Shampoos can be classified into four main categories: [ 23 ]


Shampoo is generally made by combining a  surfactant , most often  sodium lauryl sulfate  or  sodium laureth sulfate , with a co-surfactant, most often  cocamidopropyl betaine  in  water  to form a thick, viscous liquid. Other essential ingredients include salt ( sodium chloride ), which is used to adjust the viscosity, a  preservative  and  fragrance . [ 24 ] [ 25 ]  Other ingredients are generally included in shampoo formulations to maximize the following qualities:


Many shampoos are  pearlescent . This effect is achieved by the addition of tiny flakes of suitable materials, e.g.  glycol distearate , chemically derived from  stearic acid , which may have either animal or vegetable origins. Glycol distearate is a wax. Many shampoos also include  silicone  to provide conditioning benefits.


In the United States, the  Food and Drug Administration  (FDA) mandates that shampoo containers accurately list ingredients on the products container. The government further regulates what shampoo manufacturers can and cannot claim as any associated benefit. Shampoo producers often use these regulations to challenge marketing claims made by competitors, helping to enforce these regulations. While the claims may be substantiated, however, the testing methods and details of such claims are not as straightforward. For example, many products are purported to protect hair from damage due to  ultraviolet radiation . While the ingredient responsible for this protection does block UV, it is not often present in a high enough concentration to be effective. The North American Hair Research Society has a program to certify functional claims based on third-party testing. Shampoos made for treating medical conditions such as  dandruff [ 29 ]  or  itchy scalp  are regulated as  OTC  drugs [ 30 ]  in the US marketplace.


In the European Union, there is a requirement for the anti-dandruff claim to be substantiated as with any other advertising claim, but it is not considered to be a medical problem. [ citation needed ]


A number of contact  allergens  are used as ingredients in shampoos, and  contact allergy  caused by shampoos is well known. [ 31 ]   Patch testing  can identify ingredients to which patients are allergic, after which a physician can help the patient find a shampoo that is free of the ingredient to which they are allergic. [ 31 ] [ 32 ]  The US bans 11 ingredients from shampoos, Canada bans 587, and the EU bans 1328. [ 33 ]


Cosmetic companies have developed shampoos specifically for those who have  dandruff . These contain  fungicides  such as  ketoconazole ,  zinc pyrithione  and  selenium disulfide , which reduce loose dander by killing  fungi  like  Malassezia furfur .  Coal tar  and  salicylate  derivatives are often used as well.
Alternatives to medicated shampoos are available for people who wish to avoid synthetic fungicides. Such shampoos often use  tea tree oil ,  essential oils  or herbal extracts. [ 34 ]


Many companies have also developed color-protection shampoos suitable for colored hair; some of these shampoos contain gentle cleansers according to their manufacturers.  Shampoos for color-treated hair are a type of moisturizing shampoo. [ 23 ]


Shampoo for  infants  and young children is formulated so that it is less irritating and usually less prone to produce a stinging or burning sensation if it were to get into the eyes. [ 23 ]  For example,  Johnson's Baby  Shampoo advertises under the premise of "No More Tears". This is accomplished by one or more of the following formulation strategies.


The distinction in 4 above does not completely surmount the controversy over the use of shampoo ingredients to mitigate eye sting produced by other ingredients, or the use of the products so formulated. The considerations in 3 and 4 frequently result in a much greater multiplicity of surfactants being used in individual baby shampoos than in other shampoos, and the detergency or foaming of such products may be compromised thereby. The monoanionic sulfonated surfactants and viscosity-increasing or foam stabilizing alkanolamides seen so frequently in other shampoos are much less common in the better baby shampoos.


Sulfate-free shampoos are composed of natural ingredients and free from both  sodium lauryl sulfate  and  sodium laureth sulfate . [ 35 ]  These shampoos use alternative surfactants to cleanse the hair.


Shampoo intended for animals may contain  insecticides  or other medications for treatment of skin conditions or  parasite  infestations such as  fleas  or  mange . These must never be used on humans. While some human shampoos may be harmful when used on animals, any human haircare products that contain active ingredients or drugs (such as zinc in anti-dandruff shampoos) are potentially toxic when ingested by animals. Special care must be taken not to use those products on pets. Cats are at particular risk due to their instinctive method of grooming their fur with their tongues.


Shampoos that are especially designed to be used on  pets , commonly  dogs  and  cats , are normally intended to do more than just clean the pet's  coat  or skin. Most of these shampoos contain ingredients which act different and are meant to treat a skin condition or an  allergy  or to fight against  fleas .


The main ingredients contained by pet shampoos can be grouped in insecticidals, antiseborrheic, antibacterials, antifungals,  emollients ,  emulsifiers  and  humectants . Whereas some of these ingredients may be efficient in treating some conditions, pet owners are recommended to use them according to their  veterinarian 's indications because many of them cannot be used on cats or can harm the pet if it is misused.
Generally, insecticidal pet shampoos contain  pyrethrin ,  pyrethroids  (such as permethrin and which may not be used on cats) and  carbaryl . These ingredients are mostly found in shampoos that are meant to fight against parasite infestations.


Antifungal shampoos are used on pets with yeast or  ringworm  infections. These might contain ingredients such as  miconazole ,  chlorhexidine ,  providone iodine ,  ketoconazole  or  selenium sulfide  (which cannot be used on cats).


Bacterial infections in pets are sometimes treated with antibacterial shampoos. They commonly contain  benzoyl peroxide ,  chlorhexidine , povidone iodine,  triclosan ,  ethyl lactate , or sulfur.


Antipruritic  shampoos are intended to provide relief of itching due to conditions such as atopy and other allergies. [ 36 ]  These usually contain colloidal  oatmeal ,  hydrocortisone ,  Aloe vera , pramoxine hydrochloride,  menthol ,  diphenhydramine , sulfur or salicylic acid. These ingredients are aimed to reduce the inflammation, cure the condition and ease the symptoms at the same time while providing comfort to the pet.


Antiseborrheic shampoos are those especially designed for pets with scales or those with excessive oily coats. These shampoos are made of sulfur,  salicylic acid , refined  tar  (which cannot be used on cats),  selenium sulfide  (cannot be used on cats) and benzoyl peroxide. All these are meant to treat or prevent seborrhea oleosa, which is a condition characterized by excess oils. Dry scales can be prevented and treated with shampoos that contain sulfur or salicylic acid and which can be used on both cats and dogs.


Emollient shampoos are efficient in adding oils to the skin and relieving the symptoms of a dry and itchy skin. They usually contain oils such as  almond ,  corn ,  cottonseed ,  coconut ,  olive ,  peanut , Persia,  safflower ,  sesame ,  lanolin ,  mineral  or  paraffin oil . The emollient shampoos are typically used with emulsifiers as they help distributing the emollients. These include ingredients such as  cetyl alcohol ,  laureth-5 ,  lecithin , PEG-4 dilaurate,  stearic acid ,  stearyl alcohol ,  carboxylic acid ,  lactic acid ,  urea ,  sodium lactate ,  propylene glycol ,  glycerin , or  polyvinylpyrrolidone .


Although some of the pet shampoos are highly effective, some others may be less effective for some condition than another. Yet, although natural pet shampoos exist, it has been brought to attention that some of these might cause  irritation  to the skin of the pet. Natural ingredients that might be potential allergens for some pets include  eucalyptus ,  lemon  or  orange  extracts and  tea tree oil . [ citation needed ]  On the contrary, oatmeal appears to be one of the most widely skin-tolerated ingredients that is found in pet shampoos. Most ingredients found in a shampoo meant to be used on animals are safe for the pet as there is a high likelihood that the pets will lick their coats, especially in the case of cats.


Pet shampoos which include  fragrances ,  deodorants  or colors may harm the skin of the pet by causing inflammations or irritation. Shampoos that do not contain any unnatural additives are known as  hypoallergenic  shampoos and are increasing in popularity.


Solid shampoos or shampoo bars can either be soap-based or use other plant-based surfactants, such as sodium cocoyl isethionate or sodium coco-sulfate combined with oils and waxes. Soap-based shampoo bars are high in pH (alkaline) compared to human hair and scalps, which are slightly acidic. Alkaline pH increases the friction of the hair fibres which may cause damage to the hair cuticle, making it feel rough and drying out the scalp. [ 37 ]


Stiff, non-pourable clear gels to be squeezed from a tube were once popular forms of shampoo, and can be produced by increasing a shampoo's  viscosity . This type of shampoo cannot be spilled, but unlike a solid, it can still be lost down the drain by sliding off wet skin or hair.


Shampoos in the form of pastes or creams were formerly marketed in jars or tubes. The contents were wet but not completely dissolved. They would apply faster than solids and dissolve quickly.


Antibacterial shampoos are often used in  veterinary  medicine for various conditions, [ 38 ] [ 39 ]  as well as in humans before some  surgical procedures . [ 40 ] [ 41 ]


Closely associated with  environmentalism , the " no poo " movement consists of people rejecting the societal norm of frequent shampoo use. Some adherents of the no poo movement use  baking soda  or  vinegar  to wash their hair, while others use diluted honey. Further methods include the use of raw eggs (potentially mixed with salt water), rye flour, or chickpea flour dissolved in water. Other people use nothing or rinse their hair only with conditioner. [ 42 ] [ 43 ]


In the 1970s, ads featuring  Farrah Fawcett  and  Christie Brinkley  asserted that it was unhealthy not to shampoo several times a week. This mindset is reinforced by the greasy feeling of the scalp after a day or two of not shampooing. Using shampoo every day removes  sebum , the oil produced by the scalp. This causes the  sebaceous glands  to produce oil at a higher rate, to compensate for what is lost during shampooing. According to Michelle Hanjani, a dermatologist at Columbia University, a gradual reduction in shampoo use will cause the sebum glands to produce at a slower rate, resulting in less grease in the scalp. [ 44 ]  Although this approach might seem unappealing to some individuals, many people try alternate shampooing techniques like baking soda and vinegar in order to avoid ingredients used in many shampoos that make hair greasy over time. [ 45 ]


Whereas the use of baking soda for hair cleansing has been associated with hair damage and skin irritation, likely due to its high pH value and exfoliating properties, honey, egg, rye flour, and chickpea flour hair washes seem gentler for long-term use. [ 46 ]


Silicone gel sheeting (SGS)  has been an effective reduction and preventive scar therapy since 1980. [ 1 ]  It was first discovered to be used in treating scars by Perkins in Australia and New Zealand, and first discussed in the thesis of Karen Quinn, a British biomedical engineering student, in 1985. [ 2 ]


It is now considered the first-line prevention and treatment for  hypertrophic  and  keloid  scars by occlusion and then hydration of the scar tissue. [ 3 ]  Silicone gel is made of medical-grade silicone polymers. [ 4 ]  Silicone gel sheet consists of a soft, semi-occlusive sheet and a membrane that increases the durability of the sheet. [ 3 ]  The sheet has a solid rubber-like appearance.


Although the mechanism of action of silicone gel sheeting remains partially unknown, its efficacy is confirmed by many clinical trials, [ 5 ]  and is similar to silicone gel. [ 6 ]


Silicone gel sheeting is the gold-standard and non-invasive treatment for hypertrophic and keloid scars.  During skin injury repair, dermal cells proliferate and migrate from the skin tissue to the wound, producing collagen and causing contraction of the placement dermis. [ 5 ]  These scars are proliferative due to chronic inflammation and overproduction of abnormal collagen. [ 7 ]  Common clinical presentations of these scars are raised, thickened, red, or dark-colored. [ 4 ]  Patients may also experience pain and itching. [ 8 ]


Hypertrophic scars  are elevated scars that remain in the region of the original lesion [ 9 ]  following mechanical traumas, burns, and necrotizing infections. [ 10 ]  These scars typically develop in locations under tension, such as shoulders, ankles, knees, and the neck. [ 8 ]  Hypertrophic scars are generally confined to the boundaries of the original wound and tend to diminish over time. [ 11 ]


Keloids  grow extensively beyond the wound margins and tend to persist or even worsen over time. [ 11 ]  They are relatively difficult to treat due to their high risk of recurrence. [ 9 ]  Keloids are more common in people with darker skin tones [ 12 ]  and often occur in individuals with a genetic predisposition. [ 13 ]  Keloids are the most extreme type of scarring since minor wounds such as insect bites or piercings can all lead to an elevated tissue area. Patients may experience psychological trauma if their scars are not well-controlled. [ 8 ]  Therefore, the prevention of wound formation is crucial to them. They should avoid undergoing any unnecessary invasive procedures or cosmetic surgeries. [ 14 ]


The beneficial effects of silicone gel sheeting on the treatment and prevention of these two scars have been confirmed. [ 10 ]  Since most patients develop hypertrophic and keloid scars within 3 months after surgery or injury, the silicone gel sheeting therapy should be started in the early repair phase to achieve an optimal therapeutic effect. The maturity of scars takes over a year; therefore, silicone treatment is also effective in scars aged over 12 months. [ 15 ]  The therapy usually requires 6 to 12 months of constant wear to achieve optimum results. Recent data suggest that the combination of silicone gel sheeting and pressure therapy can improve post-traumatic scar healing. [ 4 ]


The sheet should not be used on open wounds. [ 16 ] [ 17 ]  The sheet is reusable with proper cleaning though it should be replaced when it starts to deteriorate. [ 16 ]


The exact mechanism of action of silicone gel sheeting has not been fully studied. Currently, many proposed mechanisms explain the efficacy of such treatment, including the occlusion and hydration effect, increased body surface temperature, polarized electric charge, immunological effects, etc. [ 9 ]  The occlusion and hydration effect is the most studied mechanism of action.


Silicone gel sheets occlude and hydrate the  stratum corneum  of the treated skin area. The  stratum corneum  normally conserves water and acts as a barrier to microbial infection. Its function can be disrupted by wound formation. The stratum corneum of hypertrophic scars and keloids absorbs more water than normal skin, depleting the water supply from the  stratum corneum . Excessive dehydration of  keratinocytes  stimulates cytokine production, leading to increased  collagen  production. [ 18 ] [ 5 ]  After applying the sheet, the rate of water loss via evaporation of the treated skin area is half of the untreated area. Therefore, the sheet prevents the drying up of  stratum corneum , and thus further  collagen  production. Collagen production exacerbates the growth of  hypertrophic scars  and  keloids  and thus should be avoided. [ 9 ] [ 5 ]  Hydrating a scar over a prolonged period can also relieve symptoms such as itching and pain. Such an effect is likely due to decreased capillary activity and thus local collagen deposition. [ 9 ]


Applying silicone gel sheeting causes a slight increase in surface temperature. Increased temperature intensifies the activity of  collagenase , an enzyme that breaks down  collagen . Since excessive collagen production leads to scar formation, increased levels of  collagenase  may help reduce the risk of scar formation. [ 9 ]


Silicone-related products can reduce the growth factor production of  fibroblasts  in hypertrophic scars and keloids. [ 19 ]  However, the relevance is unclear as silicone products do not have direct contact with dermal fibroblasts but with the  epidermis  only. Possible relevance may be due to the initiation of a signaling cascade by the epidermis. Through the signaling cascade, the epidermis regulates dermal fibroblast extracellular matrix production. Delayed epithelialization, which raises the risk of hypertrophic scar formation, is less likely to happen. [ 18 ]


A negative  static electric charge  is formed by friction between the silicone gel sheet and the skin. The charge induces collagen realignment, aiding the elimination of the scar. [ 18 ]  Moreover, the negative electric field leads to the polarization of scar tissues and thus scar shrinkage. [ 9 ]


Silicone gel sheeting has remained the first-line therapy stated by international clinical recommendations on scar management. [ 5 ]


Scar measurements studied in most clinical trials include color ( vascularisation  and pigmentation), thickness (height: clinical and histological), relief (surface irregularities), pliability (tissue elasticity), and surface area (scar contraction or expansion). [ 20 ]


Scar elevation index is commonly used to indicate scar improvement. It measures the height of scar tissue compared to the normal surrounding skin. [ 21 ]  Studies show the effectiveness of silicone gel sheeting in minimizing scar elevation index. [ 22 ]  Another physical measure is the pliability of the scar tissue, which is also improved by silicone gel sheeting. [ 23 ]  Scar improvement is generally measured by size reduction, appearance, and calming effect. Silicone gel sheeting addresses the 3 requirements well among scar treatments. [ 5 ]  Several randomized controlled trials were carried out to assess the effectiveness. Silicone gel sheeting produces a statistically significant reduction in scar thickness and color amelioration. Therefore, it is an evidence-based non-invasive preventive treatment. [ 24 ]


Results of comparative studies on the effectiveness of silicone gel sheeting and silicone gel do not show significant differences between the two. [ 25 ]


Another non-invasive treatment is compression therapy, in which patients wear  pressure garments  to control the growth of scars. Pressure garments apply mechanical pressure to the surface of the scar, reducing the supply of blood and oxygen to the scar tissue. Formation of excessive scar tissue is thus prevented. The combination of silicone gel sheeting and compression therapy has been proven to be more effective than using the sheet alone. [ 26 ]


Patients who find the non-invasive treatments ineffective may choose to undergo invasive treatments such as intralesional injections of  corticosteroids , surgical excision of the scars, and  radiotherapy . [ 26 ] [ 27 ]


Common side effects of silicone gel sheets include itchiness,  rash , maceration of the skin, and malodor. [ 28 ]  These symptoms are generally well-tolerated and can be minimized by rinsing the area properly daily. Patients who suffer from these side effects should wash the treated area and the silicone gel sheets with mild soap since the dirt or bacteria on the sheets may irritate the scar. [ 16 ]  In tropical climates with high humidity, excessive moisture underneath the gel may lead to heat rash and uncomfortable sensations in patients. [ 2 ]


Silicone gel sheets are usually made of medical silicone polymers such as  polysiloxane  and  polydimethylsiloxane , along with  silicon dioxide  and volatile components. The long-chain silicone polymers form cross-linking with silicon dioxide and spread as a thin sheet. [ 8 ]


They are either flesh color (most common) or clear and come as either a single large rectangle sheet or a roll. Available size varies with brands.


In  pharmaceutics , sink condition is a term mostly related to the  dissolution testing  procedure.


It means using a sheer volume of  solvent , usually about 5 to 10 times greater than the volume present in the  saturated solution  of the targeted chemical (often the  API , and sometimes the  excipients ) contained in the  dosage form  being tested. [ 1 ]


During the  dissolution testing , "sink condition" is a mandatory requirement, otherwise when the concentration begins to get too close to the  saturation point , even though the  total soluble amount  still remains constant, the  dissolution rate  will gradually begin to reduce in significant amounts, enough to corrupt the  test  results. . [ 2 ] [ 3 ] [ 4 ]


Small molecule  drug conjugates  or  SMDC s are built with three modules: a targeting  ligand , a linker and a drug payload [ citation needed ] . The targeting ligands consist of low molecular weight, high-affinity ligands that are precisely linked to potent drugs. The linkers are designed to be stable in the bloodstream and then release the active drug from the targeting ligand when the SMDC is taken up by the diseased cell. The  drug payloads  are highly active molecules that are too toxic to be administered in their untargeted forms at therapeutic dose levels [ citation needed ] . This modular approach allows varying targeting ligands, linker systems and drug payloads and generate SMDCs for different diseases. [ 1 ]
The most advanced SMDC is  vintafolide , a derivative of the anti-mitotic chemotherapy drug  vinblastine   which is chemically linked to  folic acid . [ 2 ]  Potent, bioactive natural products like triptolide that inhibit mammalian transcription has been recently reported as a glucose conjugate for targeting hypoxic cancer cells with increased glucose transporter expression. [ 3 ]


SMDCs are currently being developed by  Endocyte  for treating  cancer , inflammatory diseases and kidney disease, as well as a companion imaging agent that is created by replacing the potent drug with an  imaging agent . [ 4 ] [ 5 ]


Smoking  is a practice in which a substance is  combusted  and the resulting  smoke  is typically  inhaled  to be  tasted  and absorbed into the  bloodstream  of a person. Most commonly, the substance used is the dried  leaves  of the  tobacco  plant, which have been rolled with a small rectangle of paper into an elongated cylinder called a  cigarette . Other forms of smoking include the use of a  smoking pipe  or a  bong .


Smoking is primarily practised as a  route of administration  for  psychoactive chemicals  because the  active substances  within the burnt dried plant leaves vaporize and can be airborne-delivered into the  respiratory tract , where they are rapidly absorbed into the bloodstream of the  lungs  and then reach the  central nervous system . In the case of  tobacco smoking , these active substances are a mixture of  aerosol  particles that includes the pharmacologically active alkaloid  nicotine , which stimulates the  nicotinic acetylcholine receptors  in the  brain . Other notable active substances inhaled via smoking include  tetrahydrocannabinol  (from  cannabis ),  morphine  (from  opium ) and  cocaine  (from  crack ).


Smoking is one of the most common forms of  recreational drug use . Tobacco smoking is the most popular form, being practised by over one billion people globally, of whom the majority are in the  developing countries . [ 1 ]  Less common drugs for smoking include  cannabis  and  opium . Some of the substances are classified as hard  narcotics , like  heroin , but the use of these is very limited as they are usually not commercially available. Cigarettes are primarily industrially manufactured but also can be hand-rolled from loose tobacco and  rolling paper . Other smoking implements include  pipes ,  cigars ,  bidis ,  hookahs , and bongs.


Smoking has negative health effects , because smoke inhalation inherently poses challenges to various  physiologic  processes such as  respiration . Smoking tobacco is among the leading causes of many diseases such as  lung cancer ,  heart attack ,  COPD ,  erectile dysfunction , and  birth defects . [ 1 ]  Diseases related to tobacco smoking have been shown to kill approximately half of long-term smokers when compared to average mortality rates faced by non-smokers. Smoking caused over five million deaths a year from 1990 to 2015. [ 2 ]  Non-smokers account for 600,000 deaths globally due to  second-hand smoke . [ 3 ]  The health hazards of smoking have caused many countries to institute high taxes on tobacco products, publish advertisements to discourage use, limit advertisements that promote use, and provide help with quitting for those who do smoke. [ 1 ]


Smoking can be dated to as early as 5000 BCE, and has been recorded in many different cultures across the world. Early smoking evolved in association with religious ceremonies; as offerings to deities; in cleansing rituals; or to allow  shamans  and priests to alter their minds for purposes of divination or spiritual enlightenment. After the European exploration and conquest of the Americas, the practice of smoking tobacco quickly spread to the rest of the world. In regions like India and Sub-Saharan Africa, it merged with existing practices of smoking (mostly of cannabis). In Europe, it introduced a new type of social activity and a form of drug intake which previously had been unknown.


Perception surrounding smoking has varied over time and from one place to another: holy and sinful, sophisticated and vulgar, a  panacea  and deadly health hazard. In the last decade of the 20th century, smoking came to be viewed in a decidedly negative light, especially in Western countries.


The history of smoking dates back to as early as 5000 BCE for shamanistic rituals. [ 4 ]  Many ancient civilizations, such as the Babylonian and Chinese, burnt incense as a part of religious rituals, as did the  Israelites  and the later Catholic and Orthodox Christian churches. Smoking in the Americas probably had its origins in the incense-burning ceremonies of  shamans  but was later adopted for pleasure, or as a social tool. [ 5 ]  The smoking of tobacco, as well as various  hallucinogenic  drugs, was used to achieve trances and to come into contact with the spirit world.


Substances such as  cannabis , clarified butter ( ghee ), fish offal, dried snake skins and various pastes molded around  incense  sticks dates back at least 2000 years. Fumigation ( dhupa ) and fire offerings ( homa ) are prescribed in the  Ayurveda  for medical purposes, and have been practiced for at least 3,000 years while smoking,  dhumrapana  (literally "drinking smoke"), has been practiced for at least 2,000 years. Before modern times these substances have been consumed through  pipes , with stems of various lengths or  chillums . [ 6 ]  Archaeological findings also show the existence of pipes to smoke  opium  in  Cyprus  and  Crete  as soon as the  Bronze Age . [ 7 ]


Cannabis smoking was common in the Middle East before the arrival of tobacco, and was early on a common social activity that centered around the type of water pipe called a  hookah . Smoking, especially after the introduction of tobacco, was an essential component of Muslim society and culture and became integrated with important traditions such as weddings, funerals and was expressed in architecture, clothing, literature and poetry. [ 8 ]


Cannabis smoking was introduced to  Sub-Saharan Africa  through  Ethiopia  and the east African coast by either Indian or Arab traders in the 13th century or earlier and spread on the same trade routes as those that carried coffee, which originated in the highlands of Ethiopia. [ 9 ]  It was smoked in  calabash  water pipes with  terracotta  smoking bowls, apparently an  Ethiopian  invention which was later conveyed to eastern, southern and central Africa.


Reports from the first European explorers and conquistadors to reach the Americas tell of rituals where native priests smoked themselves into such high degrees of intoxication that it is unlikely that the rituals were limited to just tobacco. [ 10 ]


In 1612, six years after the settlement of  Jamestown ,  John Rolfe  was credited as the first settler to successfully grow tobacco as a  cash crop . The demand quickly grew as tobacco, referred to as "golden weed", revived the  Virginia Company  from its failed expeditions in search for gold in the Americas. [ 11 ]  In order to meet demands from the old world, tobacco was grown in succession, quickly depleting the land. This became a motivator to settle west into the unknown continent, and likewise an expansion of tobacco production. [ 12 ]   Indentured servants  became the primary labor force up until  Bacon's Rebellion , from which the focus turned to  slavery . [ 13 ]  This trend abated following the  American Revolution  as slavery became regarded as unprofitable. However the practice was revived in 1794 with the invention of the cotton gin. [ 14 ]


A Frenchman named  Jean Nicot  (from whose name the word nicotine is derived) introduced tobacco to  France  in 1560. From France tobacco spread to England. The first report documents an English sailor in Bristol in 1556, seen "emitting smoke from his nostrils". [ 15 ]  Like tea, coffee and opium, tobacco was just one of many intoxicants that was originally used as a form of medicine. [ 16 ]  Tobacco was introduced around 1600 by French merchants in what today is modern-day  The Gambia  and  Senegal . At the same time caravans from  Morocco  brought tobacco to the areas around  Timbuktu  and the Portuguese brought the commodity (and the plant) to southern Africa, establishing the popularity of tobacco throughout all of Africa by the 1650s.


Soon after its introduction to the  Old World , tobacco came under frequent criticism from state and religious leaders.  Murad IV , sultan of the  Ottoman Empire  1623–40 was among the first to attempt a smoking ban by claiming it was a threat to public morality and health. The  Chongzhen Emperor  of China issued an edict banning smoking two years before his death and the overthrow of the  Ming dynasty . Later, the  Manchu  rulers of the  Qing dynasty , would proclaim smoking "a more heinous crime than that even of neglecting archery". In  Edo period  Japan, some of the earliest tobacco plantations were scorned by the  shōgun  as being a threat to the military economy by letting valuable farmland go to waste for the use of a recreational drug instead of being used to plant food crops. [ 17 ]


Religious leaders have often been prominent among those who considered smoking immoral or outright blasphemous. In 1634, the  Patriarch of Moscow and all Rus'  forbade the sale of tobacco and sentenced men and women who flouted the ban to have their nostrils slit and their backs whipped until skin came off their backs. The Western church leader  Pope Urban VII  likewise condemned smoking in a papal bull of 1590. Despite many concerted efforts, restrictions and bans were almost universally ignored. When  James VI and I , a staunch anti-smoker and the author of  A Counterblaste to Tobacco , tried to curb the new trend by enforcing a whopping 4000% tax increase on tobacco in 1604, it proved a failure, as London had some 7,000 tobacco sellers by the early 17th century. Later, scrupulous rulers would realise the futility of smoking bans and instead turned tobacco trade and cultivation into lucrative government monopolies. [ 18 ]


By the mid-17th century every major civilization had been introduced to tobacco smoking and in many cases had already assimilated it into its culture, despite the attempts of many rulers to stamp the practice out with harsh penalties or fines. Tobacco, both product, and plant followed the major trade routes to major ports and markets, and then on into the hinterlands. The English language term  smoking  was coined in the late 18th century; before then the practice was referred to as  drinking smoke . [ 15 ]


Tobacco and cannabis were used in Sub-Saharan Africa, much like elsewhere in the world, to confirm social relations, but also created entirely new ones. In what is today  Congo , a society called Bena Diemba ("People of Cannabis") was organized in the late 19th century in Lubuko ("The Land of Friendship"). The Bena Diemba were collectivist pacifists that rejected alcohol and herbal medicines in favor of cannabis. [ 19 ]


The growth remained stable until the  American Civil War  in the 1860s, from which the primary labor force transition from slavery to  sharecropping . This compounded with a change in demand, lead to the industrialization of tobacco production with the cigarette.  James Albert Bonsack , a craftsman, in 1881 produced a machine to speed the production of cigarettes. [ 20 ]


In the 19th century, the practise of smoking opium became widespread in  China . Previously, opium had only been ingested via consumption, and then only for its medicinal properties (opium was an  anaesthetic ). The narcotic was also outlawed in China sometime in the early 18th century due the societal issues it caused. Due to a massive trade imbalance, however, foreign merchants started to smuggle opium into China via  Canton , to the chagrin of the Chinese authorities. Attempts by Chinese official  Lin Zexu  to eliminate the trade led to the outbreak of the  First Opium War . The Chinese defeat in the First and  Second Opium Wars  resulted in the legalization of the importation of opium into China. [ 21 ] [ 22 ]


Opium smoking later spread with  Chinese immigrants  and spawned many infamous  opium dens  in  Chinatowns  around South and Southeast Asia, Europe and the Americas. In the latter half of the 19th century, opium smoking became popular in the artistic community in Europe, especially Paris; artists' neighborhoods such as  Montparnasse  and  Montmartre  became virtual "opium capitals". While opium dens that catered primarily to emigrant Chinese continued to exist in Chinatowns around the world, the trend among the European artists largely abated after the outbreak of World War I. [ 21 ]  The consumption of Opium abated in China during the  Cultural Revolution  in the 1960s and 1970s. [ 21 ]


Many people have been critical about tobacco use since it gained popularity. In 1798, Dr.  Benjamin Rush  (early American physician, signer of the  Declaration of Independence ,  Surgeon General  under  George Washington , and anti-tobacco activist) was "against the habitual use of tobacco" because he believed it (a) "led to a desire for strong drink," (b) "was injurious both to health and morals," (c) "is generally offensive to" nonsmokers, (d) "produces a want of respect for" nonsmokers, and (e) "always disposes to unkind and unjust behavior towards them." [ 23 ] [ 24 ]


With the modernization of cigarette production compounded with the increased life expectancies during the 1920s, adverse health effects began to become more prevalent. [ 1 ]  In Germany, anti-smoking groups, often associated with anti-liquor groups, [ 25 ]  first published advocacy against the consumption of tobacco in the journal  Der Tabakgegner  (The Tobacco Opponent) in 1912 and 1932. In 1929,  Fritz Lickint  of Dresden, Germany, published a paper containing formal statistical evidence of a lung cancer–tobacco link. During the  Great Depression ,  Adolf Hitler  condemned his earlier smoking habit as a waste of money, [ 26 ]  and later with stronger assertions. This movement was further strengthened with Nazi reproductive policy as women who smoked were viewed as unsuitable to be wives and mothers in a German family. [ 27 ]


The movement in Nazi Germany did reach across enemy lines during the Second World War, as anti-smoking groups quickly lost popular support. [ clarification needed ]  By the end of the Second World War, American cigarette manufacturers quickly reentered the German black market. Illegal smuggling of tobacco became prevalent, [ 28 ]  and leaders of the Nazi anti-smoking campaign were assassinated. [ 29 ]  As part of the  Marshall Plan , the United States shipped free tobacco to Germany; with 24,000 tons in 1948 and 69,000 tons in 1949. [ 28 ]  Per capita yearly cigarette consumption in  post-war Germany  steadily rose from 460 in 1950 to 1,523 in 1963. [ 30 ]  By the end of the 20th century, anti-smoking campaigns in Germany were unable to exceed the effectiveness of the Nazi-era climax in the years 1939–41 and German tobacco health research was described by  Robert N. Proctor  as "muted". [ 30 ]


In the UK and the US, an increase in lung cancer rates, formerly "among the rarest forms of disease", was noted by the 1930s, but its cause remained unknown and even the credibility of this increase was sometimes disputed as late as 1950. For example, in Connecticut, reported age-adjusted incidence rates of lung cancer among males increased 220% between 1935–39 and 1950–54. In the UK, the share of lung cancer among all cancer deaths in men increased from 1.5% in 1920 to 19.7% in 1947. Nevertheless, these increases were questioned as potentially caused by increased reporting and improved methods of diagnosis. Although several carcinogens were already known at the time (for example,  benzo[a]pyrene  was isolated from coal tar and demonstrated to be a potent carcinogen in 1933), none were known to be contained in adequate quantities in  tobacco smoke . [ 31 ]   Richard Doll  in 1950 published research in the  British Medical Journal  showing a close link between smoking and lung cancer. [ 32 ]  Four years later, in 1954 the  British Doctors Study , a study of some 40 thousand doctors over 20 years, confirmed the link, based on which the government issued advice that smoking and lung cancer rates were related. [ 33 ] [ 34 ]  In 1964 the United States  Surgeon General 's Report on Smoking and Health demonstrated the relationship between smoking and cancer. [ 35 ]  Further reports confirmed this link in the 1980s and concluded in 1986 that  passive smoking  was also harmful. [ 36 ]


As scientific evidence mounted in the 1980s, tobacco companies claimed  contributory negligence  as the adverse health effects were previously unknown or lacked substantial credibility. Health authorities sided with these claims up until 1998, from which they reversed their position. The  Tobacco Master Settlement Agreement , originally between the four largest US tobacco companies and the Attorneys General of 46 states, restricted certain types of tobacco advertisement and required payments for health compensation; which later amounted to the largest civil settlement in United States history. [ 37 ]


From 1965 to 2006, rates of smoking in the United States have declined from 42% to 20.8%. [ 38 ]  A significant majority of those who quit were professional, affluent men. Despite this decrease in the prevalence of consumption, the average number of cigarettes consumed per person per day increased from 22 in 1954 to 30 in 1978. This paradoxical event suggests that those who quit smoked less, while those who continued to smoke moved to smoke more light cigarettes. [ 39 ]  This trend has been paralleled by many industrialized nations as rates have either leveled-off or declined. In the  developing countries , however, tobacco consumption continues to rise at 3.4% in 2002. [ 40 ]  In Africa, smoking is in most areas considered to be modern, and many of the strong adverse opinions that prevail in the West receive much less attention. [ 41 ]  Today  Russia  leads as the top consumer of tobacco followed by  Indonesia ,  Laos ,  Ukraine ,  Belarus ,  Greece ,  Jordan , and  China . [ 42 ]


At the global scale, initial ideas of an international convention towards the prevention of tobacco had been initiated in the World Health Assembly (WHA) in 1996. [ 43 ]  In 1998, along with the successful election of  Dr. Gro Harlem Brundtland  as the Director-General, the  World Health Organization  set tobacco control as its leading health concern and has begun a program known as the  Tobacco Free Initiative  (TFI) in order to reduce rates of consumption in the developing world. However, it was not until 2003 that the Framework Convention on Tobacco Control (FCTC) was accepted in WHA and entered into force in 2005. FCTC marked a milestone as the first international treaty concerning a global health issue that aims to combat tobacco in multiple aspects including tobacco taxes, advertisement, trading, environmental affects, health influences, etc. [ 44 ]  The birth of this evidence-based and systematic approach has resulted in the reinforcement of tobacco taxes and the implementation of smoke-free laws in 128 countries that led to the decrease of smoking prevalence in developing nations. [ 45 ]  In Nepal, "Smokers are not selfish", a  health campaign  lasting two weeks is started on the occasion of  Valentine day  and  Vasant panchami  to motiviate individuals to quit smoking as a sacrifice for their loved ones and making it a meaningful decision of life. This campaign is attracting public attention. [ 46 ]


In the early 1980s, organized international trafficking of  cocaine  grew. However, overproduction and tighter legal enforcement for the illegal product caused drug dealers to convert the powder to "crack" – a solid, smokable form of cocaine that could be sold in smaller quantities to more people. [ 47 ]  This trend abated in the 1990s as increased police action coupled with a robust economy caused many potential consumers to give up or fail to take up the habit. [ 48 ]


Recent years shows an increase in the consumption of vaporized heroin,  methamphetamine  and  Phencyclidine  (PCP). Along with a smaller number of  psychedelic drugs  such as  Changa ,  DMT ,  5-Meo-DMT , and  Salvia divinorum . [ citation needed ]


The most popular type of substance that is smoked is  tobacco . There are many different tobacco cultivars which are made into a wide variety of mixtures and brands. Tobacco is often sold flavored, often with various fruit aromas, something which is especially popular for use with water pipes, such as  hookahs . The second most common substance that is smoked is  cannabis , made from the flowers or leaves of  Cannabis sativa  or  Cannabis indica . The substance is considered illegal in most countries in the world and in the countries that tolerate public consumption, it is sometimes only pseudo-legal. Despite this, a considerable percentage of the adult population in many countries have tried it with smaller minorities doing it on a regular basis. Since cannabis is illegal or only tolerated in many jurisdictions, there is no industrial mass-production of cigarettes, meaning that the most common form of smoking is with hand-rolled cigarettes (often called  joints ) or with pipes. Water pipes are also fairly common; water pipes used for cannabis include designs known as bongs and bubblers, among others.


A few other recreational drugs are smoked by smaller minorities. Most of these substances are  controlled , and some are considerably more intoxicating than either tobacco or cannabis. These include  crack cocaine , heroin,  methamphetamine  and  PCP . A small number of  psychedelic drugs  are also smoked, including  DMT ,  5-Meo-DMT , and  Salvia divinorum .


Even the most primitive form of smoking requires tools of some sort to perform. This has resulted in a staggering variety of smoking tools and paraphernalia from all over the world. Whether tobacco, cannabis, opium or herbs, some form of receptacle is required along with a source of fire to light the mixture. The most common today is by far the cigarette, consisting of a mild inhalant strain of tobacco in a tightly rolled tube of paper, usually manufactured industrially and including a  filter , or hand-rolled with loose tobacco. Other popular smoking tools are various  pipes  and cigars.


A less common but increasingly popular alternative to smoking is vaporizers, which use hot air convection to deliver the substance without combustion, which may reduce health risks. A portable vaporization alternative appeared in 2003 with the introduction of  electronic cigarettes , battery-operated, cigarette-shaped devices which produce an aerosol intended to mimic the smoke from burning tobacco, delivering nicotine to the user without some of the harmful substances released in tobacco smoke.


Other than actual smoking equipment, many other items are associated with smoking;  cigarette cases ,  cigar boxes ,  lighters ,  matchboxes ,  cigarette holders , cigar holders,  ashtrays ,  silent butlers ,  pipe cleaners , tobacco cutters, match stands, pipe tampers, cigarette companions and so on. Some examples of these have become valuable  collector items  and particularly ornate and antique items can fetch high prices.


Smoking is one of the leading  preventable causes of deaths  globally and is the cause of over 8 million deaths annually, 1.2 million of which are non-smokers who die due to  second-hand smoke . [ 49 ]  In the United States, about 500,000 deaths per year are attributed to smoking-related diseases and a recent study [ as of? ]  estimated that as much as one-third of China's male population will have significantly shortened lifespans due to smoking. [ 50 ]  Male and female smokers lose an average of 13.2 and 14.5 years of life, respectively. [ 51 ]  At least half of all lifelong smokers die earlier as a result of smoking. [ 52 ] [ 53 ]  The risk of dying from lung cancer before age 85 is 22.1% for a male smoker and 11.9% for a female current smoker, in the absence of competing causes of death. The corresponding estimates for lifelong nonsmokers are a 1.1% probability of dying from lung cancer before age 85 for a man of European descent, and a 0.8% probability for a woman. [ 54 ]  Smoking just one cigarette a day results in a risk of  coronary heart disease  that is halfway between that of a heavy smoker and a non-smoker. [ 55 ] [ 56 ]  The  non-linear   dose–response relationship  may be explained by smoking's effect on  platelet aggregation . [ 57 ]


Among the diseases that can be caused by smoking are vascular  stenosis , lung cancer, [ 58 ]   heart attacks [ 59 ]  and  chronic obstructive pulmonary disease  (COPD). [ 60 ]  Smoking during pregnancy may cause ADHD to a fetus. [ 61 ]


Smoking is a risk factor strongly associated with  periodontitis  and  tooth loss . [ 62 ]  The effects of smoking on  periodontal tissues  depend on the number of cigarettes smoked daily and the duration of the habit. A study showed that smokers had 2.7 times and former smokers 2.3 times greater probabilities to have established periodontal disease than non‐smokers, independent of age, sex and plaque index, [ 63 ]  however, the effect of tobacco on periodontal tissues seems to be more pronounced in men than in women. [ 63 ]  Studies have found that smokers had greater odds for more severe dental bone loss compared to non‐smokers; [ 64 ]  also, people who smoke and drink  alcohol  heavily have much higher  risk  of developing  oral  cancer  (mouth and lip) compared with people who do neither. [ 65 ]  Smoking can also cause  milanosis  in the mouth. [ 66 ]


Smoking has been also associated with oral conditions including  dental caries ,  dental implant failures ,  premalignant lesions , and  cancer . [ 67 ]  Smoking can affect the immune-inflammatory processes which may increase susceptibility to infections; it can alter the oral mycobiota and facilitate colonization of the oral cavity with fungi and pathogenic molds. [ 68 ] [ 69 ]


Many governments are trying to deter people from smoking with anti-smoking campaigns in mass media stressing the harmful long-term effects of smoking.  Passive smoking , or secondhand smoking, which affects people in the immediate vicinity of smokers, is a major reason for the enforcement of  smoking bans . These are laws enforced to stop individuals from smoking in indoor public places, such as bars, pubs and restaurants, thus reducing nonsmokers' exposure to secondhand smoke. A common concern among legislators is to discourage smoking among minors and many states have passed laws against selling tobacco products to underage customers (establishing a  smoking age ). Many developing countries have not adopted anti-smoking policies, leading some to call for anti-smoking campaigns and further education to explain the negative effects of ETS (Environmental Tobacco Smoke) in developing countries. [ citation needed ]   Tobacco advertising  is also sometimes regulated to make smoking less appealing.


Despite the many bans, European countries still hold 18 of the top 20 spots, and according to the ERC, a market research company, the heaviest smokers are from Greece, averaging 3,000 cigarettes per person in 2007. [ 70 ]  Rates of smoking have leveled off or declined in the developed world but continue to rise in developing countries. Smoking rates in the United States have dropped by half from 1965 to 2006, falling from 42% to 20.8% in adults. [ 71 ]


The effects of addiction on society vary considerably between different substances that can be smoked and the indirect social problems that they cause, in great part because of the differences in legislation and the enforcement of narcotics legislation around the world. Though nicotine is a highly addictive drug, its effects on cognition are not as intense or noticeable as other drugs such as cocaine, amphetamines or any of the  opiates  (including heroin and  morphine ). [ citation needed ]


Smoking is a risk factor in  Alzheimer's disease . [ 72 ]  While smoking more than 15 cigarettes per day has been shown to worsen the symptoms of  Crohn's disease , [ 73 ]  smoking has been shown to actually lower the prevalence of  ulcerative colitis . [ 74 ] [ 75 ]


Smokers are 30-40% more likely to develop  type 2 diabetes  than non-smokers, and the risk increases with the number of cigarettes smoked. [ 76 ]


Inhaling the vaporized gas form of substances into the lungs is a quick and very effective way of delivering drugs into the bloodstream (as the gas diffuses directly into the pulmonary vein, then into the heart and from there to the brain) and affects the user within less than a second of the first inhalation. The lungs consist of several million tiny bulbs called  alveoli  that altogether have an area of over 70 m 2  (about the area of a tennis court). This can be used to administer useful medical as well as recreational drugs such as aerosols, consisting of tiny droplets of a medication, or as gas produced by burning plant material with a psychoactive substance or pure forms of the substance itself. Not all drugs can be smoked, for example the sulphate derivative that is most commonly inhaled through the nose, though purer free base forms of substances can, but often require considerable skill in administering the drug properly. The method is also somewhat inefficient since not all of the smoke will be inhaled. [ 79 ]  The inhaled substances trigger chemical reactions in nerve endings in the brain due to being similar to naturally occurring substances such as  endorphins  and  dopamine , which are associated with sensations of pleasure. The result is what is usually referred to as a "high" that ranges between the mild stimulus caused by  nicotine  to the intense euphoria caused by heroin,  cocaine  and  methamphetamines . [ 80 ]


Inhaling smoke into the lungs, no matter the substance, has adverse effects on one's health. [ citation needed ]  The incomplete combustion produced by burning plant material, like tobacco or cannabis, produces  carbon monoxide , which impairs the ability of blood to carry oxygen when inhaled into the lungs. There are several other toxic compounds in tobacco that constitute serious health hazards to long-term smokers from a whole range of causes; vascular abnormalities such as  stenosis , lung cancer, heart attacks, strokes,  impotence , low birth weight of infants born by  smoking mothers . 8% of long-term smokers develop the characteristic set of facial changes known to doctors as  smoker's face . [ 81 ]


Tobacco smoke is a complex mixture of over 5,000 identified chemicals, of which 98 are known to have specific  toxicological  properties. [ 82 ]  The most important chemicals  causing cancer  are those that produce  DNA damage  since such damage appears to be the primary underlying cause of cancer. [ 83 ]  Cunningham et al. [ 84 ]  combined the microgram weight of the compound in the smoke of one cigarette with the known  genotoxic  effect per microgram to identify the most  carcinogenic  compounds in cigarette smoke. The seven most important carcinogens in tobacco smoke are shown in the table, along with DNA alterations they cause.


Most tobacco smokers begin during adolescence or early adulthood. Smoking has elements of risk-taking and rebellion, which often appeal to young people. The presence of high-status models and peers may also encourage smoking. Because teenagers are influenced more by their peers than by adults, [ 93 ]  attempts by parents, schools, and health professionals at preventing people from trying cigarettes are not always successful.


Smokers often report that cigarettes help relieve feelings of stress. However, the stress levels of adult smokers are slightly higher than those of nonsmokers. Adolescent smokers report increasing levels of stress as they develop regular patterns of smoking, and  smoking cessation  leads to reduced stress. Far from acting as an aid for mood control, nicotine dependency seems to exacerbate stress. This is confirmed in the daily mood patterns described by smokers, with normal moods during smoking and worsening moods between cigarettes. Thus, the apparent relaxant effect of smoking only reflects the reversal of the tension and irritability that develop during nicotine depletion. Dependent smokers need nicotine to remain feeling normal. [ 94 ]


In the mid-20th century psychologists such as  Hans Eysenck  developed a personality profile for the typical smoker of that period;  extraversion  was associated with smoking, and smokers tended to be sociable, impulsive, risk taking, and excitement-seeking individuals. [ 95 ]  Although personality and social factors may make people likely to smoke, the actual habit is a function of  operant conditioning . During the early stages, smoking provides pleasurable sensations (because of its action on the  dopamine  system) and thus serves as a source of  positive reinforcement . After an individual has smoked for many years, the avoidance of withdrawal symptoms and  negative reinforcement  become the key motivations. Like all addictive substances, the amount of exposure required to become dependent on nicotine can vary from person to person.


In terms of the  Big Five personality traits , research has found smoking to be correlated with lower levels of  agreeableness  and  conscientiousness , as well as higher levels of  extraversion  and  neuroticism . [ 96 ]


Education and counselling by physicians of children and adolescents has been found to be effective in decreasing the risk of tobacco use. [ 97 ]  Systematic reviews show that psychosocial interventions can help women stop smoking in late pregnancy, reducing low birthweight and preterm births. [ 98 ]  A 2016 Cochrane review showed that the combination of medication and behavioural support was more effective than minimal interventions or usual care. [ 99 ]  Another Cochrane review "suggests that neither reducing smoking to quit nor quitting abruptly results in superior quit rates; people could therefore be given a choice of how to quit, and support provided to people who would specifically like to reduce their smoking before quitting." [ 100 ]


Smoking, primarily of tobacco, is an activity that is practiced by some 1.1 billion people, and up to 1/3 of the adult population. [ 107 ]  The image of the smoker can vary considerably, but is very often associated, especially in fiction, with individuality and aloofness. [ citation needed ]  Even so, smoking of both tobacco and cannabis can be a social activity which serves as a reinforcement of social structures and is part of the cultural rituals of many and diverse social and ethnic groups. Many smokers begin smoking in social settings and the offering and sharing of a cigarette is often an important rite of initiation or simply a good excuse to start a conversation with strangers in many settings; in bars,  night clubs , at work or on the street. Lighting a cigarette is often seen as an effective way of avoiding the appearance of idleness or mere loitering. For adolescents, it can function as a first step out of childhood or as an act of rebellion against the adult world. Also, smoking can be seen as a sort of camaraderie. It has been shown that even opening a packet of cigarettes, or offering a cigarette to other people, can increase the level of dopamine (the "happy feeling") in the brain, and it is doubtless that people who smoke form relationships with fellow smokers, in a way that only proliferates the habit, particularly in countries where smoking inside public places has been made illegal. [ citation needed ]  Other than recreational drug use, it can be used to construct identity and a development of self-image by associating it with personal experiences connected with smoking. The rise of the modern anti-smoking movement in the late 19th century did more than create awareness of the hazards of smoking; it provoked reactions of smokers against what was, and often still is, perceived as an assault on personal freedom and has created an identity among smokers as rebels or outcasts, apart from non-smokers:


There is a new Marlboro land, not of lonesome cowboys, but of social-spirited urbanites, united against the perceived strictures of public health. [ 108 ]


The importance of tobacco to soldiers was early on recognized as something that could not be ignored by commanders. By the 17th century allowances of tobacco were a standard part of the naval rations of many nations and by World War I cigarette manufacturers and governments collaborated in securing tobacco and cigarette allowances to soldiers in the field. It was asserted that regular use of tobacco while under duress would not only calm the soldiers but allow them to withstand greater hardship. [ 109 ]  Until the mid-20th century, the majority of the adult population in many Western nations were smokers and the claims of anti-smoking activists were met with much skepticism, if not outright contempt. Today the movement has considerably more weight and evidence of its claims, but a considerable proportion of the population remains steadfast smokers. [ 110 ]


Smoking has been accepted into culture, in various art forms, and has developed many distinct, and often conflicting or mutually exclusive, meanings depending on time, place and the practitioners of smoking.  Pipe smoking , until recently one of the most common forms of smoking, is today often associated with solemn contemplation, old age and is often considered quaint and archaic. [ citation needed ]  Cigarette smoking, which did not begin to become widespread until the late 19th century, has more associations of  modernity  and the faster pace of the industrialized world. Cigars have been, and still are, associated with  masculinity , power and is an iconic image associated with the stereotypical capitalist. In fact, some evidence suggests that men with higher than average testosterone levels are more likely to smoke. [ 111 ]  Smoking in public has for a long time been something reserved for men and when done by women has been associated with  promiscuity . In Japan during the  Edo period , prostitutes and their clients would often approach one another under the guise of offering a smoke; the same was true for 19th-century Europe. [ 17 ]


The earliest depictions of smoking can be found on Classical Mayan pottery from around the 9th century. The art was primarily religious in nature and depicted deities or rulers smoking early forms of cigarettes. [ 112 ]  Soon after smoking was introduced outside of the Americas it began appearing in painting in Europe and Asia. The painters of the  Dutch Golden Age  were among the first to paint portraits of people smoking and still lifes of pipes and tobacco. For southern European painters of the 17th century, a pipe was much too modern to include in the preferred motifs inspired by mythology from Greek and Roman antiquity. At first smoking was considered lowly and was associated with peasants. [ 113 ]  Many early paintings were of scenes set in taverns or brothels. Later, as the  Dutch Republic  rose to considerable power and wealth, smoking became more common amongst the affluent and portraits of elegant gentlemen tastefully raising a pipe appeared. Smoking represented pleasure, transience and the briefness of earthly life as it, quite literally, went up in smoke. Smoking was also associated with representations of both the sense of smell and that of taste.


In the 18th century smoking became far more sparse in painting as the elegant practice of taking  snuff  became popular. Smoking a pipe was again relegated to portraits of lowly commoners and country folk and the refined sniffing of shredded tobacco followed by sneezing was rare in art. When smoking appeared it was often in the exotic portraits influenced by  Orientalism . Many proponents of  postcolonialism  controversially believe this portrayal was a means of projecting an image of European superiority over its colonies and a perception of the male dominance of a feminized Orient. Proponents believe the theme of the exotic and alien "Other" escalated in the 19th century, fueled by the rise in the popularity of  ethnology  during the  Enlightenment . [ 114 ]


In the 19th century smoking was common as a symbol of simple pleasures; the pipe smoking "noble savage", solemn contemplation by Classical Roman ruins, scenes of an artist becoming one with nature while slowly toking a pipe. The newly empowered middle class also found a new dimension of smoking as a harmless pleasure enjoyed in smoking saloons and libraries. Smoking a cigarette or a cigar would also become associated with the  Bohemian , someone who shunned the conservative middle class values and displayed his contempt for conservatism. But this was a pleasure that was to be confined to a male world; women smokers were associated with prostitution and smoking was not considered an activity fit for proper ladies. [ 115 ]  It was not until the start of the 20th century that smoking women would appear in paintings and photos, giving a chic and charming impression.  Impressionists  like  Vincent van Gogh , who was a pipe smoker himself, would also begin to associate smoking with gloom and  fin-du-siècle  fatalism.
While the symbolism of the cigarette, pipe and cigar respectively were consolidated in the late 19th century, it was not until the 20th century that artists began to use it fully; a pipe would stand for thoughtfulness and calm; the cigarette symbolized modernity, strength and youth, but also nervous anxiety; the cigar was a sign of authority, wealth and power. The decades following World War II, during the apex of smoking when the practice had still not come under fire by the growing anti-smoking movement, a cigarette casually tucked between the lips represented the young rebel, epitomized in actors like  Marlon Brando  and  James Dean  or mainstays of advertising like the  Marlboro Man . It was not until the 1970s when the negative aspects of smoking began to appear, yielding the image of the unhealthy lower-class individual, reeking of cigarette smoke and lack of motivation and drive, which was especially prominent in art inspired or commissioned by anti-smoking campaigns. [ 116 ]  In his painting "Holy Smokes", artist  Brian Whelan  pokes fun at the smoking debate and its newly found focus on morality and guilt.


Ever since the era of  silent films , smoking has had a major part in film symbolism. In the hard-boiled  film noir  crime thrillers, cigarette smoke often frames characters and is frequently used to add an aura of mystique or  nihilism . One of the forerunners of this symbolism can be seen in  Fritz Lang 's  Weimar era   Dr Mabuse, der Spieler , 1922 ( Dr Mabuse, the Gambler ), where men mesmerized by card playing smoke cigarettes while gambling.


Female smokers in film were also early on associated with a type of sensuous and seductive sexuality, most notably personified by German film star  Marlene Dietrich . Similarly, actors like  Humphrey Bogart  and  Audrey Hepburn  have been closely identified with their smoker persona, and some of their most famous portraits and roles have involved them being haloed by a mist of cigarette smoke. Hepburn often enhanced the glamor with a cigarette holder, most notably in the film  Breakfast at Tiffany's . Smoking could also be used as a means to subvert censorship, as two cigarettes burning unattended in an ashtray were often used to suggest sexual activity.


Since World War II, smoking has gradually become less frequent on screen as the obvious health hazards of smoking have become more widely known. With the anti-smoking movement gaining greater respect and influence, conscious attempts not to show smoking on screen are now undertaken in order to avoid encouraging smoking or giving it positive associations, particularly for family films. [ 117 ]  Smoking on screen is more common today among characters who are portrayed as anti-social or even criminal. [ 118 ]


According to a 2019 study, the introduction of television in the United States led to a substantial increase in smoking, in particular among 16–21-year-olds. [ 119 ]  The study suggested "that television increased the share of smokers in the population by 5–15 percentage points, generating roughly 11 million additional smokers between 1946 and 1970." [ 119 ]


Just as in other types of fiction, smoking has had an important place in literature and smokers are often portrayed as characters with great individuality, or outright eccentrics, something typically personified in one of the most iconic smoking literary figures of all,  Sherlock Holmes . Other than being a frequent part of short stories and novels, smoking has spawned endless eulogies, praising its qualities and affirming the author's identity as a devoted smoker. Especially during the late 19th century and early 20th century, a panoply of books with titles like  Tobacco: Its History and associations  (1876),  Cigarettes in Fact and Fancy  (1906) and  Pipe and Pouch: The Smokers Own Book of Poetry  (1905) were written in the UK and the US. The titles were written by men for other men and contained general tidbits and poetic musings about the love for tobacco and all things related to it, and frequently praised the refined bachelor's life.  The Fragrant Weed: Some of the Good Things Which Have been Said or Sung about Tobacco , published in 1907, contained, among many others, the following lines from the poem  A Bachelor's Views  by Tom Hall that were typical of the attitude of many of the books:


So let us drink To her, – but think Of him who has to keep her; And  sans  a wife Let's spend our life In bachelordom, – it's cheaper.


These works were all published in an era before the cigarette had become the dominant form of tobacco consumption and pipes, cigars, and chewing tobacco were still commonplace. Many of the books were published in novel packaging that would attract the learned smoking gentleman.  Pipe and Pouch  came in a leather bag resembling a tobacco pouch and  Cigarettes in Fact and Fancy  (1901) came bound in leather, packaged in an imitation cardboard cigar box. By the late 1920s, the publication of this type of literature largely abated and was only sporadically revived in the later 20th century. [ 121 ]


There have been few examples of tobacco in music in early modern times, though there are occasional signs of influence in pieces such as  Johann Sebastian Bach 's  Enlightening Thoughts of a Tobacco-Smoker . [ 122 ]  However, from the early 20th century and onwards smoking has been closely associated with popular music.  Jazz  was from early on closely intertwined with the smoking that was practiced in the venues where it was played, such as bars, dance halls, jazz clubs and even brothels. The rise of jazz coincided with the expansion of the modern tobacco industry, and in the United States also contributed to the spread of cannabis. The latter went under names like "tea", "muggles" and "reefer" in the jazz community and was so influential in the 1920s and 30s that it found its way into songs composed at the time such as  Louis Armstrong 's  Muggles ,  Larry Adler 's  Smoking Reefers , and  Don Redman 's  Chant of The Weed . The popularity of marijuana among jazz musicians remained high until the 1940s and 50s, when it was partially replaced by the use of heroin. [ 123 ]


Another form of modern popular music that has been closely associated with cannabis smoking is  reggae , a style of music that originated in  Jamaica  in the late 1950s and early 60s. Cannabis, or  ganja , is believed to have been introduced to Jamaica in the mid-19th century by Indian immigrant labor and was primarily associated with Indian workers until it was appropriated by the  Rastafari movement  in the middle of the 20th century. [ 124 ]  The Rastafari considered cannabis smoking to be a way to come closer to God, or  Jah , an association that was greatly popularized by reggae icons such as  Bob Marley  and  Peter Tosh  in the 1960s and 70s. [ 125 ]


Estimates claim that smokers cost the U.S. economy $97.6 billion a year in lost productivity and that an additional $96.7 billion is spent on public and private health care combined. [ 126 ]  This is over 1% of the  gross domestic product . A male smoker in the United States that smokes more than one pack a day can expect an average increase of $19,000 just in medical expenses over the course of his lifetime. A U.S. female smoker that also smokes more than a pack a day can expect an average of $25,800 additional healthcare costs over her lifetime. [ 127 ]


In  chemistry , a  solution  is defined by  IUPAC  as "A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are called solutes. When, as is often but not necessarily the case, the sum of the mole fractions of solutes is small compared with unity, the solution is called a dilute solution. A superscript attached to the ∞ symbol for a property of a solution denotes the property in the limit of infinite dilution." [ 1 ]  One important parameter of a solution is the  concentration , which is a measure of the amount of solute in a given amount of solution or solvent. The term " aqueous solution " is used when one of the solvents is  water . [ 2 ]


Homogeneous  means that the components of the mixture form a single phase.  Heterogeneous  means that the components of the mixture are of different phase. The properties of the mixture (such as concentration, temperature, and density) can be uniformly distributed through the volume but only in absence of diffusion phenomena or after their completion. Usually, the substance present in the greatest amount is considered the solvent. Solvents can be gases, liquids, or solids. One or more components present in the solution other than the solvent are called solutes. The solution has the same  physical state  as the solvent.


If the solvent is a  gas , only gases (non-condensable) or vapors (condensable) are dissolved under a given set of conditions. An example of a gaseous solution is  air  (oxygen and other gases dissolved in nitrogen). Since interactions between gaseous molecules play almost no role, non-condensable gases form rather trivial solutions. In the literature, they are not even classified as solutions, but simply addressed as homogeneous  mixtures  of gases. The  Brownian motion  and the permanent molecular agitation of gas molecules guarantee the homogeneity of the gaseous systems. Non-condensable gaseous mixtures (e.g., air/CO 2 , or air/xenon) do not spontaneously demix, nor sediment, as distinctly stratified and separate gas layers as a function of their  relative density .  Diffusion  forces efficiently counteract  gravitation  forces under normal conditions prevailing on Earth. The case of condensable vapors is different: once the  saturation vapor pressure  at a given temperature is reached, vapor excess condenses into the  liquid state .


Liquids  dissolve gases, other liquids, and solids.  An example of a dissolved gas is  oxygen  in water, which allows fish to breathe under water.  An examples of a dissolved liquid is ethanol in water, as found in  alcoholic beverages .  An example of a dissolved solid is sugar water, which contains dissolved  sucrose .


If the solvent is a  solid , then gases, liquids, and solids can be dissolved.


The ability of one  compound  to dissolve in another compound is called  solubility . [ clarification needed ]  When a liquid can completely dissolve in another liquid the two liquids are  miscible . Two substances that can never mix to form a solution are said to be  immiscible .


All solutions have a positive  entropy  of mixing. The interactions between different molecules or ions may be energetically favored or not. If interactions are unfavorable, then the  free energy  decreases with increasing solute concentration. At some point, the energy loss outweighs the entropy gain, and no more solute particles [ clarification needed ]  can be dissolved; the solution is said to be  saturated . However, the point at which a solution can become saturated can change significantly with different environmental factors, such as  temperature ,  pressure , and contamination. For some solute-solvent combinations, a  supersaturated  solution can be prepared by raising the solubility (for example by increasing the temperature) to dissolve more solute and then lowering it (for example by cooling).


Usually, the greater the temperature of the solvent, the more of a given solid solute it can dissolve. However, most gases and some compounds exhibit solubilities that decrease with increased temperature. Such behavior is a result of an  exothermic   enthalpy of solution . Some  surfactants  exhibit this behaviour. The solubility of liquids in liquids is generally less temperature-sensitive than that of solids or gases.


The physical properties of compounds such as  melting point  and  boiling point  change when other compounds are added. Together they are called  colligative properties . There are several ways to quantify the amount of one compound dissolved in the other compounds collectively called  concentration . Examples include  molarity ,  volume fraction , and  mole fraction .


The properties of  ideal solutions  can be calculated by the  linear combination  of the properties of its components. If both solute and solvent exist in equal quantities (such as in a 50%  ethanol , 50% water solution), the concepts of "solute" and "solvent" become less relevant, but the substance that is more often used as a solvent is normally designated as the solvent (in this example, water).


In principle, all types of liquids can behave as solvents: liquid  noble gases , molten metals, molten salts, molten covalent networks, and molecular liquids. In the practice of chemistry and biochemistry, most solvents are molecular liquids. They can be classified into  polar and non-polar , according to whether their molecules possess a permanent  electric dipole moment . Another distinction is whether their molecules can form  hydrogen bonds  ( protic  and aprotic solvents).  Water , the most commonly used solvent, is both polar and sustains hydrogen bonds.


Salts dissolve in polar solvents, forming positive and negative ions that are attracted to the negative and positive ends of the solvent molecule, respectively. If the solvent is water,  hydration  occurs when the charged solute ions become surrounded by water molecules. A standard example is aqueous saltwater. Such solutions are called  electrolytes . Whenever salt dissolves in water  ion association  has to be taken into account.


Polar solutes dissolve in polar solvents, forming polar bonds or hydrogen bonds. As an example, all alcoholic beverages are  aqueous solutions  of  ethanol . On the other hand, non-polar solutes dissolve better in non-polar solvents. Examples are hydrocarbons such as  oil  and  grease  that easily mix, while being incompatible with water.


An example of the immiscibility of oil and water is a leak of petroleum from a damaged tanker, that does not dissolve in the ocean water but rather floats on the surface.


Sonophoresis  also known as  phonophoresis , is a method that utilizes  ultrasound  to enhance the delivery of topical medications through the  stratum corneum , to the  epidermis  and  dermis . Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as  iontophoresis , to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in  transdermal   drug delivery , but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.


Sonophoresis, also known as  phonophoresis , was dated back all the way to the 1950s in its first mention in a published report. [ 1 ]  This report showcased that a  hydrocodone  injection yielded better outcomes for  bursitis  when combined with an ultrasound massage. [ 2 ]  Following this, a series of publications from several investigators showed the increased therapeutic effect when combining ultrasound with  hydrocortisone  injections for various other disease states, further demonstrating the novelty of sonophoresis. [ 2 ]  However, while some researchers provided evidence that ultrasound had a positive effect on the transdermal permeation of drugs, others contradicted this information by displaying research that showed no quantitative effect using ultrasound. [ 2 ]  These early studies mainly investigated the combination of therapeutics with high-frequency sonophoresis (HFS), which can be categorized into frequencies greater than 0.7 MHz. [ 1 ]  High frequency sonophoresis usually includes a range between 0.7 – 16 MHz. [ 1 ]  Studies evolved and HFS was continually studied for four decades until a greater understanding of a mechanism of action,  cavitation , was discovered. [ 1 ]  Cavitational effects are inversely proportional to the frequency of the ultrasound applied, which led to further studies of low-frequency sonophoresis (LFS) for use in transdermal drug delivery due to studies showing greater efficacy in enhancing skin permeability in comparison to HFS. [ 1 ]  Low-frequency sonophoresis usually includes a range between 20 and 100 kHz. [ 1 ]  For this reason, currently HFS focuses on topical applications for penetration through the stratum corneum, whereas LFS focuses on transdermal drug delivery applications.


Ultrasonic  sonicators  generate ultrasound waves, which is a longitudinal compression wave, by converting electrical energy into mechanical energy by deformation of  piezoelectric  crystals in response to an electric field. [ 1 ] [ 3 ]  The frequency of the waves generated by this method can range from 20 kHz up to 3 MHz. [ 3 ]  The ultrasound waves generated from this device allow for penetration through biological tissue by molecular oscillation of the biological tissue they travel through. [ 1 ] [ 3 ]  The amplitude of the wave can be modified by manipulating the displacement of the ultrasound horn for each half cycle as they are proportional.


The primary purpose of phonophoresis is to assist in transdermal drug delivery, usually with the help of a coupling agent or medium. Transdermal drug delivery sometimes does not permeate the skin to reach a targeted area within the body because of the  stratum corneum  layer of the skin, a layer that prevents foreign substances from penetrating the body. [ 4 ] [ 5 ] [ 6 ]  Transdermal drug delivery is patient-compliance, [ 7 ]  usually avoids  digestive system  degradation, [ 8 ]  and has the ability to use drugs with short  half-lives . [ 9 ]


While increased skin permeability is seen through sonophoresis, the precise mechanisms to describe sonophoresis are yet to be fully discovered. However, there are several important mechanisms that have been identified that contribute to the phenomenon of sonophoresis.


Cavitation is generally determined to be the dominant mechanism that drives sonophoresis. It can be described as the distortion, expansion, and contraction of gas bubbles in a liquid medium. [ 10 ]  The frequency of the ultrasound waves helps determine the bubble parameters, such as size and shape. There exist two types of cavitation, stable and transient. Stable cavitation is when cavitation bubbles persist over many acoustic pressure cycles without collapsing. On the other hand, transient cavitation is where these cavitation bubbles uncontrollably and rapidly grow and decay over many acoustic pressure cycles. [ 1 ]  However, while cavitation is considered the primary mechanism for sonophoresis, the gas bubbles that contribute to cavitation are generated by a process termed rectified diffusion. [ 1 ]


Rectified diffusion is the process where cavitation bubbles experience growth. [ 1 ]  The growth of these bubbles occurs by encountering a negative pressure half cycle, expanding the gas inside the bubble. Similarly, the gas bubble will dramatically decay in size when encountering the other positive half of the pressure cycle. [ 1 ]  There are further factors that manipulate the oscillation of the bubbles’ size, such as temperature and composition of the gas and liquid phases. Depending on the dramatization of the oscillation from previously mentioned factors, stable or transient cavitation occurs. A rapid process will lead to transient cavitation bubbles, whereas a slower process will lead to stable cavitation bubbles. [ 1 ]


An important consideration when transferring energy to a patient would be the thermal energy generated from heating of the biological tissue due to energy losses from the ultrasound waves. It has been shown that increases in temperature can increase skin permeability through several factors. [ 1 ]  Two factors are increased kinetic energy and diffusivity of drugs, which allow for compounds to pass through the stratum corneum. Moreover, hair follicles and sweat glands are dilated, allowing for more points of entry for compounds. The enhanced circulation of blood that comes as a result of increased temperature from ultrasound parameters also allows for better diffusion of compounds. [ 1 ]  While the intensity and duty cycle of the ultrasound are directly proportional to the corresponding thermal effects, surprisingly thermal effects are not a considerable mechanism for HFS in ranges from 1 – 2 degrees Celsius. [ 1 ]  However, once larger temperature changes are observed, such as an excess of 10 degrees Celsius, permeant transport was increased. [ 1 ]  When it comes to LFS, thermal effects are an important consideration on the side of safety. Thermal effects need to be minimized at higher amplitudes, as burns and  necrosis  of tissues can occur due to exposure to high, sustained temperatures. [ 1 ]  A simple solution to counteract sustained exposure to high temperatures is to periodically replace the coupling agent every so often. [ 11 ]


While sonophoresis alone is able to increase the permeability of skin by several factors depending on the procedure and the drug being delivered, a synergistic combination of sonophoresis with other enhancers, such as iontophoresis and  electroporation , has shown greater enhancement as well as increased safety in reduction of individual enhancer parameters. [ 2 ]


Iontophoresis is similar to sonophoresis as it is a method for transdermal drug delivery but does so by applying a  voltage  gradient across the skin. Since there are differences in pathways between iontophoresis and sonophoresis, a combination of these two methods allows for greater enhancement. [ 2 ]  For example, Le et al. displayed, for the case of  heparin , that a combination of iontophoresis and sonophoresis resulted in a 56-fold enhancement of heparin flux in comparison to sonophoresis having a 3-fold enhancement and iontophoresis having a 15-fold enhancement. [ 12 ]


Electroporation allows the cell membrane to open up after applying an  electric field . By applying short, high voltage pulses to the stratum corneum, the lipid structure will become disorganized and allow enhancement of drug delivery. [ 3 ]  There are currently very few reports of the combination of these modalities being used together. However, in these reports, there is mention that the  transdermal  enhancement created by the combination was greater than the sum of the individual enhancers, suggesting that electroporation and sonophoresis work together synergistically. [ 3 ]


Phonophoresis can be performed using two main methods: The first is simultaneous treatment, where the drug can be applied at the same time as the ultrasound. The second method is pretreatment, where the  ultrasound  is used briefly before drug delivery. [ 8 ] [ 9 ] [ 13 ] [ 7 ]  This is to ensure that the skin is permeable prior to the drug being applied.


When using an ultrasound, cavities will develop due to the pressure change. Stable cavitation describes the repetitive oscillations of a cavity bubble, while inertial cavitation describes the collapse of a cavity bubble. [ 8 ]  If the developed cavities fall apart, the effect on the  stratum corneum   lipids  will increase the permeability of the skin. [ 9 ] [ 6 ]  These areas of increased permeability are often called localized transport regions, where there is lower  electrical resistivity . [ 14 ]  One potential method is to use cavitation seed at the surface of the skin. [ 15 ]  Another potential method is to use ultrasound-responsive liquid-core nuclei (URLN). [ 6 ]


Low-frequency ultrasound is seen as the optimal level of ultrasound frequency. This is typically characterized as 20 to 100 kHz (sometimes 18 to 100 kHz). [ 7 ]  Low frequency makes cavitation more likely. For reference, high frequency ultrasound is typically in the range of 1 to 3 MHz. [ 8 ]


The drug should be able to work together with the coupling agent. [ 9 ]  In a 2019 study, they used the drug  diclofenac  in coordination with  thiocolchioside  gel to treat patients who suffer from  acute lower back pain . [ 16 ]  An application of a drug serving as a coupling agent is the use of  piroxicam  gel mixtures and  dexamethasone sodium phosphate  gel mixtures to treat patients who suffer from  carpal tunnel syndrome . [ 17 ]


Various conditions that can be addressed include  cervical spine  pain, [ 18 ]  acute lower back pain, [ 16 ]   carpal tunnel syndrome , [ 17 ]  muscle injury, [ 19 ]   rheumatoid arthritis , [ 20 ]  and  venous thrombosis . [ 5 ]  Examples of drugs that have been used with sonophoresis include  hydrocortisone ,  mannitol ,  dexamethasone , and  lidocaine . [ 9 ]


Several products have been marketed to use phonophoresis for transdermal drug delivery. [ 9 ]


A potential future application of phonophoresis is to use it with vaccines, as phonophoresis is considered a less painful alternative to needles. [ 14 ] [ 9 ] [ 7 ] [ 4 ]  Another potential use is in cancer therapeutics; one such application that has been explored is the delivery of  cisplatin  for patients who have  cervical cancer . [ 21 ]  Genetic skin diseases and  wound healing  may be assisted by phonophoresis. [ 9 ]


Regarding high frequency sonophoresis (HFS), the future potential is very similar to its usage in the past. Many of the treatments involving HFS are topical and regional. [ 1 ]  Commonly used drugs in these topical applications include anti-inflammatory medications such as  cortisol  and  dexamethasone . However, there has been a notable shift towards using  non-steroidal anti-inflammatory drugs  (NSAIDs), such as  ibuprofen  and  ketoprofen . [ 1 ]  NSAIDs commonly cause  gastrointestinal  side effects such as nausea and heartburn, which can all be bypassed by delivering NSAIDs using sonophoresis. [ 1 ]  With its credible safety and useful ability in penetrating the stratum corneum, HFS remains an incredibly versatile option for delivering drugs topically. Low frequency sonophoresis (LFS), on the other hand, has a variety of applications that can be built upon in the future. Since LFS is not restricted by its ability to deliver molecules of varying sizes, drugs such as  proteins ,  nanoparticles , and  vaccines  are all possible targets. [ 22 ]


In previous literature, it has been demonstrated that ocular delivery of drugs can be achieved with high efficacy and minimal invasion. With 20 kHz ultrasound waves at an average temporal intensity of 2 W/cm^2applied every second, the permeability of drugs with varying  lipophilicity  were investigated, such as  atenolol  and  carteolol , increased by 2.6 and 2.8-fold respectively. [ 3 ]


Topical  gene therapy  is another area for investigation in combination with sonophoresis.  Since there exists a need to enhance gene transfer into cells, sonophoresis has the ability to achieve higher  transfection  rate through acoustic cavitation. [ 23 ]  Additionally, there is the advancement of using  microbubbles  with a  contrast agent  to diagnostically image the brain, as LFS and cavitation allows for disruption of the  blood brain barrier . [ 24 ]  Gene therapy using ultrasound and microbubbles is also being investigated for ocular disease. [ 25 ]  In cardiovascular disease, for example, the efficiency of gene therapy can be improved by  ultrasound targeted microbubble destruction  where a gene-loaded microbubble can be burst to release its contents. [ 26 ]


Research being done on sonophoresis is poorly standardized. For example, the emission of ultrasound waves further away from the source results in a greater beam area, which drastically changes the ultrasound energy at the targeted area. [ 3 ]  More challenges surround the cost of the actual ultrasound devices used in sonophoresis in more clinical settings. There still yet exists a low-cost device with high efficacy. [ 27 ]  Additionally the precise mechanisms as to how sonophoresis works is currently yet to be discovered. Further research into the mechanisms, and the dominant mechanisms, can allow for better optimization of sonophoresis parameters, which will increase the efficacy of treatments.


Areas of sonophoretic research include the application of various drugs, dual-frequency sonophoresis, combined transdermal drug delivery techniques, and the use of nanoparticles to carry drugs. [ 28 ]


At an optimal frequency, phonophoresis will be painless and have minimal to no risk. The heat that is emitted from ultrasound use can also be damaging to the surface of the skin, [ 13 ]  and cavitation can potentially lead to tissue damage. [ 13 ]   Nanoparticle toxicity  is another potential risk. [ 13 ]


Conventional  drug delivery  is limited by the inability to control dosing, target specific sites, and achieve targeted permeability. Traditional methods of delivering therapeutics to the body experience challenges in achieving and maintaining maximum therapeutic effect while avoiding the effects of drug toxicity. Many drugs that are delivered orally or parenterally do not include mechanisms for sustained release, and as a result they require higher and more frequent dosing to achieve any therapeutic effect for the patient. [ 1 ]  As a result, the field of drug delivery systems developed into a large focus area for pharmaceutical research to address these limitations and improve quality of care for patients. Within the broad field of drug delivery, the development of  stimuli-responsive drug delivery systems  has created the ability to tune drug delivery systems to achieve more controlled dosing and targeted specificity based on material response to exogenous and endogenous stimuli.


Endogenous stimuli consist of chemical, biological, and physical stimuli that occur naturally in the body, such as changes in pH, temperature, enzymatic action, pressure, and shear forces. More specifically, endogenous chemical stimuli include environmental pH, redox reactions, and chemical gradients, each of which are typically out of physiological range or unique to a specific or diseased tissue, which provides the ability to achieve target specificity using these particular stimuli for release. [ 2 ]  Researchers have worked to develop numerous types of drug delivery systems that harness a response to endogenous chemical stimuli to achieve targeted delivery and controlled release of drug into a specific environment. These chemically responsive drug delivery systems can be created using a wide variety of materials and carriers, including lipid, protein, or polymeric materials to create degradable scaffolds or depots and micelles and nanoparticles. [ 3 ]  An example of this includes the engineering of biopolymeric nanospheres that are triggered to release an encapsulated therapeutic when they enter the tumor microenvironment due to the drop in pH associated with the tumor microenvironment. Many of these systems rely on the application and manipulation of  click chemistry  to achieve stimulated response [ 2 ]  The field of endogenous chemical-responsive systems has developed greatly within the last 20 years and continues to grow as researchers determine new applications for the field, including the development of chemically responsive systems for diagnostic purposes. [ 1 ]


Endogenous chemical stimuli-responsive drug delivery systems are important in the field of drug delivery because of their ability to harness chemical phenomena within the body to overcome traditional therapeutic release limitations such as temporal release and tissue permeability. These drug delivery systems can be applied both as diagnostic and treatment tools for diseases like cancer to achieve long-term action and maximize the therapeutic effect.


While the study of drug delivery methods and techniques has been around for centuries, the modern field of drug delivery we know today was not introduced until the 1960s, when the concept of controlled drug delivery systems was introduced by Judah Folkman, MD of Harvard. [ 4 ]  He first introduced the idea of a prolonged drug release system as a means of constant rate delivery while experimenting with anesthetic gases and arterio-venous shunts on mice [ 4 ]  This inspired the formation of a company called ALZA by a chemist named Alejandro Zaffaroni, whose primary focus was on the development of drug carrying systems that would increase the specificity and efficacy of drugs. [ 1 ]  The introduction of this concept led to the development of the field we know today, with macro scale delivery devices being developed in the 1970s and 1980s before moving into more focused development of microscale and nanoscale devices in the late 1980s onward. [ 4 ]  The concept of stimuli-responsive drug delivery systems can actually be seen as ahead of this time, since the first pH-responsive drug coating was used in the late 1950s in Europe. [ 4 ]  These coatings were used on drugs delivered to the stomach, so that they would protonate and dissolve at low pH to release drug. [ 4 ]  The development of stimuli-responsive drug carriers was not popularized until the mid-1980s by researchers at Utah University, who created thermally-responsive drug delivery systems. [ 4 ]   Since the eruption of this field, substantial research has been conducted to tune stimuli-responsive drug delivery systems despite several limitations. As of 2013, a redox-responsive therapy targeting metastatic breast cancer had been approved by the FDA but was not yet currently in use. [ 1 ]  Much work is still being done to continue the development of this field in hopes of one day making stimuli-responsive drug delivery systems commonplace in medical practice.


pH responsive drug delivery systems respond to the environmental pH of a tissue, which, when existing within a certain acidic range, can lead to structural and chemical changes of the drug delivery system. These changes can include conformational changes and surface interactions that can lead to the degradation or swelling/shrinking of the drug carrier. [ 1 ]  pH responsive drug delivery systems are possible because of the tendency of diseased or cancerous tissues to maintain a lower pH value than is physiologically normal due to high rates of tumor cell metabolism (normal: 7.4, lower range: 5.0-6.5). [ 2 ] [ 5 ]  These systems are governed by hydrophilic and hydrophobic interactions of self-assembled drug carriers within a certain pH range. [ 2 ]  These hydrophilic and hydrophobic interactions can cause the destabilization of these systems, which lead to conformational changes that cause the drug carrier to breakdown or degrade. As a result, the drug is released from the system. pH responsive drug delivery systems are typically synthesized from pH-responsive polymers that have been conjugated with ionic residues that change charge based on the pH of the environment. [ 1 ]  Systems used with pH-responsive polymers include implantable hydrogels and micro- and nanoparticles. pH-responsive drug delivery systems are particularly suitable for the design of chemotherapeutic delivery systems due to the naturally low pH found in tumor microenvironments, but can be applied in other disease settings where the pH of the varies from physiological pH. The highly targeted and controlled release ability, as well as their broad applications, make pH-responsive drug delivery systems some of the most well-researched and sought after clinical solutions in stimuli-responsive drug delivery. [ 3 ]