FIELD OF THE INVENTION

Compositions and methods directed to the use of the sense of smell to influence mood, development and behaviors are disclosed. The compositions and methods may provide multifunctional benefit expressing properties such as anti-anxiety/calming, antimicrobial, anti emetic and analgesic.

BACKGROUND AND DESCRIPTION OF THE INVENTION

One of the most basic functions of the brain is to perceive and evaluate sensory information obtained from the external world to induce adequate motivational and behavioral responses. ¹ Olfaction, the sense of smell, plays a key role in the daily life of humans as it enables one to perceive odors. Studies have shown olfaction has the potential to create moods and influence emotions as well as evoke associations from memory. ²

Anthropology of Odor

Evolution of Modern Man/Importance of the Sense of Smell

The sense of smell, in terms of evolution, is one of the oldest senses, allowing organisms with receptors for the odorants to identify food, potential mating partners, dangers and enemies. For most living creatures and for mankind, olfaction is one of the most important ways of interaction with the environment as well as survival of the species as a form of communication. Even in humans and other animals today, these survival and communication aspects are still functioning. ^{3 ,4}

Cultural Aspects

In various parts of the world, cultures differ in the meaning and importance they attach to the five senses. Anthropologist E.T. Hall states in The Hidden Dimension that with respect to our own culture, the use of the olfactory apparatus in Americans is culturally underdeveloped. ⁵ For example, the Ongee of the Andaman Islands believe the universe and everything in it is defined by smell. ⁶ In this culture, odor is the source of personality and their spirit resides in the nose. ⁷ Their calendar is constructed on the basis of the odors of flowers which come into bloom at different times of the year. ⁶

Among the indigenous people of Brazil, the Borono associate personal identity with smell. The two basic smells, putrid and sweet, signify the two basic cosmic forces: life and spirit. This simple olfactory division provides the foundation on which the edifice of Bororo beliefs and practices concerning the body, the social and natural orders, and the spirits, is constructed. ⁶

In India, the traditional affectionate greeting, equivalent of the Western hug or kiss, was to smell someone’s head. Similar practices are found in Arab countries where breathing on people with your“breath smell” as you speak to them signals friendship and goodwill, where denying them of this conveys a shameful avoidance of involvement. ⁶

Olfactory System

Anatomy and Physiology

The sense of smell, like the sense of taste, is part of the chemosensory system, or the chemical senses. The ability to smell comes from specialized sensory cells called olfactory sensory neurons which are found in a small patch of tissue high inside the nose. These cells connect directly to the brain where each olfactory neuron has one odor receptor. ⁸ Figure 1 below shows a diagram of a neuron. ⁸

olfactory system. ¹⁰

Figure 2: The Human Olfactory System

Odors reach the olfactory sensory neurons through two pathways. The first pathway is through the nostrils where the odorants are drawn into the nasal cavity during the inhalation phase of respiration. They are received by odor receptors expressed on the cilial surface membrane of olfactory sensory neurons. ⁹ The second pathway is through a channel that connects the top of the throat to the nose. When food is masticated, it releases aromas that access the olfactory sensory neurons through the second channel. If the channel is blocked, such as when the nose is blocked by a cold or flu, odors can't reach the sensory cells that are stimulated by smells. As a result, the ability to taste the food is lost, demonstrating that the senses of smell and taste work closely together. ⁹

Smell vs. Other Senses

Olfactory information is the only sensory information that is integrated directly into cortical regions of the brain without a preliminary processing in the thalamus. ¹¹ In humans, all fibers from the olfactory bulb pass through the lateral olfactory strie and the other two strie are only vestiges. Unlike the other major sensory pathways, the main cortical projection of the bulb is ipsilateral. ¹²

All structures of the primary olfactory cortex have rich and reciprocal relations with one another and with other central brain structures, including the hippocampus. The olfactory system is unique in that it has the most direct access to the hippocampus of all other sensory systems in terms of synaptic connections. ¹²

Associative Learning and Emotion

Associative learning is the process in which a new response becomes associated with a particular stimulus. ¹³ It has been proposed that associative learning principles can explain human perceptual and cognitive behavioral responses to odors. ¹⁴ The amygdala, a small almond-shaped structure located anterior to the hippocampus in the medial temporal lobe ¹⁵ , synapses directly with the olfactory nerve and is critical for emotional associative learning. ¹⁴

Previous studies have shown that during the associative learning process, odors serve to reinforce or avert behavior, depending on the whether the odors are presented in a positive or negative state. Schoenbaum et. al. conducted a study in 1999 with rats to explore the development of associative encoding over the course of learning. The rats were presented with novel odors that were informative about the outcome of making a response and had to learn to withhold a response after sampling an odor that signaled a negative outcome. ¹⁶ A“go response” resulted in delivery of a rewarding sucrose solution after presentation of a“positive” odor, or an aversive quinine solution after presentation of a“negative” odor; therefore, the animal had to learn new associations. Based on the data, learning was evident when the rats began to withhold responses (“no-go response”) after sampling the negative odor to avoid quinine delivery, suggesting that the basolateral amygdala complex (ABL) developed selective responses during odor sampling. The neural activity in ABL reflected the acquired significance of olfactory cues based on associations between the originally neutral odors and the motivational properties of reinforcement. ¹⁶

Memory

Episodic memory is a neurocognitive system uniquely different from other memory systems which enables human beings to remember past experiences. ¹⁷ Interactions between the amygdala and hippocampus are necessary for the retrieval of emotional memories and are heavily interconnected. Their interaction in the encoding and consolidation of emotional memories has been well established, correlating with successful episodic retrieval of memories. ¹⁸ This direct connection between olfactory processing and the amygdala-hippocampal complex can make the emotions elicited by odor-evoked memories arise immediately upon perception. ¹⁹

Habituation to Odor

Habituation, a simple form of non-associative memory, is a common feature of sensory systems and is characterized as a decrease in responsiveness to repeated stimuli. ²⁰ It a very useful mechanism that prevents becoming overwhelmed by numerous stimulations of the external environment. Sensory habituation allows filtering of less significant, or predictable events, and has been shown to involve higher-order processing. This contrasts with receptor adaptation of olfactory receptor cells which occurs relatively slow, requiring several seconds of continuous stimulation. ²⁰

Donald A. Wilson has conducted several animal studies exploring odor stimuli and how it relates to the main olfactory bulb (MOB) and the anterior piriform cortex (aPCX). ²⁰ The data suggests the aPCX is a rapidly adapting system, highly responsive to change, and has excellent odor-discrimination and segmentation capabilities. ²⁰ · ²¹ This combination of rapid habituation and precise odor discrimination allows filtering of background or currently nonrelevant stimuli while maintaining responsiveness to similar, novel odors or change. ²¹

Odor Preference

The olfactory system is one of the most advanced sensory systems to develop in the womb. ²² Within days of birth, human infants will orient toward the odor of their own amniotic fluid, which suggests that prenatal sensory experiences can bias a newborn’s behaviors and preferences. ²³ The primary olfactory receptors are formed by the 8 ^th week of gestation and are functional as early as the 24 ^th week. ²⁴ Previous studies have shown that when a newborn is exposed to certain odors which were introduced to the fetus via the pregnant woman’s diet, discriminative and reduced aversive responses were observed. However, a more recent study conducted by Schaal et. al in 2000 demonstrated that fetuses are not only able to detect but record odor information as a response to an aroma consumed by the pregnant mother. ²⁵

Depending on the particular food consumed and the mother’s metabolism, various amounts of metabolites, including those with olfactory properties, increase in the maternal and fetal plasma and are transferred to the amniotic fluid. Furthermore, these studies suggest prenatal exposure to certain odors affect postnatal preferences. ²⁵ · ²⁶

Trigeminal Sensations

As previously mentioned, the sense of smell is part of the chemosensory system, specifically the trigeminal chemosensory system. Sensory endings of the trigeminal nerve (cranial nerve V) innervate the skin on the face, the mucus membranes of the nasal and oral cavities, as well as the cornea and conjunctiva of the eye. These sensory endings can be activated by physical stimuli (such as mechanical forces and temperature), as well as by a huge array of chemical agents, stimulating chemosensitive channels and evoking sensations of touch, temperature and pain. ²⁷

Trigeminal sensations (e.g. stinging, burning, cooling, tingling) are typically activated by chemicals classified as irritants. Polymodal nociceptive neurons and axons found in the trigeminal chemosensory system alert an organism to potentially harmful chemical stimuli that have been ingested, respired, or come into the contact with the face, as they are closely tied to the trigeminal pain system. Examples include air pollutants (e.g. sulfur dioxide), ammonia (smelling salts), acetic acid (vinegar), and capsaicin (the main compound responsible for the pungency of hot peppers). ²⁸ In addition, few chemosensory stimulants produce exclusively olfactory or trigeminal, as the vast majority possess characteristics of both odor and irritation. Therefore, it has been suggested that the trigeminal nerves associated with the non-olfactory mucosa play a fundamental role in the olfactory process in a more complex manner. ²⁹ · ³⁰ Studies with anosmics, individuals with loss of the sense of smell, have shown that subjects are able to distinguish between odorants based on their trigeminally mediated sensitivity. ³¹ Thus, both the olfactory and trigeminal systems contribute to the overall sensory experience, allowing one to “feel” an odor.

A plurality of published data investigating trigeminal sensations is related to irritant odorant molecules. In the heath-care industry, there has been a desire to create sensations of irritation such as pungency, warmth, cooling and tingling. An application of this is through the use of counterirritants. Counterirritants are defined by the US Food and Drug Administration as “an externally applied substance that causes irritation or mild inflammation of the skin for the purpose of relieving pain in muscles or joints by reducing inflammation in deeper adjacent structures.” ³² However, they differ from the anesthetics, analgesics, and antipruritic agents, in that the pain relief they produce results from stimulation, rather than depression, of the cutaneous sensory receptors and occurs in structures of the body other than the skin areas to which they are applied (e.g. joints, muscles, tendons and certain viscera). ³³ Some examples of counterirritants are capsaicin, menthol, methyl salicylate and camphor. As a topical treatment, counterirritant creams penetrate the epithelial layer of the skin and stimulate cutaneous sensory receptors, which in turn can evoke a range of sensations. The counterirritant-induced sensations suppress or relieve the perception of deeper pain. ³⁴

Conversely, activity in the trigeminal nerve may not always be perceived as stinging, burning, or an easily characterized non-olfactory sensation, but may sometimes manifest itself as a non-abstractable part of what appears to be purely olfactive sensations. ³⁵ Therefore, there may be an opportunity for the cosmetic industry to capitalize on the concept of trigeminal sensations as an emerging area for fragrance innovation in consumer products. The food industry has been known to use different food additives to enhance the overall tasting experience, leaving the consumer to want more. For example, spilanthol is an ingredient that has been known to trigger trigeminal sensations, where sensory testing data has shown when a spilanthol/ethanol solution is diluted in an 11% sucrose in water solution, trained panelists rated spilanthol to have intense tingling and mouth-watering effects. ³⁶ This same concept can be applied to consumer products, creating purposeful fragrances to produce specific trigeminal sensations and trigger a perceived benefit when the consumer is using the product. For example, creating an acne wash with a purposeful fragrance which triggers a tingling and slight cooling feeling during usage. The trigeminal sensations produced by the fragrance may cue the benefits of superior cleansing and removal of dirt and bacteria while effectively treating the acne. Ultimately, this provides the consumer with the perception of efficacy and creates a multisensorial experience while driving consumer acceptability and compliance.

Importance of Smell

Human Development and Functioning

Infants

A mother’s maternal odor has been shown to have beneficial effects on a newborn baby. In particular, breast odor been shown to reduce arousal states in active newborns and increase them in sleepy newborns. Furthermore, it elicits positive head turning, stimulates oral appetite activity, and may induce directional crawling in newborns. ³⁷

Sullivan et. al. conducted a study to characterize newborns’ responses to maternal odor by assessing a wide range of behaviors during maternal odor presentation ( own mother odor vs. other mother’s odor vs. clean gown vs. nothing) in crying, sleeping and awake newborn infants. ³⁸ When presented with a maternal odor, whether their own mother or other mother’s odor, both the breast-fed and bottle-fed infants responded to the maternal odor, where crying stopped sooner than the control infants. ³⁸

Figure 3 shows the mean latency to Figure 3: Mean Latency to Stop Crying as a function of stop crying as a function of odor Odor Presentation

other mother groups, there was no significant difference in the latency to stop crying of breast fed vs. bottle-fed infants. ³⁸

As a secondary part of the study, once an infant stopped crying, they were presented with one of the four variables. As shown in Figure 4, infants receiving a presentation of their own mother’s odor were more likely to exhibit mouthing (p<0.05) when compared to either of the control groups {clean gown or no gown). The data indicated that the own mother group was statistically different from the no gown group (p<0.0l); whereas the other mother’s odor did not differ significantly from any other condition. ³⁸

Figure 4: Mean Change in Mouthing as a function of

Odor Presentation in Crying Infants

Figure 5: Mean Change in Mouthing as a function of Odor

Presentation in Non-Crying Infants

Sullivan et. al. also looked at the impact of maternal odor on awake infants and found their own mother’s odor increased mouthing. In contrast to the soothing effects of maternal odor, the mouthing response appears to be specific to the maternal odor of the infant’s mother. ³⁸ Figure 5 displays the mean change in mouthing as a function of odor presentation in non-crying infants. The asterisk represents a significant difference of the own mother’s odor group compared to the other three conditions. ³⁸ The increased mouthing elicited by maternal odor may enhance nipple acceptance and feeding in certain newborns, especially those who are not feeding well. For sleeping infants, among the four groups, there were no statistical differences in the behavior of mouthing as a function of odor presentation. ³⁸ These findings indicate that postpartum maternal odor soothes newborn infants, particularly in distressed infants, by shortening the latency to stop crying. However, infants were more likely to mouth to their own mother’s odor compared to any unfamiliar maternal odor, as there maybe a specific component of the odor triggering oral activity.

It would be interesting to further investigate the soothing effects of maternal odor presentation ( own mother vs. other mother’s odor) in bottle-fed infants given own mother vs. other mother’s breast milk. This may help to get additional information as to whether their own mother’s maternal odor contains unique components which creates a stronger soothing effect when paired with their own mother’s breast milk, compared to an infant who is presented with their own mother’s odor and fed another mother’s breast milk.

Decades of data has demonstrated that naturally emitted volatile compounds from the breast of lactating women impinge on the behavior of infants. The arousing properties of areolar odor stimuli function to initiate the chain of behavioral and physiological events such as latching and sucking that can foster engagement between a mother and child, as well as reinforce early interactive processes, leading to maternal bonding. ³⁷ Furthermore, the areolar odor may be involved in the coactivation of other neonatal sensory system involving the development of, perception of, and selective response to the mother. ³⁷ Overall, these findings emphasize the importance of a maternal odor, and how critical it is for bonding between parent and child as it ultimately affects infant arousal, behavior and learning.

Impact on Aging

As a critical component of human physiology, olfaction plays an essential role in health and behavior. With aging, functionality of the olfactory system declines, including the ability to discriminate between smells. ³⁹ It has been reported that more than 75% of people over the age of 80 years have evidence of major olfactory impairment and olfaction declines considerably after the seventh decade. ³⁹ · ⁴⁰

Physiological impairment of the olfactory system can impact overall well-being as it allows one to maintain adequate nutrition through appetite and food preferences, ⁴¹ enables detection of environmental hazards, and is associated with memory, emotions and social relationships. Unique among the senses, the olfactory system depends on stem cell turnover, and thus may serve as an indicator of deterioration in age-related regenerative capacity more broadly or as a marker of physiologic repair function. Specifically, normal olfactory function depends on cellular regeneration of the olfactory neuroepithelium, olfactory bulb and hippocampus, a capacity impaired by telomere shortening which is a known indicator of aging in many systems. ⁴² As part of the normal aging process, studies have shown that both the number of fibers in the olfactory bulb, as well as olfactory receptors decrease noticeably with age. Sensory cell loss in the olfactory mucosa, along with a general deterioration in central nervous system cognitive processing functions also play a role in degeneration of olfaction. Even in the absence of disease, olfactory receptor neurons undergo apoptosis at a baseline rate in each individual. ⁴³ As previously mentioned, these cells can be regenerated to replace these cells, however this process degenerates with ageing. This results in a reduction in the surface area of olfactory epithelium, along with reduced numbers of olfactory receptor neurons. ³⁹

Olfactory Dysfunction

As many as two million people in the United States experience some type of olfactory dysfunction. ⁴⁴ Disorders of smell are classified as "-osmias" . ⁴⁵ These disorders that describe different degrees of smell aberration can be categorized as quantitative and/or qualitative.

Anosmia, the complete loss of olfaction, and hyposmia, the partial loss of olfaction, are classified as quantitative disorders as they can be measured. ⁴⁵ The term dysosmia refers to a qualitative olfactive disorder in which there is an alternation or distortion in the perception of smell.

Dysosmia can be classified as either parosmia (also called troposmia) or phantosmia. Parosmia refers to a distortion in the perception of an odor where odors smell different from what one remembers. ⁴⁶ A more specific term, cacosmia, refers to an unpleasant perception of an odor due to nasosinusal or pharyngeal infection. Phantosmia refers to the perception of an odor when there is no actual odor present. The cause of dysosmia still remains a theory. Olfactory dysfunction including anosmia, hyposmia, and dysosmia can be either bilateral or unilateral on either nostril. ⁴⁶ They can also be classified as partial where it affects a several odors, or can be specific where it affects only one or a select few odors. ⁴⁵

Additionally, studies have shown a clinical correlation with olfactory dysfunction and early signs of neurological diseases such as Alzheimer’s disease, Huntington’s disease,

Parkinson’s disease, vascular dementia, and idiopathic rapid eye movement sleep behavior disorder. ⁴⁷ However, less than one-fourth of individuals with olfactory dysfunction are cognizant of their sensory problem until being formally tested. More importantly, in elderly people olfactory dysfunction has been associated with early mortality. ⁴⁷

From Natural Odor to Fragrance

Anatomy of a Fragrance

A fragrance, or parfum, is defined as a mixture of fragrance essential oils or aroma compounds, fixatives and solvents, used to give the human body, animals, food, objects and living spaces an agreeable scent. ⁴⁸ Individual fragrance ingredients are blended together to create “notes“ which are descriptors of scents, to form a balanced fragrance. An olfactory pyramid is a concept used to visualize a fragrance’s lifecycle. The different notes are classified by their volatility to create clear distinction between each phase. ⁴⁹ They are arranged into three groups from the most to least volatile: top/head notes, middle/heart notes, and base/dry notes. ⁵⁰ Top/head notes are the first notes perceived after applying a fragrance. Consisting of the most volatile compounds which evaporate very quickly, they are short-lived but strong and sharp. As the top/head notes fade, the middle/heart notes begin to emerge. These are transitory notes that linger as the base/dry notes become noticeable. Middle/heart notes are usually designed to hide base notes, which take time to mature and can be unpleasant at first. Base/dry notes are the foundation of a fragrance. They are the long-lasting aromas that usually form accords with the middle/heart notes. ⁴⁹ An accord is a harmonious blend of two or more scents to create a new and different fragrance entity. An accord may be a simple mixture, or may consist of many materials, where each component material is balanced so that no one single component can be detected. ⁵¹ Base/dry notes are what provides a Figure 6: Conventional Fragrance Pyramid fragrance’s longevity and usually lasts for hours.

Certain fragrances cycle through their notes one

after the other in a straight-forward manner, while

others can be quite complex as their notes will

overlap with one another to form different

accords. ⁴⁹ A fragrance’s lifecycle is often

visualized in the form of a pyramid. Figure 6

shows a conventional fragrance pyramid where the

notes are stacked on top of each other in layers,

which serve to indicate the life-cycle’s

chronology. ⁴⁹ The three different classes of notes

can be detected with respect to the time after

application of a fragrance. ⁴⁹ · ⁵⁰

The process of developing a fragrance is a

complex mixture of chemistry and art as it is based on the knowledge of the volatility of the individual fragrance ingredients and the intended use in the end product, often times conveying abstract concepts and moods with different fragrance compositions. ⁵⁰ · ⁵² Classification of Fragrance Oils: Natural vs. Synthetic

Natural fragrance oils are wholly composed of one or more constituents derived or purified from natural sources, such as fragrance absolutes. Essential oils are a complex blend of constituents extracted from the flowers, barks, stem, leaves, roots, fruits and other parts of the plant, often through steam distillation. ⁵³ The methods used to extract fragrance ingredients from their natural sources have changed over time as technology in general has advanced. However, both old and new methods fall into three basic classes: expression, distillation and solvent extraction. ⁵⁴

The use of essential oils is restricted by price, availability and chemical stability;

therefore, the application of synthetic fragrance oils has grown tremendously. Synthetic fragrance oils are derived from synthetic sources and can be a novel ingredient or nature identical. In general, they are cheaper to produce than natural fragrance oils and supply is more secure. Additionally, when creating synthetic fragrance ingredients, more robust molecules can be produced, which allows it to survive in acidic, basic, and even oxidizing media. ⁵⁴

Use of Fragrances in Personal Care Products

Consumer Perception

Studies have shown that fragrance is a key attribute in a consumer’s purchase decision, spanning across an array of different product categories including personal care products.

According to research conducted by Mintel, a global marketing intelligence agency, when choosing body care products, two-thirds of U.S. consumers rank fragrance as the most important attribute. Similarly, in categories such as soap, bath and shower gel, and deodorant, fragrance ranks as high or even higher than functional benefits. ⁵⁵

Fragrances instantly connect to an individual’s emotions, mood, and memory, both consciously and subconsciously, which affect consumer preferences. Since the neurological substrates of olfaction are especially geared for associative learning and emotional processing, this intimate link allows marketers to connect a fragrance with an unconditioned stimulus, eliciting the desired response and eventually prompting a conditioned response from

consumers. ⁵⁶ In addition, the fragrance of a product enables more segmentation within product categories, offering various options depending on demographics, type of occasion, time of day and location of where it is used. An example of this is Proctor & Gamble’s Sweet Dream Collection® laundry line that contains a calming scent to help consumers relax before falling asleep. The line features products such as Tide ^® plus A touch of Downy™ Sweet Dreams™ Liquid detergent and Downy Infusions ^® Sweet Dreams™ Fabric Softener, among others, that are formulated with ingredients to clean, soften and freshen bedtime fabrics to help create an ideal sleep environment. ^{55, 57}

Furthermore, when fragrance is used in personal care products, a triggered emotional response can sometimes affect the consumer’s perception of product performance as well as cue skincare benefits. ⁵⁸ Thus, as the first sensory cue the consumer experiences with the product, the fragrance developers must be cognizant of the target audience as scent is a critical element of the overall product. For example, Dawn® Ultra Hand Renewal with Olay Beauty Dish Soap is a dishwashing liquid detergent that features a peach and almond fragrance. Fruity notes, such as peach, strawberry and apricot, connote the feeling of clean and fresh, while almond is associated with nourishment. ⁵⁹ Skillfully blending these key olfactive notes with other fragrance ingredients to create a soft, caring scent, in combination with a formulation with an opaque, creamy appearance, helps legitimize the product performance to remove greasy residue while cueing the skincare benefits of leaving hands feeling soft and moisturized.

Brands and Iconic Fragrances

Iconic is defined as“widely known and acknowledged especially for distinctive excellence”. ⁶⁰ In order to achieve this notoriety, a brand needs to be a symbol of excellence which others aspire, and provide a unique experience that gives emotional as well as rational benefits. Iconic fragrances are often associated with iconic brands as they are frequently linked with past memories, an emotional connection for the consumer. Pamela Dalton, a researcher at the Monell Chemical Senses Center in Philadelphia, stated,“We know that people often report that smells are particularly evocative in bringing back memories, often from childhood”. ⁶¹ A key example of this is Johnson’s® Baby, specifically Johnson’s® Baby Gold Shampoo, among other classic Johnson’s® Baby products. Originating from the l950s, this unique fragrance truly interacts with the emotion and memory centers of the brain, triggering happy memories of parents as they remember using these baby products during bath time on their children.

Johnson’s® Baby Gold Shampoo’s iconic scent also creates a multi-generational impact as new parents recall special memories from their childhood as they use the same beloved products on their own children. With delicate florals, blended together with juicy fruity notes, the Johnson’s® Baby Gold Shampoo fragrance is associated with intimate memories, allowing consumers to enjoy time and time again the classic“smell of baby” and recall special, loving moments shared between parent and child.

Another example of an iconic fragrance is Old Spice. Classified as a“Classic American Fragrance”, this scent has been around for many generations, originating as a women’s fragrance in 1937. Following its success, a men’s version was released the following year, and has thus been applied in a vast range of products from colognes and aftershaves to deodorants and shower gels, allowing the iconic fragrance to survive into the 2l ^st Century. ⁶² Consumers of Old Spice often talk about their associations with the product, making the emotional connection with their fathers or grandfathers; some will even reminisce about their first loves. Old Spice’s iconic spicy amber notes provide a deep, nostalgic foundation to its invigoratingly fresh and citrus notes, connoting virility and gruffness in this distinctively masculine fragrance. Therefore, Old Spice has established itself as a classic scent and can be defined as one of the most iconic barbershop fragrances in history. ⁶²

It is critical to recognize the power of fragrance to drive product upgrade, category segmentation, and added value in personal care and household products. Since fragrance can be a powerful motivator for sales, manufacturers of consumer products intentionally connect the product’s fragrance with the brand’s market position. ⁶³

Fragrance vs. Fragrance-Free

In the personal care space,“fragrance-free” is term used for a product that has no ingredients added for the sole purpose of imparting scent. ⁶⁴ These products are not free of aroma compounds as they will exhibit characteristic scents from other cosmetic ingredients in the formulation. However, there are several brands of consumer products currently on the market that state“fragrance-free” and remove“fragrance” from the ingredient list, yet there are individual ingredients listed on the label which are providing the product with a fragrant odor (e.g. the essential oil, citrus aurantium dulcis (orange) peel oil). This practice can be misleading, and even harmful for consumers with extra-sensitive skin or medically diagnosed contact allergies. “Unscented” products are cosmetics that use individual fragrance ingredients to mask characteristic scents of other essential ingredients. The collective term“fragrance” on a label is often representative of a complex mixture of chemicals. A fragrance oil can be made up of hundreds of ingredients as each fragrance is a unique formulation. As per the FDA’s labeling regulations, section 21 CFR 701.3 states it is legal to put“fragrance” on an ingredient list while avoiding the subcomponents which make up the fragrance. ⁶⁵ This exception not only protects a fragrance company’s trade secret, but it also avoids increasing the length of a product’s ingredient list unnecessarily. However, fragrance ingredients may contain allergens which could cause the consumer to have an allergic reaction. Therefore, many medical professionals recommend“fragrance-free” products for consumers with allergies and/or sensitive skin.

Formulation in Personal Care Products

Once a fragrance is developed for a particular product application, the fragrance oil needs to be assessed in the product base. This could be problematic since the fragrance may not always be easily incorporated into the final formulation due to the chemical composition of the fragrance oil. Solubility of the fragrance could potentially be an issue; for example, in a clear aqueous surfactant system, such as a shampoo, the fragrance may manifest itself as a haziness, as floating droplets of oil, or as complete separation of a clear or milky layer. Therefore, it is important for the perfumer developing the fragrance oil to know the end application of the finished product as this will influence diluent and fragrance ingredient selection.

Application of a fragrance oil in a talc, cornstarch, or powder detergent product may also pose some formulation challenges. Determining the appropriate dosing as well as method of incorporation into the powder may be tricky as it could affect the flow characteristics or cause clumping. These issues may be mitigated by adjusting the dosage of the fragrance and/or changing the manufacturing process. ⁵⁴

Once the product has been successfully dosed, there are several other factors to consider. The finished product needs to be evaluated in accelerated storage conditions, placing samples at extreme temperatures and at different levels of humidity to access physical and chemical characteristics, ensuring there are no significant changes over time and the product still performs as it was designed. Light testing is also conducted as the product will be exposed to different lights throughout its lifecycle, especially fluorescent lighting to represent products sitting on a store shelf. These harsh conditions can sometimes degrade fragrance components over time, which may result in changes in color changes as well as odor intensity where the key fragrance notes may fade, allowing the product base odor to become more apparent; or these conditions may result in a change in the overall fragrance profile. ⁵⁴

Safety and Regulatory Considerations

IFRA

The use of fragrance is cosmetic products is regulated in the United States by the US Food and Drug Administration (FDA) under the Federal Food, Drug and Cosmetic Act (FD&C Act). In general, manufacturers of personal care products must substantiate the safety of their ingredients and products. ⁶⁶ Fragrance ingredients are assessed by a comprehensive program operated by the International Fragrance Association (IFRA). Active since 1973, this program contains a Code of Practice that provides guidelines on fragrance ingredient safety assessments, including fragrance safety standards which define quality and limits, as well as banning the usage of certain fragrance materials. IFRA oversees the gathering of information about the safety of individual fragrance ingredients and reviews this information to determine safety under conditions of use. The conclusions of the IFRA safety review are published in the IFRA Code of Practice which provides critical guidance to fragrance formulators and users to ensure their products are safe. ⁶⁷

RIFM

The Research Institute for Fragrance Materials (RIFM) is a nonprofit corporation formed in 1966 with the purpose to gather and analyze scientific data, engage in testing and evaluation, distribute information, cooperate with official agencies, and encourage uniform safety standards related to the use of fragrance ingredients. ⁶⁸ The RIFM Database is the largest available worldwide database of fragrance and flavor ingredients, classifying more than 6,000 materials. ⁶⁸ All of RIFM’ s research is reviewed by an independent Expert Panel, comprised of internationally known academic scientists, including dermatologists, pathologists, toxicologists and

environmental scientists. Additional expertise is provided by adjunct groups with knowledge in genetic toxicity, respiratory science, reproductive effects and environmental fate and

epidemiology. ⁶⁹ The Expert Panel has no commercial ties to the fragrance industry, as they provide strategic guidance, determine scientific study design, and interpret test results for relevance to human health and environmental protection. The Expert Panel’s independent conclusions are presented to professional, scientific and medical societies and are published in peer-reviewed scientific journals. When critical for consumer and environmental protection, decisions of the Expert Panel regarding restrictions of use are published as IFRA Standards. ⁶⁹

Fragrance Testing

Laboratory Testing

Sensory Analysis

Sensory analysis involves using human subjects as a measuring tool. Each person can perceive the same product differently, therefore, it is essential when conducting a sensory test that all variables, except what is actually being tested, are carefully controlled as much as possible to minimize variability. When the testing is being conducted, the panelists are often placed in a neutral environment that is free of noise or movement, each with an individual booth to complete their evaluation. All samples are blinded where the samples all look identical. Odors can be described using a number of different dimensions, each of which can be measured using different sensory tests: threshold, intensity and quality.

Threshold can be described at three different levels to assess (1) if the odor can be detected, (2) if the odor be identified, and (3) is there a difference between two odors. Intensity is assessing how strong is an odor as there are different sensory scales to measure perceived intensity. Lastly, quality evaluates what the odor smells like utilizing a qualitative descriptive analysis (QDA) technique, to obtain detailed information about subtle product differences, as well as odor profiling. ⁵⁴

Nuclear Magnetic Resonance Brain Imaging

Nuclear Magnetic Resonance (NMR) is a physical phenomenon in which nuclei in a magnetic field absorb and re-emit electromagnetic radiation. ⁷⁰ NMR is routinely used in advanced medical imaging techniques, such as in functional magnetic resonance imaging (fMRI). fMRI measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area of the brain is in use, blood flow to that region also increases. ⁷¹

In 2013, Herz et. al. conducted a study to assess emotional distinctiveness of odor-evoked memories. fMRI is ideally suited to assess whether there are neurological differences between the experience of significant personal memories elicited by odors in comparison to memories elicited by the same cues mediated by other senses such as vision. ⁷² For this study in particular, fMRI was utilized to compare regions of activation during recall triggered by olfactory and visual cues that were connected to a personally meaningful memory and a comparable control cue. Analysis of the fMRI data indicated there was significant neurobiological evidence that the subjective experience of the emotional potency of odor-evoked memory was correlated with specific activation in the amygdala during recall. It was also observed that the experimental odor cues elicited greater activation in the amygdala-hippocampal complex than a comparable but non-personally meaningful control odor. ⁷² Consequently, the findings in this study indicate that although odors generally elicit activation in limbic structures, the neurobiological activity was due to the emotionality of memory and not an olfactory artifact.

Consumer Testing

Consumer testing is a critical part of the fragrance development process. It is extremely helpful to obtain consumer feedback on prototypes to ensure the fragrance development is progressing accordingly. A central location test is a useful method to quickly assess fragrance prototypes where the consumer can smell and potentially use the product, often followed up with questions about their experience in order to obtain consumer direction. ⁷³

In-use testing is another method where consumers are asked to use the product as they normally would for a particular period of time followed by a series of questions about their experience. This method can be used to determine whether the fragrance performs and meets the expectations set by the concept, or it can be used to check a fragrance’s performance to confirm it performs as theorized. Several key research designs frequently used for consumer testing are single product (monadic), paired comparison, multiple product, sequential monadic, and duo- trio. ⁷³

How Fragrance Can Influence Mood, Development and Behaviors Research has suggested that humans are able to retain odor recognition as far back as early childhood with the belief that odors having the extraordinary ability to remind us of long- forgotten events. ⁵⁸ · ⁷⁴ Although odor recognition typically does not have as high of a

performance compared to visual recognition when memory is tested immediately, forgetting odors is considerably slower over time. ⁷⁴ Our ability to recognize previously presented odors is relatively robust, yet not all aspects of odor memory are strong, where the ability to recall names of even familiar odors is often weak. ⁷⁴

Scientists have long established a neuronal- olfactory relationship with certain odors. Neuroscientific studies have clarified the characteristics of odor-evoked memories as they stimulate more emotional and evocative recollections than memories triggered by any other cue. ⁷⁵ A French writer, Marcel Proust, is known for his novel, In Search of Lost Time, coining the term“involuntary memory”. ⁷⁶ The most famous example being the“episode of the madeleine”, where the narrator distinctly remembers childhood experiences triggered by the smell of tea-soaked madeleine cakes. ⁷⁷ Proust’s experiences formed the basis of what has become known as the“Proust Phenomenon” which is the ability of odors to spontaneously cue highly vivid autobiographical memories. ⁷⁸ The intensity of olfactory recollection and its visceral characteristics have been related to the specific and unique connections of the olfactory system with the neural structures involved in emotion and associative learning. ⁷⁵ These connections in the temporal lobe overlay those of the amygdala, the emotion center of the brain, and

hippocampus which plays an essential role in the formation of new memories about past experiences. Therefore, the connectivity with these structures is responsible for associating emotional response and highly evocative experiences of memory upon odor sensation. ⁷⁹

Mother-Infant Bonding

In order for an infant to develop a preference for their mother, they must be able to discriminate between their mother and others, as individual recognition is a prerequisite for the establishment of particular social relationships. ⁸⁰ Specifically, this recognition between and mother and infant is a fundamental behavior interaction that contributes to mother-infant bonding. ⁸¹ The emotional relationship between a mother and infant begins with mutual recognition, which starts during gestation, continues through birth, and is augmented by body contact and lactation. ⁸¹ Cernoch et. al. conducted several experiments to determine whether neonates, approximately two weeks of age, can recognize their mother solely through axillary odors. For the first three experiments, breast-feeding infants were presented with their mother’s axillary odor as well as one of three other axillary odors: a nonparturient female, an unfamiliar lactating female, or their father’s axillary odor, to compare their responsiveness of the two different olfactory stimuli. For the fourth and fifth experiment, bottle-feeding infants were presented with their mother’s axillary odor as well as one of two other axillary odors: an unfamiliar bottle- feeding female or a nonparturient female. Individuals (mothers and fathers) who served as sources of odor stimuli were instructed to secure a 10 x 10 cm gauze pads in the underarm area for approximately eight hours during the night preceding testing. The gauze pads were sealed in zip-lock plastic bags after being removed from the axillary region; testing was conducted within 11.5 hours after removal of the stimulus pads. ⁸⁰

For each of the experiments, the infants were presented with the soiled gauze pad and the infant’s response to the olfactive stimuli was recorded, noting the duration of orientation. The results of the five experiments are summarized in Table l. ⁸⁰

Table 1:

MEAN DURATIONS OF CEMENTATION TO THE SIMULTANEOUSLY PRESENTS» OLFACTORY STIMULI IN:

EXPERIMENTS 1-5

5 (iV— 15 bottle-feedrag infants):

Mother s axillary odor. , . . . 49.3 ,26, df ^~ 14. vs. N.S.

N'cmpartarient fe ale's axillary odor , . . 51.3 Breast-feeding infants were able to discriminate their mother’s axillary odor from axillary odors produced by a nonparturient female or an unfamiliar lactating female. In contrast, breast feeding infants did not recognize the father’s axillary odors. Bottle-fed infants appeared unable to recognize the odor of their mother when presented along with odors from a nonparturient

female or an unfamiliar bottle-feeding female. Overall, infants were significantly more familiar with the odor of their mother than with the odor of unfamiliar women. ⁸⁰

Additional studies have been conducted to further understand the chemical signals which seem to have a fundamental role in the mechanism of mother-child identification. It is

hypothesized that women develop a volatile profile, through pregnancy and childbirth, that

enables identification of the mother by their newborn. Breast-fed infants are exposed to maternal odors and rapidly become familiarized with their mother’s unique olfactory signature. In 2008, a study conducted by Vaglio et. al. identified volatiles compounds in sweat patch samples

collected from the para-axillary and nipple-areola regions of women during pregnancy and after childbirth. The data showed that during pregnancy, women developed a distinctive pattern of five volatile compounds common to the para-axillary and nipple-areola regions: l-dodecanol, 1- G-oxybis octane, isocurcumenol, a-hexyl-cinnamic aldehyde and isopropyl myristate. These compounds were not detected in an equivalent control sample of nonpregnant and nonlactating females. Thus, the volatile composition changes during pregnancy. ⁸¹ · ⁸² Figure 7 shows the

comparison of relative frequency of occurrence of volatile compounds in samples from the para- axillary and nipple-areola regions from women (n=20) during three sampling periods. ⁸²

The presence of these volatile compounds may Figure 7: Comparison of relative frequency have implications from an evolutionary point of view as of occurrence of volatile compounds in the pattern of volatiles from the nipple-areola region may samples from the para-axillary and nipple- areola regions from women (n=20) during function as an aid to finding sustenance. ⁸² Therefore, it is

three sampling periods

suggested that not only does smell contribute to mother- infant bonding, but it may also indicate infants are programmed to detect their mother’s odor as a survival instinct. ⁸⁰ Although there are practical implications of the present data, I feel additional research should be conducted to further investigate how the mother’s distinctive pattern of these five volatile compounds correlates to the smell of their infant and its potential impact on mother- infant bonding.

.

Lavandula (common name lavender) is a enus of more

Australia, and the United States. The different varieties of this plant range in height from 9 inches to 3 feet, although some may grow taller with age. ^{84, 85}

Lavender is divided into four main categories: o Lavandula angustifolia (L. angustifolia) (commonly known as English Lavender, formerly known as Lavandula vera (L. Vera ) or L Lavandula officinalis (L. officinalis))- is the most widely cultivate species;

o Lavandula stoecha (L. stoecha)- late blooming with a very strong odor (often known as French lavender);

o Lavandula latifolia (L. latifolia)- a Mediterranean grass-like lavender;

o Lavandula intermedia (L. intermedia)- is a sterile cross between L. latifolia and L. angustifolia.

The various lavenders have similar ethnobotanical properties and major chemical constituents. ⁸⁵ · ⁸⁶

To get a further understanding of the potentially therapeutic effects of lavender,

Buchbauer et. al. conducted a study using Swiss mice to assess the sedative properties of the essential oil lavender ( . angustifolia ) and of its main constituents, linalool and linalyl acetate. ⁸³ For this study, each mouse was injected intraperitoneally with 0.5 mL of a 0.1% caffeine solution (1 mg/mL phosphate buffered saline) and placed in a polycarbonate cage. The cage was equipped with a pumping-evaporating-system to supply fresh air and to guarantee a steady air flow into the cage. The respective fragrance material was injected into a small, glass tube which constantly released the fragrance into the cage for the duration of the study. Caffeine was used to increase the motor activity of the mice to understand if the theorized sedative effects of lavender and/or its main constituents would counteract the hyperactivity of the mice. The motor activity of the animals was measured during the 60 minute adaptation time without treatment and 30, 60 and 90 minutes after the fragrance was injected into the cage. Upon evaluating the data, the untreated mice showed a high tendency to perform activities for social and physiological reasons such as grooming, food and water uptake, and exploring their environment. For the treated mice, the sedative effects of the fragrance compounds were expressed by the characteristic crouching in a corner of the cage. The inactive and drowsy behavior of the treated mice was expressed as a significant decrease in impulse counts. Figure 8 shows the decrease of motor activity of 6-8 week old mice (A) and 6 month old mice (B) after inhalation of lavender oil (sfc), linalool ( _■ ) and linalyl acetate (·). Motor activity values of untreated control mice were arbitrarily fixed as 100%. ⁸³ As shown on the graph, the 6 month old mice had a higher threshold of effectiveness of the aroma compounds. This can be explained by differences in fat tissue in the 6-8 week old mice compared to the 6 month old mice and the very lipophilic properties of these terpenoid aroma compounds. Therefore, the higher amount of fat tissue in the 6 month old mice resulted in the aroma compounds

, . , . Figure 8: Decrease of motor activity of 6-8 week old mice (A) and 6 to accumulate within

month old mice (B) after inhalation of lavender oil (at), linalool (■) the fat tissue resulting _{a nd} , _{jna |y| acetate (e)}

in a reduced effective

plasma concentration.

Based on the data, it can be concluded there is evidence for sedative activity of the

essential oil of lavender and its main constituents, linalool and linalyl acetate after inhalation absorption. Although this is compelling data, from my point of view I would like to get further understanding on several other points. It would be interesting to investigate whether the results would be as statistically significant if the motor activity baseline were established in accordance with the animal’s average daily motor activity levels in contrast to caffeine induced

hyperactivity. Furthermore, would the same impact occur if the mice were physically and/or mentally stressed first and then given aromatherapy treatment? This may provide additional data to support how the scent of lavender in the application of personal care products could be used as a means to relax. I would also be curious to know how the exposure levels of aroma chemicals used in this study compare with the typical exposure levels when using personal care products, e.g. in the form of an air freshener or when applying a scented lotion. Testing different exposure levels of these aroma compounds over the course of varying time periods can help identify maximum dosage levels with efficacious results. Moreover, this may be further investigated for potential use of aromatherapy treatments in pharmaceutical applications, possibly as an alternative treatment for anti-anxiety and panic disorders with the prospect of less side effects.

To further support the sedative and calming effects of lavender, Diego et. al. conducted a study to examine aromatherapy effects on feelings of relaxation, anxiety, mood and alertness as well as the impact on electroencephalogram (EEG) activity and math computations. In this study, two odorants were examined: lavender, as a calming odorant, and rosemary, as an alerting odorant. EEG alpha and beta power was assessed where an increase in frontal alpha and beta bands suggests increased relaxation; in contrast, a decrease in alpha and beta bands suggests greater alertness and theoretically should translate to better performance executing a cognitive task. ⁸⁷

In order to obtain baselines, EEG readings were conducted and subjects were asked to complete the State-Trait Anxiety Inventory (STAI), the Profile of Mood States (POMS), the tense/relaxed and drowsy/alert visual analog mood scales, and the math computations. ⁸⁷ The STAI is a self-reported instrument designed to assess levels of state anxiety and trait anxiety through 40 items scored by a likert-scale, which is used to allow the individual to express how much they agree or disagree with a particular statement. State anxiety can be defined as a transient momentary emotional status that results from situational stress, whereas trait anxiety represents a predisposition to react with anxiety in stressful situations. All items are rated in terms of severity with 1 representing“not so much” and 4 representing“very much”. A summary score is obtained by adding the weight of each item where higher scores indicate greater anxiety. ⁸⁷ · ⁸⁸ STAI was originally developed as a research instrument to study anxiety in normal adult population samples, though it can also be used to screen for anxiety disorders as well as different types of patients (e.g. working adults vs. students under high stress). ⁸⁹ Once baselines were obtained, subjects were presented with a cotton swap which contained either three drops of lavender essential oil or rosemary essential oil, both diluted to a 10% concentration in grapeseed oil. Subjects were then instructed to hold the swap three inches from their nose for three minutes and breathe normally through their noses while sitting quietly with their eyes closed. Assessments were repeated and compared to the baseline data. The research findings support that lavender has a calming effect as the subjects in the lavender group reported feeling drowsy and more relaxed, also noting the frontal alpha and beta power significantly increased. This data supports earlier findings on lavender’s ability to promote drowsiness and induce sleep. In contrast, the subjects in the rosemary group had decreased frontal alpha power suggesting increased alertness. ⁸⁷

Anti-microbial

Cinnamon is a multifaceted plant that is used worldwide not only for cooking but also in traditional and modern medicines. Mainly used in the aroma and essence industries due to its fragrance, the bark of various cinnamon species contains vital oils and other derivatives such as cinnamaldehyde, cinnamic acid and cinnamate which contribute to the fragrance as well as various biological activities. ⁹⁰ Studies have shown the cinnamaldehyde component in cinnamon oil has antimicrobial activity, inhibiting the growth of organisms such as Escherichia coli (E. coli), Listeria innocua (L. innocua), and Salmonella typhimurium (S. iyphimurium), among others. ⁹¹ · ⁹² Cinnamaldehyde has been found to cause structural alterations to the outer envelope in E. coli as it penetrates the periplasm, and to the cell interior of the gram-negative bacteria through membrane-traversing porin proteins. ⁹² · ⁹³ However, the antimicrobial activity of cinnamaldehyde affect S. typhimurium both internally and externally where penetration of the cell envelope causes internal cellular damage and leads to excessive loss of viability. ⁹³

A study conducted by Nuryastuti et. al. investigated the effect of cinnamon oil on biofilm formation by Staphylococcus epidermidis (S. epidermidis) ⁹⁴ S. epidermidis is notorious for its biofilm formation on medical devices, where novel approaches to prevent and kill S. epidermidis biofilms are desired. Data from this study demonstrates that cinnamaldehyde, one of the main components in cinnamon oil, has potent antibacterial activity. High and intermediate biofilm producing strains of S. epidermidis were exposed to 1% cinnamon oil and 2% cinnamon oil. As shown in Figure 9A, the high biofilm producing strains with 24-hour exposure to 1% cinnamon oil did not result in the complete loss of biofilm forming capacity but showed 20 to 30% residual metabolic activity. Whereas in Figure 9B, 24-hour exposure to 2% cinnamon oil resulted in complete disappearance of metabolic activity. ⁹⁴ Figure 9: Effect of cinnamon oil exposure on metabolic activity of S. epidermidis biofilms after lh, 3h, and 24h of exposure

Furthermore, additional Figure 9A experiments Figure 9B indicated

cinnamon oil had synergistic activity with other antimicrobial agents such as triclosan, gentamicin and chlorhexidine against clinical S. epidermidis isolates. ⁹⁴ The synergism between an essential oil and an antimicrobial agent may be due to their action on either different or similar targets of bacterial cells (i.e. cell membranes). As previously mentioned,

cinnamaldehyde acts on plasma membranes, similarly to chlorhexidine as it inhibits the same target. Conversely, gentamicin inhibits protein synthesis while triclosan inhibits a specific metabolic pathway required for fatty acid synthesis in bacteria, as they impact different targets. Overall, cinnamon oil was able to inhibit biofilm formation, detaching existing biofilms and kill bacteria in biofilms of clinical S. epidermidis strains. ⁹⁴ Understanding the complex mode of action of cinnamon oil and its components against biofilms of S. epidermidis as well as other clinically relevant microbes may be key to creating new approaches to preventing and killing biofilms. Further investigation may lead to more innovative ways to use cinnamon oil in the applications of consumer products, potentially in the areas of oral health care and acne. Antiemetic

Ginger, the rhizome of Zingiber officinalis, has a long history of medicinal use, commonly as an antiemetic. As a member of the same plant family which includes cardamom and turmeric, ginger is known for its pungent and warming aroma which is the result of volatile pungent ketones, such as gingerols and shogaols, among others. ⁹⁵ · ⁹⁶ Previous studies have been conducted to gain a deeper understanding of the effects of Zingiber officinalis on nausea and vomiting, often in the cases of induced emesis via pregnancy, chemotherapy and following surgery. Recent animal models and in vitro studies have demonstrated that several components of ginger such as 6-gingerol, 6-shogaol and galanolactone have antiserotoninergic and 5-HT3 receptor antagonist effects which play a role in the etiology of emesis. ⁹⁷

In case of chemotherapy patients, chemotherapy agents release large amounts of serotonin from enterochromaffin cells in the small intestine where these cells aid in the production of gastric acid. The release of serotonin stimulates vagal afferent nerves (via the 5- HT3 receptors) and this action initiates the vomiting reflex. The 5-HT3 receptor antagonists suppress nausea and vomiting by inhibiting serotonin from binding to the 5-HT3 receptors and sensitizing the vagal afferent nerves. ⁹⁷ Therefore, it can be concluded that the antiserotoninergic and 5-HT3 receptor antagonist effects of 6-gingerol, 6-shogaol and galanolactone may be directly related to the antiemetic effects of ginger. Due to its widespread availability, low cost and great tolerability profile, ginger alone, or as a component of an antiemetic regimen can be an alternative option to treat nausea and vomiting.

In 2015, Lua et. al. conducted a study to assess the efficacy of inhaled ginger as a form of aromatherapy on nausea and vomiting in chemotherapy breast cancer patients. ⁹⁸ A single-blind, controlled, randomized cross-over study was performed, where patients received 5-day aromatherapy treatment using either ginger essential oil, or fragrance-matched artificial placebo which was instilled in a necklace and worn by the patients. Frequency of vomiting was measured, as well as the severity of nausea as indicated on a visual analog scale (VAS), with the left end corresponding to“no nausea” and the right to“severe nausea”. When reviewing the data, the only statistically significant information were the differences in the VAS nausea score between the two treatment groups on Day-l (p=0.040). Overall, it was concluded that the data obtained from this study was not sufficient to support the hypothesis that inhaled ginger aromatherapy is an effective therapy for chemotherapy-induced nausea and vomiting. ⁹⁸ For future studies, I believe the it would be valuable to understand how the specific components of ginger interact with olfactory receptors, especially since certain odors can trigger vomiting and nausea in chemotherapy patients as well as pregnant women. There may be a similar connection associated with trigeminal sensations (e.g. cooling benefits of menthol), as ginger has a known warming effect which could be linked to its potential soothing effects.

Analgesic

Pain relief can be achieved by a variety of methods, with drug use being the basis of analgesic treatment. Analgesics are sometimes referred to as painkiller medications where analgesic agents reduce neurosensory sensations, such as pain, itch, sting and burning without resulting in the loss of consciousness. ⁹⁹ · ¹⁰⁰ There are many different types of analgesic medications available in prescription and over-the-counter preparations. Since many of these compounds have undesirable side effects, there is a greater interest in natural compounds such as herbal remedies which have been used for centuries to reduce pain. ¹⁰¹

Menthol is a naturally organic compound of plant origin present in the volatile oil of several species of mint plants such as peppermint (Mentha piperita), and cornmint (Mentha arvensis) ¹⁰² Known for its fresh and herbaceous smell and flavor, this compound is also known for its cooling sensation and is widely used in a number of products including toothpaste, cough drops, mouthwash, chewing gum, and topical analgesics. As an aromatic substance, menthol’s peppermint smell causes a cooling sensation when applied topically to the skin or to mucous membranes as it enters the nasal passageway. However, cooling effects of menthol are not caused by its rapid evaporation from the surface as it was previously assumed, but rather through the effect of menthol on thermosensitive nerve endings via the TRPM8 (transient receptor potential melastatin) channel, as the receptor for menthol and mild cold are identical. ¹⁰³ Upon activation of the TRPM8 channel, Na ⁺ and Ca ²⁺ ions enter the cell which leads to depolarization and the generation of an action potential. The signal conducted eventually leads to the sensation of cold and cold pain as this channel is the primary transducer of cold somatosensation in humans. ¹⁰⁴ Cells expressing TRPM8 have demonstrated increased intracellular calcium levels when exposed to cold or menthol. Central nervous system mechanisms have been described where stimulation of cold fibres inhibits conduction on nociceptive pathways. Nociceptors are the sensory nervous system’s response to certain harmful or potentially harmful stimuli. ¹⁰⁵ Menthol’s ability to affect the cellular influx of calcium ions and ultimately desensitize the

nociceptors suggests this is the mechanism of its therapeutic analgesic activity. ¹⁰⁶

Galeotti et. al. conducted a study to explore the potential antinociceptive effects of

menthol. ¹⁰² An analgesic test was used to investigate the optical isomers, (-)-menthol (the main form occurring in nature), and (+)-menthol, in which a thermal (hot plate) stimulus was applied to mice. For the hot plate test, the mice were placed inside a stainless steel container, which was thermostatically at 52.5 +/- 0.1 °C in a water bath. The mice were administered menthol orally

(p.o.) and the reaction times of the mice were measured before and 15, 30, 45 and 60 minutes after administration. The endpoint used was the licking of the fore or hind paws as this behavior is observed as a way to relieve discomfort. Figure

Figure 10: Effect of (-)-menthol and (+)-menthol in 10 displays the effects of (-)-menthol and (+)- the mouse hot-plate test

menthol in the mice at varying levels using the hot

plate method. ¹⁰² Licking latency behavior of the mice was measured over time, using saline as the control. The doses are expressed as mg kg p.o., each point representing a mean of at least 10 mice. As a result of the hot plate test, (-)-

threshold, whereas (+)-menthol was completely

devoid of any analgesic effect. ¹⁰²

Studies evaluating menthol in topical applications have also provided further evidence of its analgesic activity. Liu et. al. compared the analgesic effects of L-menthol (also known as (-)- menthol) in wildtype and TRPM8-deficient (TRPM8 ^_/ ) mice in models of acute cutaneous, visceral, and inflammatory pain. ¹⁰⁷ The data confirmed L-menthol efficiently inhibited pain behavior induced by chemical stimuli (capsaicin, acrolein and acetic acid), as well as physical stimuli using the hot plate method. Reviewing data from the Galeotti et. al. study (oral

Figure 11: Paw withdrawal latencies of wild-type and TRPM8 mice in the hot plate test after topical application of 30% L-menthol and ethanol (Veh)

administration), and from the Liu et. al. study (topical administration) using the same hot plate method, there were comparable results. Paw withdrawal latencies of the wild-type mice and TRPM8 ^_/ mice were observed after topical administration of 30% L-menthol and ethanol (vehicle). The two hind paws were immersed into either the L-menthol or ethanol for five seconds and allowed to dry for 1 minute (n=7-9 mice per group). The data in Figure 11 shows topical application of menthol to the mouse paws produced a strong analgesic effect in the wild- type mice that was abolished in TRPM8 ^_/ mice. ¹⁰⁷

Overall, the analgesic effects of menthol were completely eliminated in TRPM8 ^_/ mice in all the models studied. Therefore, the genetic deletion of TRPM8 completely eliminated the analgesic effects by L-menthol, further suggesting that TRPM8 is the principal mediator of menthol’s analgesic effects in vivo. ¹⁰⁷

Future Direction

The olfactory system is a highly complex sensory network in which certain aspects of functionality and its impact on mood, development and behavior are still unclear. One area of research that needs further evaluation is quantitatively mapping odors and fragrances. Just as colors are mapped using hue, brightness and saturation, being able to map odor compounds could help isolate particular components within a fragrance which may be providing additional functional benefits.

Emotion is a broad concept that is not well defined in traditional psychology, making the selection of appropriate tasks to quantify emotion difficult. Future research could further explore the limits of the influence of odor and emotion on semantic memory. The use of fMRI or other brain images could help researchers to better understand how odors are processed, the biological routes taken, and how they differ between autobiographical and semantic memory. Additionally, getting a deeper understanding of how odors influence memory retrieval mechanisms.

Lastly, a potential opportunity for future areas of research may include exploring factors that influence how individuals perceive and respond to chemosensory irritants, and how different irritants interact. Furthermore, fragrance ingredients that evoke trigeminal sensations could be further expanded, discovering ways to incorporate them into new products or create new product forms to deliver a superior multisensorial consumer experience.

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