Chemical View ...... 7 Botanical Family ...... 8 Latin Name and Common Name ...... 8 Chemical Families ...... 8 Chemical Components ...... 8 Chemical Structures ...... 11 Therapeutic Benefits of the main components ...... 11 Natural sources of beta caryophyllene ...... 12 Contraindications ...... 12

Application & Sources of Copaiba ...... 13 Therapeutic Uses ...... 13 Application Methods ...... 15 Recipes ...... 15

Interesting Facts ...... 16 Cannabinoids, Cannabis, and Caryophyllene ...... 16 Price Comparisons ...... 18 Further Studies of Copaiba & β-caryophyllene ...... 19

Resources for this paper ...... 23

Introduction

The essential oil community has heard a lot about the beautiful benefits of Cannaboid in Hemp Oil. There have been many studies and success stories but we have rarely heard about the fantastic chemical constituent β-caryophyllene. The subject of rheumatism and arthritis has been an important focus for me since I started studying essential oils because my mother has suffered from these conditions for many years.

My initial research brought me to many existing case studies, which seemed promising and led me to research and choose the Copaiba Oil, and especially the chemical component β- caryophyllene . This video is a small introduction of the oil from doTERRA at one of their Global Conventions in 2017. Dr. Hill introduced doTERRA’s new oil: https://youtu.be/vI8- TbcfY_M. As you will see further down below, I have found a few sources for Copaiba Balsam which a few of them are very promising such as the “Rainforest Chica” company.

While beta-caryophyllene is primarily known for its presence in the essential oils extracted from Black Pepper, Clove, Melissa, and Rosemary, the best source is actually the lesser- known Copaiba tree. GC-MS assessments have shown that many sources of Copaiba essential oil contains more than 50% and often up to 70% of beta-caryophyllene, and not surprisingly, the properties of the oil extracted from the oleoresin of Copaifera species is becoming a popular topic of research. There have been over 70 peer-reviewed studies published in scientific journals in the last few years evaluating the benefits of Copaiba, several of which focus on its CB2-binding properties and the associated health benefits. [7]

R. Tisserand said: “Did you know that copaiba essential oil can make your skin happy?

Copaiba essential oil and oleoresin contain large amounts of beta-caryophyllene, a molecule that interacts with cannabinoid receptors in your skin. This causes skin cells to produce beta-endorphin, one of the happiness hormones. [23]

Due to the Chemical make up of β-caryophyllene, α-copaene, and α-humulene it has gained a large interest and fairly large amount of scientific studies.

COPAIBA

Copaiba Tree 1

Copaiba Tree & History

Copaiba is pronounced “Co-Pah-Ee-Bah”. Copaifera species (Leguminoseae) are popularly known as “copaiba” or “copaíva“, which grow mainly in the states of Amazonas, Pará and Ceará in Northern of Brazil. Copaiba balsam is a sap-like substance (oleoresin) collected from the trunk of trees that belong to the Copaifera species. The tree can reach 5 to 40 meters in height and can live up to 400 years. Copaiba balsam is processed to make copaiba oil. Both copaiba balsam and copaiba oil are used to make medicine. The oleoresins obtained from the trunk of Copaifera species have been extensively used in folk medicine as an anti- inflammatory, anticancer, antioxidant, antihelmintic, repellent of insect, antimicrobial, antiulcer, antitetanus, urinary antiseptic, as well as to treat gonorrhea, syphilis, bronchitis, skin diseases and wounds. Veiga et al. reported the chemical composition and anti-inflammatory activity of copaiba oils from three copaiba species. Copaiba oleoresins are largely used in alternative medicine, as a dietary supplement, in the production of flavoring agents, food additives, and it is extensively commercialized in Brazil as crude oil and in

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com several pharmaceutical and cosmetic products, such as capsules, shampoos, soaps, capillary lotions and bathing foams. [1]

Copaiba oil-resins extracted have been used medicinally dating back to the 16th century by the natives of north and northeastern Brazil. The folk remedies were administered orally or used as an ointment in the treatment of various diseases. [2]

Tribal and herbal medicine uses

On the Rio Solimoes in northwest Amazonia, copaiba resin is used topically by indigenous tribes as a wound healer, to stop bleeding, for skin sores and psoriasis, and to treat gonorrhea. Healers and curanderos in the Amazon today use copaiba resin for all types of pain, skin disorders and insect bites, and to cool inflammation.

In Brazilian herbal medicine systems the resin is used as a strong antiseptic and expectorant for the respiratory tract (including bronchitis and sinusitis), as an anti- inflammatory and antiseptic for the urinary tract (for cystitis, bladder, and kidney infections), as a topical anti-inflammatory agent for all types of skin problems. Copaiba resin is sold in gel capsules in stores and pharmacies in Brazil and recommended for all types of internal inflammation, stomach ulcers and cancer. One of its more popular home-remedy uses in Brazil is as an antiseptic gargle for sore throats and tonsillitis (15 drops of resin in warm water). In Peruvian traditional medicine, three or four drops of the resin are mixed with a spoonful of honey and taken as a natural sore throat remedy. It is also employed in Peruvian herbal medicine systems to reduce inflammation and increase urination, and in the treatment of incontinence, urinary problems, stomach ulcers, syphilis, tetanus, bronchitis, catarrh, herpes, pleurisy, tuberculosis, hemorrhages, and leishmaniasis (applied as a plaster).

Copaiba resin was first recorded in European medicine in 1625 (brought back from the New World by the Jesuits (called Jesuit's balsam) and has been used there since in the treatment of chronic cystitis, bronchitis, chronic diarrhea, and as a topical preparation for hemorrhoids. In the United States, it was an official drug in the U. S. Pharmacopeia from 1820 to 1910. Noted ethnobotanist and author Mark Plotkin reports that copaiba oil has been used in the United States as a disinfectant, diuretic, laxative, and stimulant-in addition to being used in cosmetics and soaps. The Encyclopedia of Common Natural Ingredients cites that copaiba has diuretic, antibacterial, anti-inflammatory, expectorant, disinfectant, and stimulant activities. [3]

Copaiba Species

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com Variation in chemical composition is common among different species and even among individual trees (Cascon & Gilbert 2000). For example, resin oils from C. reticulata collected in Acre and Pará showed differences in activity against bacteria because of differences in chemical composition. [5]

• Copaifera epunctata • Copaifera guyanensis • Copaifera langsdorffii - Diesel Tree, Kerosene Tree, Kupa'y, Cabismo, Copaúva • Copaifera martii • Copaifera multijuga • Copaifera officinalis • Copaifera panamensis - Cabimo • Copaifera reticulata • Copaifera salikounda • Copaifera trapezifolia • Copaifera cearensis • Copaifera jacquinii • Copaifera coriacea [9]

The main species are: officinalis, langsdorffii, reticulata [3]

Countries of Origin and Region

There are 35 species of Copaifera, found mainly in tropical South America (particularly in Brazil, Argentina, Bolivia, Guyana, Colombia, Peru, and Venezuela). Several different species are used as traditional medicines interchangeably: C. langsdorffii is found mostly in the cerrados of central Brazil, C. reticulata is indigenous to the Amazon region, and C. officinalis occurs widely throughout South America, including the Amazon. All three varieties are used interchangeably. [3]

HARVESTING

Extraction Method

Oleoresin: Here is an example of retrieving 100ml of Copaifera langdsdorffii The sample was collected by perforating the trunk of the plant about 1 m above the soil level, by using a metal auger measuring 2.0 cm diameter and 1.5 m of length. After reaching the center of the trunk, the auger was removed, a 100 mL aliquot of the crude oleoresin was collected in a glass flask, and the hole was properly sealed. [11]

There are not many true oleoresins available on the market.

Steam Distilled: Through the process of steam distillation, the essential oil is extracted from the resin. Copaiba Essential oil is clear white.

Sustainability

There is a fear that the precious Copaiba tree is being over harvested due to the furniture and wood making industry. One of the current projects in Peru, Iquitos, is to retrieve the resin sustainably from the Copaiba tree through the careful and considerate harvesting of the resin, the Matsés can realize a sustainable income stream that lessens their dependency on external aid or the lure of the petroleum or gold industries. [15]

The reasons for using the oleoresin in aromatherapy are that it does less damage to the trees than distilling the essential oil, and that it contains more therapeutic compounds - these diterpenic acids - than the distilled oil. [12] Do use copaiba oleoresin in preference to the distilled oil, as it is more environmentally friendly – no trees or branches are cut down. The oleoresin is also more useful in healing due to its content of diterpenes such as kaurene, not found in the distilled oil. You can use Copaiba oleoresin just like any other viscous essential oil. It is similar in consistency to sandalwood oil. [13]

The production of copaiba oleoresin was greater than 500 tons in 2008, considering only the production from three states in the Amazon region, the Amazonas state being responsible for more than 90% of the production. There is an intense

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com commercialization of it as crude oil, capsules, ointments and soaps among others in Brazil, as well as exports to England, France, Germany and United States. [1]

Plant Parts used, Color and Aroma

Copaiba (and all of its species) has a very distinct balsamic, subtle, mild & sweet aroma.

There are two versions of Copaiba. One is the Oleoresin and the other one is the steam distilled Copaiba Essential Oil. For the Oleoresin the tree is tapped. The other method is to use branches and leaves.

Copaiba is a stimulant oleoresin obtained from the trunk of several pinnate-leaved South American leguminous trees (genus Copaifera). The thick, transparent exudate varies in color from light gold to dark brown, depending on the ratio of resin to essential oil.

The balsam may be steam distilled to give copaiba oil, a colorless to light yellow liquid with the characteristic odor of the balsam and an aromatic, slightly bitter, pungent taste. The oil consists primarily of sesquiterpene hydrocarbons; its main component is caryophyllene. [14]

CHEMICAL VIEW POINT

Copaiba Flower Part [10]

Fabaceae

Latin Name and Common Name

Latin Name Common Name Copaifera coriacea Sapucaia tree Copaifera guyanensis Hoepel, Guyanense Copaiba Copaifera langsdorffii Copaiba, Langsdorf's copaifera Copaifera multijuga Hayne oil, Copaiba Copaifera officinalis Copaiba Balsam, Medicinal Copaiba

Chemical Families

Sesquiterpenes Diterpenes Terpenic acids

The resin contains up to 15% volatile oil; the remaining materials are resins and acids. The active biological properties of copaiba resin are attributed to a group of phytochemicals called sesquiterpenes (over 50% of the resin may be sesquiterpenes), diterpenes, and terpenic acids. [3]

Chemical Components

Several of the chemicals of copaiba are novel ones and only found in copaiba. Copaiba resin is the highest known natural source of caryophyllene, comprising up to 480,000 parts per million. Caryophyllene is a well known plant chemical which has been documented to have strong anti-inflammatory effects (among other actions). [3]

Chemicals listed in detail found in copaiba: alloaromadendrene, alpha- bergamotene, alpha-cubebene, alpha-multijugenol, alpha-selinene, ar-curcumene, beta-bisabolene, beta-cubebene, beta-elemene, beta-farnesene, beta-humulene, beta-muurolene, beta-selinene, calamenene, calamesene, carioazulene, caryophyllenes, coipaiferic acid, copaene, copaiferolic acid, copalic acid, copaibic acids, cyperene, delta-cadinene, delta-elemene, enantio-agathic acid, gamma- cadinene, gamma-elemene, gamma-humulene, hardwickic acids, illurinic acid, kaurenoic acids, kaurenic acid, kolavenol 1, maracaibobalsam, methlyl copalate, paracopaibic acids, polyalthic acid, and trans-alpha-bergamotene.

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com The exclusive terpenoid composition of copaiba oils is evidenced by around 72 different types of sesquiterpenes and diterpenes already identified in 27 different species of copaiba oils. Kaurenoic, kovalenic, hardwickiic, polyalthic, and copalic acids are the major diterpenes, while β-caryophyllene, α-copaene, zingiberene, β- bisabolene, and bergamotene are the major sesquiterpenes reported in the oils.

For the sake of looking at a comparison of different test results I have added the below test round carried out by Deivid C. Soares et al. for a Antileishmanial study. (For the full study paper please go to the following website: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705974/)

In the test images below (Table 1) it shows in detail the main chemical components. Commercial samples of copaiba oils C1, C2, and C3 were donated by a cooperative from Acre state (Brazil) and were collected between 1999 and 2000. Samples C1, C2 and C3 originated from the Tarauacá region situated in Acre. Sample C4 was collected in Baía do Portel, PA, Brazil, and donated by an oil extractive company. After receipt, all the samples were transferred and kept in amber glass bottles at 20–22°C. The chemical profiles of the samples were assessed periodically by gas chromatography and shown to remain unchanged. Even though the Copaiba oil came from the same region (C1, C2 and C3) they had quiet a big variety in results. Especially for the β-caryophyllene and the α- humulene. [4]

The three main components shown in Table 1 are β-caryophyllene, trans-α- bergamotene, and β-bisabolene.

Copaifera oleoresins are composed of a high amount of hydrocarbon sesquiterpenes. The main constituent is β-caryophyllene, which is found as one of the most abundant sesquiterpene in copaiba oleoresins and appears to be ubiquitous in angiosperms. β-Caryophyllene is a bi-cyclic hydrocarbon sesquiterpene that occurs in essential oils of several plants, including Piper nigrum L. (Piperaceae), Baccharis spp. (Asteraceae) and Copaifera spp. (Leguminoseae). A variety of biological activities, including anti-carcinogenic, anti-inflammatory, and antioxidant have been related to this hydrocarbon sesquiterpene. Moreover, due to its woody and spicy odor, β-caryophyllene is commonly used as a flavoring agent. [1]

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com Table 1 (detailed view of the chemical family sesquiterpenes) [4]

Chemical Structures

In Table 3 the chemical structures of: 1: α-copaene, 2: β-caryophyllene, and 3: α-humulene are shown. [16]

Table 3 - Chemical Structures [16]

Therapeutic Benefits of the main component

Beta-Caryophyllene There is a breadth of research that suggests terpenoid compounds found in many essential oils can have a vast influence on these receptors, but the research is particularly strong in regards to one specific sesquiterpene. Recent research has demonstrated that the bicyclic sesquiterpene beta-caryophyllene has the ability to bind to CB2 receptors. What this means is that along with its cellular and skin- health supporting properties, due to its activation of CB2 receptors, beta- caryophyllene may also support healthy nervous and immune function, and have similar soothing and relaxing properties on the body (similar to that prompted by CB1 activation), without the potential psychoactive side effects.

Natural sources of caryophyllene

Below is a beautiful quick percentage comparison between the different oils, which contain caryophyllene. Copaiba is bar far ahead of the content of caryophyllene, followed by Cannabis. The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]): • Cannabis, hemp, marijuana (Cannabis sativa) [3.8–37.5% of cannabis flower essential oil][12] [13] • Black caraway (Carum nigrum) [7.8%] [3] [14] • Cloves (Syzygium aromaticum) [1.7–19,5% of clove bud essential oil] [15] [16] • Hops (Humulus lupulus) [5.1–14.5%] [17] • Basil (Ocimum spp.) [5.3–10.5% O. gratissimum; 4.0–19.8% O. micranthum][18] [19] [20][21] • Oregano (Origanum vulgare) [4.9–15.7%] [7] • Black pepper (Piper nigrum) [7.29%] [22][23] • Lavender (Lavandula angustifolia) [4.62–7.55% of lavender oil] [4] [24] • Rosemary (Rosmarinus officinalis) [0.1–8.3%] [25] • True cinnamon (Cinnamomum zeylanicum) [6.9–11.1%] [26] • Malabathrum (Cinnamomum tamala) [25.3%] • Ylang-ylang (Cananga odorata) [3.1–10.7%] [8]

• Copaiba oil (Copaifera spp.) [30-81%]

Contraindications

Tisserand and Young do not indicate any special precautions when using Copaiba Balsam. However, reading Tisserand and Young's full profile is recommended. [17]

Do not take any oils internally and do not apply undiluted essential oils, absolutes, CO2s or other concentrated essences onto the skin without advanced essential oil knowledge or consultation from a qualified aromatherapy practitioner. If you are pregnant, epileptic, have liver damage, have cancer, or have any other medical problem, use oils only under the proper guidance of a qualified aromatherapy practitioner. Use extreme caution when using oils with children. It is safest to consult a qualified aromatherapy practitioner before using oils with children. For in-depth information on oil safety issues, read Essential Oil Safety by Robert Tisserand and Rodney Young.

Therapeutic Uses

Copaiba Balsam contains a very high amount of sesquiterpenes. It is a very powerful anti-inflammatory. It also shows anti-bacterial and antimicrobial properties.

Jane Buckle cites a study that indicates that Copaiba Balsam shows promise in assisting with acne. [Jane Buckle, PhD, RN, Clinical Aromatherapy: Essential Oils in Healthcare, Edition 3 (London, UK: Elsevier, 2015), 272.]

Julie Lawless cites these additional possible uses: bronchitis, colds, stress, and perfumery fixative. [Julia Lawless, The Illustrated Encyclopedia of Essential Oils (Rockport, MA: Element Books, 1995), 126.] [18]

Next to being an incredible anti-inflammatory, scientists have also found additional potential benefits:

• Neuroprotective Benefits • Anti-Proliferative Properties • Anti-tumoral Effects • Psoriasis Improvement • Natural Pain Reliever • Wound and Scar Healing

Potent Anti-Inflammatory

The most plentiful phytochemical (plant-based chemical) in copaiba is beta-caryophyllene. The presence of this phytochemical is what gives copaiba its anti-inflammatory action. There are many research papers indicating the anti-inflammatory benefits of copaiba. Cancer is an inflammatory process in the body, so any natural compound that can arrest or slow this process becomes a welcome ally. Copaiba’s natural anti-inflammatory properties means that it may reduce the inflammatory processes by which cancer can spread.

Neuroprotective Benefits

One interesting study reported in 2012 found that not only was copaiba a potent anti-inflammatory, it also had neuroprotective properties. For those undergoing chemotherapy, copaiba may offer some protection to the nervous system and brain, which are often damaged by such drugs.

Anti-Proliferative Properties

Copaiba has been noted to have anti-proliferative activity. This means that it can prevent the spread of malignant cells into surrounding tissue. Research reported in December 2015 Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com acknowledged that copaiba was indeed a potent anti-bacterial. But interestingly, the researchers also found it was able to kill MCF-7 breast cancer cells (these are estrogen receptor positive and progesterone receptor positive, infiltrating ductal carcinoma cells) better than doxorubicin (also known as Adriamycin or the “Red Devil”), a much-utilized chemotherapy drug for breast cancer.

Anti-tumoral Effects

A small animal study reported in September 2015 showed that beta-caryophyllene potently inhibited the growth of solid tumors and lymph node metastasis (spread) in mice with melanoma. An older study released in December 2007 revealed that beta-caryophyllene significantly increased anti-cancer activity against several cancer cell lines, including the aforementioned MCF-7 cells. In fact, researchers stated that “beta-caryophyllene potentiated [increased the effect of] the anticancer activity of paclitaxel,” a chemotherapy drug favored by many oncologists. The combination of beta-caryophyllene and paclitaxel increased the activity of paclitaxel by about ten-fold, helping it work better.

Psoriasis Improvement

A small clinical trial released in January 2013 indicated copaiba oleoresin reduced the pro-inflammatory cytokines associated with chronic psoriasis. Researchers noted “a significant improvement in the typical signs of this disease, i.e. erythema, skin thickness, and scaliness.”

Natural Pain Reliever

An animal study released in July 2014 revealed that beta-caryophyllene significantly decreased pain. It had a long-term effect and no side effects, especially when used together with DHA (docosahexaenoic acid), a common fatty acid found in fish oils and flaxseed oil. Indeed, South American natives have been using copaiba for pain relief for centuries.

Wound and Scar Healing

A study published in January 2016 showed that copaiba demonstrated antibacterial activity against Staphylococcus aureus (also known as Golden staph). This is one of the most difficult and drug-resistant bacteria, currently rife in hospitals. Researchers noted “even low concentrations of Copaiba oil effectively inhibited Staphylococcus aureus growth, supporting its potential use as a promising adjuvant in compounded topical formulations for wound and scar healing.” [19]

Application Methods

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com Applied topically, Inhaled, and applied directly to skin for wound healing purposes.

Copaiba blends well with: Benzoin, Black Pepper, Cajuput, Cardamom, Chamomile (German and Roman), Coriander Seed, Elemi, Eucalyptus Radiata, Geranium, Ginger, Hyssop Decumbens, Juniper Berry, Lavender, Lemon, Manuka, Myrtle, Niaouli, Ravensara, Thyme linalool, Turmeric

Recipes

SORE MUSCLE BATH SALTS: Combine: 1 drop of Copaiba, 1 drop of Peppermint and 3 drops of Frankincense with 1 tablespoon of Jojoba oil and 1/2 cup of Epsom salts. Stir together and add to running bath water for a relaxing soak.

LINIMENT: Add the following to a 2 ounce bottle: 10 drops of Copaiba, 5 drops of Peppermint and 5 drops of Frankincense (Serrata), then fill with Avocado oil. (1.7% dilution)

FIRST AID: In a 1 ounce bottle add: 11 drops of Copaiba, 2 drops of Helichrysum and 3 drops of Lavender with 1 ounce aloe vera gel. Apply 2-3 times a day or as needed to assist the body's natural process of healing. Shelf life: 1 week (2.7% dilution) [20]

BALSAMIC ANXIETY BLEND: 5 drops of Orange Sweet Oil, 5 drops of Frankincense Oil, 5 drops of Balsam Copaiba Oil, 1 Blank Inhalers – Directions: Blend the essential oils together and drop on a cotton wick inside a blank inhaler. Inhale as needed throughout the day.

INFLAMMATION: 5 drops of Helichrysum Bracteiferum Oil, 3 drops of Chamomile German Oil (Nepal), 5 drops of Balsam Poplar Oil, 5 drops of Balsam Copaiba Oil, 2 oz. of Lotion – Unscented. Directions: Add the essential oils to 2 oz. of unscented lotion and apply to the inflamed area. You may also use trauma oil as a carrier. [21]

Interesting Facts

Cannabinoids, Cannabis, and Caryophyllens

This text below has ben written by Dr. Cody Beaumont, PhD:

It has come to my attention that there has been a lot of confusion recently surrounding the properties of cannabinoid compounds found in certain oils. Individuals with ties to the CBD oil industry would have you believe that beta- caryophyllene, a compound found in Copaiba oil and Black Pepper oil, is not a

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com cannabinoid. The same individuals would also have you believe that cannabidiol (CBD) oil never contains the psychoactive compound tetrahydrocannabinol (THC) or any of its isomers. This is not surprising, because both of these claims promote the CBD oil industry. Unfortunately, this misinformation has been perpetuated to the point that many people are convinced that it is accurate, despite strong evidence to the contrary.

I’ve prepared this article in hopes that I can set the facts straight. Having worked as a medicinal chemist for 15 years, I’ve learned a great deal about the chemical properties of all kinds of essential oils. I’ve even conducted my own chemical analyses of hemp, CBD, and cannabis oil in my lab at doTERRA. In this article, I will discuss the chemical properties of cannabinoid compounds found in the various cannabis oils and compare them with beta-caryophyllene. Beta-caryophyllene is the main compound found in Copaiba, doTERRA’s alternative to cannabis.

Beta-Caryophyllene is a Cannabinoid

There is a wealth of information available in the scientific literature regarding the classes of cannabinoid compounds and the receptors involved in the endocannabinoid system. For several years now, beta-caryophyllene has been known to be a cannabinoid. But don’t just take my word for it. Back in 2008, a study by J. Gertsch et al. rolled off the press with the unambiguous headline, “Beta- caryophyllene is a dietary cannabinoid.”1 The study was published in Proceedings of the National Academy of Sciences of the United States of America, a prestigious scientific journal. Since then, at least a dozen more papers have been published on the subject, reemphasizing the fact that beta-caryophyllene is a cannabinoid.2-13

By definition, a cannabinoid is any ligand, molecule, or class of molecules that acts on either or both of the currently identified cannabinoid receptors, CB1 and CB2. Interestingly, these two receptors produce significantly different physiological responses when activated. CB1 activation, caused by THC and other similar cannabinoids, results in a psychoactive drug high. On the other hand, CB2 activation by beta-caryophyllene (BCP) has produced results showing some promising therapeutic benefits. These include supporting a healthy inflammatory response, soothing discomfort, and positively affecting mood without the psychoactive side effects associated with other cannabinoids.2-4,10 It is true that the positive benefits associated with BCP have also been observed using other cannabinoids, such as THC, cannabidiol, and cannabinol, but using these compounds can also come with unwanted psychological effects, especially in the case of THC.

There are three distinct classes of cannabinoids: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Synthetic cannabinoids are found in certain pharmaceutical products designed to help with glaucoma, appetite stimulation, antiemetics, and other disease-linked targets. Endocannabinoids, on the other hand, are produced naturally by the body. These molecules are mainly composed of amines and amides. Endocannabinoids are pharmacologically similar to some phytocannabinoids, but vary greatly in their chemical structure. This gives different endocannabinoids the ability to produce different neurological responses, even when administered in similar therapeutic doses. The primary function of endocannabinoids is to modulate normal physiological functions.

The last class of cannabinoids is known as the phytocannabinoids. These are molecules that are produced by plants such as Cannabis and Copaifera. The Cannabis species produces the commonly known molecules THC and CBD, while the Copaifera plant family produces only BCP. Although BCP differs significantly from other cannabinoids in its structure, it nonetheless reacts selectively with the CB2 receptor, thus defining it as a cannabinoid.2 However, it is chemically distinct from other cannabinoids, which is why it cannot cause a positive result on a drug test. BCP is classified as a sesquiterpene based on its chemical structure and makeup. Research on BCP is ongoing and will continue to add to our understanding of its potential value.

Cannabidiol (CBD) oil can contain the psychoactive tetrahydrocannabinol (THC)

To be legally marketable, CBD oil is not supposed to contain any discernable amount of THC.14 However, our own internal investigation involving analytical testing and evaluation has found that various CBD oils on the market do contain significant levels of THC and therefore could very likely trigger a psychoactive response and/or positive drug test. Our evaluation has also shown that commonly purchased brands of CBD oil can vary greatly in their claimed CBD content. In fact, in some samples we were not able to identify the presence of any CBD at all. In contrast, my analyses have shown that doTERRA oils are 100% free of THC, and oil compositions are consistent between batches.

Conclusion In summary, this article is not intended to be a complete picture of the benefits of beta-caryophyllene nor an outline of the properties of the endocannabinoid system. Rather, it is a statement of scientifically-accepted facts aimed to clear up the misleading information on the molecules in question. My hopes are that reading this article will help individuals in their personal research on cannabinoids and, most importantly, their decisions about which oils to use in their daily life. [22] Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com Price Comparison

Rainforest Chica OIL-RESIN of COPAÍBA - (Copaifera spp., Leguminosae – Caesalpinoideae) Extraction Method: cut in the trunk of the tree - sustainable extraction. Copaiba Oil - Resin 15ml - $ 7.50 https://rainforestchica.com/products/copaiba-oil-resin

Stillpoint Aromatics Country of Origin: Brazil Plant Parts: Gum/Resin Cultivation Method: Wild Harvested Method of Extraction: Steam or Hydro Distillation 15ml $22.50 (https://www.stillpointaromatics.com/balsam-copaiba-Copaifera-officinalis-essential- oil-aromatherapy)

Young Living: Copaiba (oleoresin) (Copaifera officinalis)† wood oil): 15ml Retail: $58.22 USD Wholesale: $44.25 USD (https://www.youngliving.com/en_US/products/copaiba-essential-oil)

Aromatics: Balsam Copaiba Oil (Copaifera officinalis) 15ml $12 Raw Resin (steam distilled) https://www.aromatics.com/products/balsam-copaiba-essential-oil

Oshadhi: Copaiba Balsam Copaifera officinalis (1280 - 10ml) is a pure therapeutic-quality aromatherapy essential oil produced using wild-crafted plants and traditional methods from Brazil, and is obtained from the resin. 10ml £9.99 (inc VAT) https://www.oshadhi.co.uk/copaiba-balsam-copaifera-officinalis/

Plant Therapy: Copaiba Oleoresin Organic Copaifera officinalis Tree Tapping 10ml $8.95 https://www.planttherapy.com/copaiba-oleoresin-organic?v=1830 doTERRA: Plant Part: Resin from Copaifera reticulata, officinalis, coriacea, and langsdorffii Extraction Method: Steam distillation

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com 15ml Retail: $46.67 Wholesale: $35.00 https://www.mydoterra.com

Further Copaiba Essential Oil studies

Copaiba Essential Oil

1. A. G. da Silva et al., “Application of the essential oil from copaiba (Copaifera langsdori Desf.) for acne vulgaris: a double-blind, placebo-controlled clinical trial,” Altern. Med. Rev. J. Clin. Ther., vol. 17, no. 1, pp. 69–75, Mar. 2012. 2. S. S. Dahham et al., “The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene β-Caryophyllene from the Essential Oil of Aquilaria crassna,” Mol. Basel Switz., vol. 20, no. 7, pp. 11808–11829, 2015. 3. B. Bayala et al., “Chemical Composition, Antioxidant, Anti-Inflammatory and Anti- Proliferative Activities of Essential Oils of Plants from Burkina Faso,” PLoS ONE, vol. 9, no. 3, p. e92122, Mar. 2014. 4. M. A. Abbas, M. O. Taha, M. A. Zihlif, and A. M. Disi, “β-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility,” Eur. J. Pharmacol., vol. 702, no. 1–3, pp. 12–19, Feb. 2013. 5. M. I. Campos, W. Vieira, C. Campos, F. Aarestrup, and B. Aarestrup, “Atorvastatin and trans caryophyllene for the prevention of leukopenia in an experimental chemotherapy model in Wistar rats,” Mol. Clin. Oncol., Apr. 2015. 6. D. Dias et al., “Copaiba Oil Suppresses Inflammatory Cytokines in Splenocytes of C57Bl/6 Mice Induced with Experimental Autoimmune Encephalomyelitis (EAE),” Molecules, vol. 19, no. 8, pp. 12814–12826, Aug. 2014. 7. C. Vilanovabr, S. Ribeirobr, R. Machadobr, S. Vieirabr, S. debrLimabr, and P. Martins, “Evaluation of oil-resin activity of Copaifera sp. on gastric emptying in Rattus<br>novergicus,” Emir. J. Food Agric., vol. 23, no. 1, p. 394, 2013. 8. Y.-T. Tung, M.-T. Chua, S.-Y. Wang, and S.-T. Chang, “Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs,” Bioresour. Technol., vol. 99, no. 9, pp. 3908–3913, Jun. 2008. 9. M. J. Chavan, P. S. Wakte, and D. B. Shinde, “Analgesic and anti-inflammatory activity of Caryophyllene oxide from Annona squamosa L. bark,” Phytomedicine Int. J. Phytother. Phytopharm., vol. 17, no. 2, pp. 149–151, Feb. 2010. 10. C. Ghelardini, N. Galeotti, L. Di Cesare Mannelli, G. Mazzanti, and A. Bartolini, “Local anaesthetic activity of beta-caryophyllene,” Farm. Soc. Chim. Ital. 1989, vol. 56, no. 5–7, pp. 387–389, Jul. 2001. 11. J. Y. Cho, H.-J. Chang, S.-K. Lee, H.-J. Kim, J.-K. Hwang, and H. S. Chun, “Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of beta-caryophyllene, a sesquiterpene,” Life Sci., vol. 80, no. 10, pp. 932–939, Feb. 2007.

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com 12. F. A. Pieri, M. C. M. Mussi, J. E. Fiorini, M. A. S. Moreira, and J. M. Schneedorf, “Bacteriostatic effect of copaiba oil (Copaifera officinalis) against Streptococcus mutans,” Braz. Dent. J., vol. 23, no. 1, pp. 36–38, 2012. 13. A. O. Santos, T. Ueda-Nakamura, B. P. Dias Filho, V. F. Veiga Junior, A. C. Pinto, and C. V. Nakamura, “Effect of Brazilian copaiba oils on Leishmania amazonensis,” J. Ethnopharmacol., vol. 120, no. 2, pp. 204–208, Nov. 2008. 14. E. S. Otaguiri et al., “Antibacterial combination of oleoresin from Copaifera multijuga Hayne and biogenic silver nanoparticles towards Streptococcus agalactiae,” Curr. Pharm. Biotechnol., Dec. 2016. 15. C. A. C. G. Simões, N. C. de O. Conde, G. N. Venâncio, P. S. L. L. Milério, M. F. C. L. Bandeira, and V. F. da Veiga Júnior, “Antibacterial Activity of Copaiba Oil Gel on Dental Biofilm,” Open Dent. J., vol. 10, pp. 188–195, May 2016. 16. L. a. F. Paiva et al., “Protective effect of Copaifera langsdorffii oleo-resin against acetic acid-induced colitis in rats,” J. Ethnopharmacol., vol. 93, no. 1, pp. 51–56, Jul. 2004. 17. A. Guimarães-Santos et al., “Copaiba Oil-Resin Treatment Is Neuroprotective and Reduces Neutrophil Recruitment and Microglia Activation after Motor Cortex Excitotoxic Injury,” Evid.-Based Complement. Altern. Med. ECAM, vol. 2012, 2012. 18. C. Kobayashi et al., “Pharmacological evaluation of Copaifera multijuga oil in rats,” Pharm. Biol., vol. 49, no. 3, pp. 306–313, Mar. 2011. 19. M. Curio, H. Jacone, J. Perrut, A. C. Pinto, V. F. V. Filho, and R. C. B. Silva, “Acute effect of Copaifera reticulata Ducke copaiba oil in rats tested in the elevated plus-maze: an ethological analysis,” J. Pharm. Pharmacol., vol. 61, no. 8, pp. 1105–1110, Aug. 2009. 20. N. de M. Gomes, C. M. de Rezende, S. P. Fontes, M. E. Matheus, A. da C. Pinto, and P. D. Fernandes, “Characterization of the antinociceptive and anti- inflammatory activities of fractions obtained from Copaifera multijuga Hayne,” J. Ethnopharmacol., vol. 128, no. 1, pp. 177–183, Mar. 2010. 21. N. M. Gomes, C. M. Rezende, S. P. Fontes, M. E. Matheus, and P. D. Fernandes, “Antinociceptive activity of Amazonian Copaiba oils,” J. Ethnopharmacol., vol. 109, no. 3, pp. 486–492, Feb. 2007. 22. V. F. Veiga Junior, E. C. Rosas, M. V. Carvalho, M. G. M. O. Henriques, and A. C. Pinto, “Chemical composition and anti-inflammatory activity of copaiba oils from Copaifera cearensis Huber ex Ducke, Copaifera reticulata Ducke and Copaifera multijuga Hayne--a comparative study,” J. Ethnopharmacol., vol. 112, no. 2, pp. 248–254, Jun. 2007. 23. M. F. C. L. Bandeira et al., “Dentin Cleaning Ability of an Amazon Bioactive: Evaluation by Scanning Electron Microscopy,” Open Dent. J., vol. 10, pp. 182– 187, May 2016. 24. M. A. Dias-da-Silva, A. C. Pereira, M. C. Marin, and M. A. Salgado, “The influence of topic and systemic administration of copaiba oil on the alveolar wound healing after tooth extraction in rats,” J. Clin. Exp. Dent., vol. 5, no. 4, pp. e169–e173, Oct. 2013. 25. P. L. Tobouti et al., “Influence of melaleuca and copaiba oils on Candida albicans adhesion,” Gerodontology, p. n/a-n/a, Nov. 2014.

Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com 26. J. Nogueira Neto et al., “Changes in the volume and histology of endometriosis foci in rats treated with copaiba oil (Copaiferalangsdorffii),” Acta Cir. Bras., vol. 26, pp. 20–24, 2011. 27. A. O. dos Santos et al., “Leishmania amazonensis: Effects of oral treatment with copaiba oil in mice,” Exp. Parasitol., vol. 129, no. 2, pp. 145–151, Oct. 2011. 28. A. O. dos Santos, T. Ueda-Nakamura, B. P. Dias Filho, V. F. da Veiga Junior, and C. V. Nakamura, “Copaiba Oil: An Alternative to Development of New Drugs against Leishmaniasis,” Evid. Based Complement. Alternat. Med., vol. 2012, pp. 1–7, 2012. 29. L. R. M. Estevão, J. P. de Medeiros, L. Baratella-Evêncio, R. S. Simões, F. de S. Mendonça, and J. Evêncio-Neto, “Effects of the topical administration of copaiba oil ointment (Copaifera langsdorffii) in skin flaps viability of rats,” Acta Cir. Bras., vol. 28, no. 12, pp. 863–869, 2013. 30. L. Garcia et al., “Biocompatibility assessment of pastes containing Copaiba oilresin, propolis, and calcium hydroxide in the subcutaneous tissue of rats,” J. Conserv. Dent. JCD, vol. 14, no. 2, pp. 108–112, 2011. 31. A. G. Guimarães et al., “Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol,” Basic Clin. Pharmacol. Toxicol., vol. 107, no. 6, pp. 949–957, Dec. 2010. 32. L. G. Lucca et al., “Determination of β-caryophyllene skin permeation/retention from crude copaiba oil (Copaifera multijuga Hayne) and respective oil-based nanoemulsion using a novel HS-GC/MS method,” J. Pharm. Biomed. Anal., vol. 104, pp. 144–148, Feb. 2015. 33. G. Svetlichny et al., “Solid lipid nanoparticles containing copaiba oil and allantoin: development and role of nanoencapsulation on the antifungal activity,” Pharm., vol. 70, no. 3, pp. 155–164, Mar. 2015.

Beta-Caryophyllene

1. Mackie K. Understanding cannabinoid psychoactivity with mouse genetic models. PLOS Biology. 2007. doi.org/10.1371/journal.pbio.0050280 2. Basu S. and Dittel B. Unraveling the complexities of the cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunologic Research. 2015;51(1):26-38. 3. Toguri j, et al. Anti-inflammatory effects of cannabinoid CB2 receptor activation in endotoxin-induced uveitis. British Journal of Pharmacology. 2014;171(6):1448- 1461. 4. Dhopeshwarker A. and Mackie K. CB2 cannabinoid receptors as a therapeutic agent – what does the future hold? Molecular Pharmacology.2014;86(4):430- 437. 5. Fidyt K, et al. βcaryophyllene and βcaryophyllene oxide—natural compounds of anticancer and analgesic properties. Cancer Medicine.2016;5(10):3007-3017.

Caryophyllene is a Cannabinoid

1. Gertsch J, Leonti M, Raduner S. et al. Beta-caryophyllene is a dietary cannabinoid. Proc Nac Acad Sci. 2008; 105(26):9099-9104. Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com 2. Nikan M, Nabavi SM, Manayi A, Ligands for cannabinoid receptors, promising anticancer agents. Life Sci. 2016; 146:124-130.

Endocannabinoids Explained

1. Leweke FM, Piomelli C, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry (2012) 2, e94; doi:10.1038/tp.2012.15 2. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9- tetrahydrocannabivarin. Br J Pharmacol. 2008 Jan; 153(2): 199–215. 3. A. Chicca et al., “Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system,” ACS Chem. Biol., vol. 9, no. 7, pp. 1499–1507, Jul. 2014.

A Chemist's Perspective: Cannabinoids, Cannabis, and Caryophyllene

1. Gertsch J, Leonti M, Raduner S et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. doi: 10.1073/pnas.0803601105. Epub 2008 Jun 23. 2. Klauke AL, Racz I, Pradier B et al. The cannabinoid CB receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014 Apr;24(4):608-20. doi: 10.1016/j.euroneuro.2013.10.008. Epub 2013 Oct 22. 3. Al Mansouri S, Ojha S, Al Maamari E et al. The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharmacol Biochem Behav. 2014 Sep;124:260-8. doi: 10.1016/j.pbb.2014.06.025. Epub 2014 Jul 3. 4. Quintans-Júnior LJ, Araújo AA et al. β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn. Life Sci. 2016 Mar 15;149:34-41. doi: 10.1016/j.lfs.2016.02.049. Epub 2016 Feb 13. 5. Chicca A, Caprioglio D, Minassi A et al. Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system. ACS Chem Biol. 2014 Jul 18;9(7):1499-507. doi: 10.1021/cb500177c. Epub 2014 May 15. 6. Horváth B, Mukhopadhyay P, Kechrid M et al. β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med. 2012 Apr 15;52(8):1325-33. doi: 10.1016/j.freeradbiomed.2012.01.014. Epub 2012 Jan 31. 7. Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. 2013 Oct 29;4(4):e0022. doi: 10.5041/RMMJ.10129. eCollection 2013. 8. Alberti TB, Barbosa WL, Vieira JL, Raposo NR, Dutra RC. (-)-β- Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Copyright 2018 Katrin Birkholz and Petal & Stem Copaiba Essential Oil Research Paper – Katrin Birkholz [email protected] - www.PetalAndStem.com Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int J Mol Sci. 2017 Apr 1;18(4). pii: E691. doi: 10.3390/ijms18040691. 9. Lou J, Teng Z, Zhang L, Yang J, Ma L, Wang F, Tian X, An R, Yang M, Zhang Q, Xu L, Dong Z. β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway. Front Pharmacol. 2017 Jan 19;8:2. doi: 10.3389/fphar.2017.00002. eCollection 2017. 10. Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β- Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24. doi: 10.1016/j.physbeh.2014.06.003. Epub 2014 Jun 13 11. Kamikubo R, Kai K, Tsuji-Naito K, Akagawa M.β-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016 Oct;60(10):2228-2242. doi: 10.1002/mnfr.201600197. Epub 2016 Jun 16. 12. Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Leite DF, Calixto JB. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011 Mar;178(3):1153-66. doi: 10.1016/j.ajpath.2010.11.052. 13. Cheng Y, Dong Z, Liu S. β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology. 2014;94(1-2):1-12. doi: 10.1159/000362689. Epub 2014 Aug 26. 14. Sourcing CBD: Marijuana, Industrial Hemp & the Vagaries of Federal Law. (n.d.). Retrieved September 26, 2017, from https://www.projectcbd.org/about/cannabis-facts/sourcing-cbd-marijuana- industrial-hemp-vagaries-federal-law [6]

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