic substances. Cannabis specifically is undergoing resurgence, specifically in America, where state laws are allowing its sale and use as a medicinal substance with huge potential to treat a wide variety of diseases from cancer to epilepsy and many more.
Drugs have often been used as tools to help ancient cultures understand the mind and promote creativity in art and music. Historically society advocated the use of drugs and it is only relatively recently that the taboo surrounding the personal freedom to change how you think and feel has been put in place. Addiction emerged as a result of prohibition – a fact that many governments still perusing the ‘War on Drugs’ are not yet ready to admit.[xxxvi]
Fortunately many tribal cultures are taking back their heritage and changes in drug laws and widespread deregulation is happening in many South American countries and the Western World. Argentina, Mexico, Uruguay, Ecuador, Colombia, Bolivia and Brazil have already made, or are making, significant changes to drug laws, adopting models which protect instead of criminalise people who chose to use drugs.[xxxvii]
Use or Abuse?
Drug addiction is characterised by: an inability to abstain from the drug; impaired behavioural control; cravings for the drug or other pleasure seeking activities which stimulate the same reward pathways; diminished recognition of behavioural problems; and a dysfunctional emotional response[xxxviii].
However, with this definition sugar is also classified as a drug.[xxxix] It is indisputable the damage the consumption of this most modern drug is doing to society (diabetes, obesity, cancer, Alzheimer’s, Cardiovascular disease and many more have all been strongly associated with sugar consumption). Following the trend set by the tobacco industry this popular, but often hidden drug, is being accompanied by warnings of its negative effects on health. The fine line society draws between use and abuse of a drug seems to depend on the taxable profit of the producer and not the effects of the drug itself.
Stigma or Acceptance?
Health professionals and senior ranking police officials agree that much harm could be avoided if we let go of the stigma and secrecy surrounding drug use and instead focussed on helping those who experience the problems associated with addiction in a balanced and non-judgemental way.
Accepting the significance of drug use throughout history and in virtually all traditional cultures around the world would go a long way to overcoming the taboo which is preventing the rational exploration of their continued use. The human appreciation for the healing, sacred, entertaining, bonding, pain relieving and mood altering experiences that drugs provide is not going to go away – the tradition of their use is simply too strong and too significant.
[i] Marc-Antoine Crocq, MD “Historical and cultural aspects of man’s relationship with addictive drugs”, Dialogues in Clinical Neuroscience, v.9(4); 2007 Dechttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202501/
[ii] Scale of harm: http://beckleyfoundation.org/wp-content/uploads/2016/04/Colin_Blakemore.pdf
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[iv]Elisa Guerra-Docea “Psychoactive Substances in Prehistoric Times: Examining the Archaeological Evidence”, Time and Mind: The Journal of Archaeology, Consciousness and Culture, Volume 8, Issue 1, 2015http://www.tandfonline.com/doi/abs/10.1080/1751696X.2014.993244#.V4YbX9IrLZ4
[v]Froese, T., A. Woodward, and T. Ikegami. 2014. “Are Altered States of Consciousness Detrimental, Neutral or Helpful for the Origins of Symbolic Cognition? A Response to Hodgson and Lewis-Williams.” Adaptive Behavior 22 (1): 89–95. doi:10.1177 http://adb.sagepub.com/content/22/1/89.abstract
[vi]Hallucinogenic Plants and Their Use in Traditional Societies – An Overviewhttps://www.culturalsurvival.org/publications/cultural-survival-quarterly/botswana/hallucinogenic-plants-and-their-use-traditional-so
[vii] The Role of Drugs in Prehistory: http://www.ancient-wisdom.com/prehistoricdrugs.htm
[viii] Robin Room, “Drugs, Consciousness And Society: Can We Learn From Others’ Experience?”Alcohol, Drugs, and Tobacco: An International Perspective – Past, Present and Future. Proceedings of the 34 International Congress on Alcoholism and Drug Dependence, vol. th 2. Edmonton: Alberta Alcohol and Drug Abuse Commission, 1985, pp. 174-176 http://www.robinroom.net/drugscon.pdf
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[x] Richard Evans Schultes and Albert Hoffman“The Tracks Of The Little Deer”, Plants of the Gods – Their Sacred, Healing and Hallucinogenic Powers, Healing Arts Press (Vermont) 1992, http://peyote.org/
[xi]Humphry Osmond “OLOLIUQUI: The Ancient Aztec Narcotic – Remarks on the Effects of RiveaCorymbosa”, The British Journal of Psychiatry Jul 1955, 101 (424) 526-537, http://bjp.rcpsych.org/content/101/424/526
[xii] Richard Rudgley, “San Pedro Cactus”, The Encyclopedia of Psychoactive Substances, Brown and Company (1998) http://www.mescaline.org/sanpedro/index.html
[xiii] Karl R. Hanes, “Salvia divinorum: Clinical and Research Potential” http://www.maps.org/news-letters/v13n1/13118han.html
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[xv]Yopo: the Ancient Amazonian DMT Snuff: http://fractalenlightenment.com/24280/culture/yopo-the-ancient-amazonian-dmt-snuff
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[xvii]Coca and Andean Culture – The New Dangers of an Old Debate: https://www.culturalsurvival.org/ourpublications/csq/article/coca-and-andean-culture-the-new-dangers-old-debate
[xviii] A Hallucinogenic History of Pyschoactive Drugs http://historycooperative.org/a-hallucinogenic-history-of-psychoactive-drugs/
[xix]Abel, E.L., “Marijuana, The First Twelve Thousand Years”, New York: Plenum Press, 1980, http://druglibrary.org/schaffer/hemp/history/first12000/abel.htm
[xx]History of Cannabis in Ancient China: https://www.psychologytoday.com/blog/the-teenage-mind/201105/history-cannabis-in-ancient-china
[xxi] Bryan Hill, “Cannabis: A Journey Through the Ages”, http://www.ancient-origins.net/history/cannabis-journey-through-ages-003084
[xxii]DawleyHH Jr, Winstead DK, Baxter AS, Gay JR, “An attitude survey of the effects of marijuana on sexual enjoyment.”,Journal of Clinical Psychol. 1979 Jan;35(1):212-7, http://www.ncbi.nlm.nih.gov/pubmed/422726
[xxiii]The Plant Of Joy: http://opiates.net/
[xxiv]Papaver somniferum – Opium Poppy: http://www.entheology.org/edoto/anmviewer.asp?a=259
[xxv]RajendraToprani and DaxeshPatel , “Betel leaf: Revisiting the benefits of an ancient Indian herb”, South Asian J Cancer. 2013 Jul-Sep; 2(3): 140–141, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892533/
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[xxviii]Al-Mugahed, Leen, “Khat Chewing in Yemen: Turning over a New Leaf – Khat Chewing Is on the Rise in Yemen, Raising Concerns about the Health and Social Consequences”, Bulletin of the World Health Organization, Vol. 86, No. 10, October 2008, https://www.questia.com/library/journal/1G1-188738635/khat-chewing-in-Yemen-turning-over-a-new-leaf-khat
[xxix]Iboga and Bwiti: http://www.ebando.org/en/EN.iboga.htm
[xxx]Blue Lotus : The Entheogen of Ancient Egypt: http://www.psychedelicadventure.net/2014/08/blue-lotus-entheogen-of-ancient-egypt.html
[xxxi]ElisabettaBertol, Vittorio Fineschi, Steven B Karch, Francesco Mari and Irene Riezzo, “Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology”, Journal of the Royal Society of Medicine, 2004 Feb; 97(2): 84–85. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1079300/
[xxxii] Lee MR, “Solanaceae IV: Atropa belladonna, deadly nightshade.”, J R Coll Physicians Edinb. 2007 Mar;37(1):77-84.
[xxxiv]Nesse Randolph M., Berridge Kent C. “Psychoactive Drug Use in Evolutionary Perspective.”Science 278 (1997): 63-66 http://www.ncbi.nlm.nih.gov/pubmed/9311928
[xxxv]Sullivan RJ, Hagen EH. “Psychotropic substance-seeking: evolutionary pathology or adaptation?” Addiction. 2002 Apr;97(4):389-400. http://www.ncbi.nlm.nih.gov/pubmed/11964056
[xxxvi] Role of drugs in society: http://beckleyfoundation.org/policy/society-and-drugs-a-rational-perspective/the-role-of-drugs-in-society-2003/
[xxxvii]Coletta A. Youngers, John M. Walsh, “Drug Decriminalization: A Trend Takes Shape”, Americas Quarterly (The Environment, Fall 2009), http://www.americasquarterly.org/node/978
[xxxviii]ASAM Definition of Addiction: http://www.asam.org/quality-practice/definition-of-addiction
[xxxix]Nicole M. Avena, Pedro Rada, and Bartley G. Hoebel, “Evidence for sugar addiction: Behavioural and neurochemical effects of intermittent, excessive sugar intake”, Neuroscience Biobehavioral Reviews. 2008; 32(1): 20–39. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2235907/