Terpenes

Terpenes are a family of organic compounds obtained mainly from plants and trees, such as cannabis, tea, pine, lavender, thyme and citrus fruits like lemon.

 

Cannabis is very aromatic, with different strains having their unique scents. Some people find the smell of cannabis unpleasant while others find it very calming and enjoyable; some strains smell fruity and sweet while others smell like pine, lavender, earthy or pungent. The components responsible for the unique aromas and flavors of different cannabis strains are terpenes, aromatic molecules secreted inside the tiny resin glands of cannabis flowers. But there is more to terpenes than their scent.

 

Terpenes are also believed to have a wide range of medical effects although research remains inadequate to identify definitive clinical benefits at this time. There are at least 80-100 terpenes found in cannabis and the combination of terpenes and cannabinoids are responsible for the therapeutic effects of cannabis. For more information about terpenes, see below.

 

 

See:

Medical Marijuana – LA Marijuana Products

Marijuana – Medical Use Overview

“Medical Marijuana” – Getting Started

 

Cannabis-Based Medications:

Over-the-Counter Cannabinoid Medications:

Cannabidiol (CBD) – Introduction

Cannabidiol (CBD) – Clinical Use

Cannabidiol (CBD) – Drug Actions & Interactions

 

Prescription Cannabis-Based Medications:

FDA-Approved Prescription Cannabis-Based Medications

Louisiana Prescription Cannabis-Based Products – “Medical Marijuana”

 

Clinical Applications of Cannabis:

Cannabis – Anxiety (coming soon)

Cannabis – Fibromyalgia

Cannabis – Headaches (coming soon)

Cannabis – Inflammatory Bowel Disease (coming soon)

Cannabis – Neuroinflammation (coming soon)

Cannabis – Pain (coming soon)

Cannabis – Sleep (coming soon)

 

The Medical Science of Cannabis:

The Endocannabinoid System

Marijuana – Botanical

Marijuana – Pharmacokinetics

Marijuana – Inhaled (Smoked and Vaporized)

Marijuana – Cannabinoids and Opioids

 

Cannabinoids and Terpenes:

 

Cannabinoids:

Cannabidiol (CBD)

Cannabinoids

 

Terpenes:

Terpenes – An Overview

 

See also:

Marijuana – Discontinuing Use

Marijuana Addiction – Cannabis Use Disorder (CUD)

  

Key to Links:

Grey text – handout

Red text – another page on this website

Blue text – Journal publication

 

The medical information on this site is provided as a resource for information only, and is not to be used or relied upon for any diagnostic or treatment purposes and is not intended to create any patient-physician relationship.  Readers are advised to seek professional guidance regarding the diagnosis and treatment of their medical concerns.

 

 

 

Terpenes

More than 540 chemicals, including 18 different chemical classes, more than 100 different cannabinoids (including THC and CBD) and more than 400 terpenes have been identified in marijuana plants (cannabis). In addition, a group of compounds called flavonoids – about 20 of them – have also been identified in cannabis. Flavonoids, one of the largest nutrient families known, are a group of plant metabolites thought to provide health benefits through cell signalling pathways and antioxidant effects. It is believed that the therapeutic benefits attributed to cannabis are derived from all of these families of compounds. This page focuses on terpenes.

   

What are Terpenes (or Terpenoids)?

Terpenes are fragrant essential oils manufactured by many different types of plants and herbs, including cannabis. Terpenes (and terpenoids) are organic chemicals produced by most plants, as well as some animals such as swallowtail butterflies and termites. Terpenes are volatile aromatic molecules, meaning they evaporate easily, and are some of the primary components of plant resins and flowers, providing flavor and fragrance to fruits and spices commonly found in a normal diet. Terpenes, not cannabinoids, are responsible for the aroma of cannabis and are the source of the aromas, flavors, and other characteristics that help distinguish different cannabis strains.

 

Terpenes are built up from building blocks called isoprenes, molecules that consists of five carbon atoms attached to eight hydrogen atoms (C5H8) . Terpenes are classified according to the number of pairs of isoprenes in the individual terpene – mono, sesqui, di etc. composing either 10- carbon monoterpenes, 15-carbon sesquiterpenes or 20- carbon diterpenes, respectively. These three groups (mono-, di-, and sesqui-terpenes) are the most abundant in cannabis. See: Types of Terpenes and Terpenoids

 

The terms terpene and terpenoid are often used interchangeably but these terms do have different meanings. The main difference between terpenes and terpenoids is that terpenes are hydrocarbons (meaning the only elements present are carbon and hydrogen); whereas, terpenoids are the oxygenated derivatives of terpenes. Terpenoids are relatively more volatile and have a higher susceptibility to degradation than terpenes by oxidation (drying and curing the flowers). The term “terpene” will be used here but recognize some “terpenes” described here may actually be terpenoids. The most commonly studied terpenes found in cannabis plants include alpha-pinene, myrcene, beta-caryophyllene, caryophyllene oxide, linalool, limonene, nerolidol and phytol.

 

 

Terpenes have been proposed to exert therapeutic effects, especially in combination with the cannabinoids. They are quite potent, and have been shown to affect human behavior when inhaled from ambient air at serum levels less than 10 ng/mL Terpenes that occur in plants, however, are often found in very trace amounts. Terpenes may only compose the weight of 1-2% of dried plant matter and terpenes account for less than 1% in most cannabis plants in which the monoterpenes usually predominate (limonene, myrcene and pinene). Trichomes, the glands that produce resin in a cannabis plant, contain the majority of cannabinoids and terpenes found in cannabis. Terpenes comprise about 10% of trichome content by weight and are a significant component of cannabis resin. Terpene concentrations >500 ppm are of pharmacological interest, but in general, only terpene components in concentrations above 0.05% of a cannabis plant are considered potentially pharmacological active.

 

What do Terpenes do?

In general, of the 400 terpenes known in cannabis, very few have been examined at the functional level. Research evidence is convincing that the medical benefits of cannabis cannot be achieved by simple isolates of the cannabinoids THC and CBD. The different therapeutic benefits that vary between different marijuana strains cannot be explained by their THC and/or CBD content alone. Evidence shows  that non-cannabinoid marijuana plant components, including terpenes modulate the intoxicating effects of THC and the clinical effects of both THC and CBD.

 

Each terpene may have unique therapeutic effects. For example, some scents promote sleep: lavender oil, which contains the terpene linalool, improves sleep efficiency, increased total sleep time, elevated vigor the following morning, and promotes sleep in patients with insomnia. Terpenes may also contribute significantly to the synergistic (“entourage”) effects of cannabis-based products. The “entourage” effect is a proposed synergistic pharmacologic effect created by the combination of the different constituents in cannabis, especially with different cannabinoids and terpenes.  Different mechanisms of synergy have been proposed: (i) multiple effects on different targets; (ii) pharmacokinetic effects such as improved solubility or bioavailability; and (iii) modulation of adverse effects.

 

The synergy of cannabinoid-terpene interactions contribute to the medical benefits (and side effects) of cannabis with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer and infections. Terpenes are pharmacologically versatile: they are lipophilic, interact with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled (odorant) receptors, second messenger systems and enzymes. Terpenes may also increase the permeability of the blood-brain barrier, allowing greater access of substances in the blood to enter the brain. It has recently been shown that most terpenes do not synergistically interact with cannabinoid receptors (CB1 or CB2) in the body as was once proposed. The majority of the anti-inflammatory effects of terpenes and terpenoids has been shown to be mediated by a decrease in the levels of pro-inflammatory mediators, such as nitrous oxide (NO), interleukins, TNF-α, and PGE2.

 

 

Level of Evidence

Research on terpenes is mainly pre-clinical, consisting mostly of animal studies and lab (in vitro) studies. The proposed benefits of the individual terpenes described below have not, in most cases, been backed up with quality human studies. That being said, lack of evidence does not necessarily equate to lack of benefit. In the case of therapeutic benefits achieved with marijuana, it is generally accepted that terpenes play a significant role but studies are still lacking to further understand their specifics. The information presented here represents early evidence and theoretical benefits only.

 

Cannabis Strains

Due to a lack of research that evaluates terpenes directly for their therapeutic benefits, one means of assessing their benefits is to evaluate different Cannabis cultivars, or strains, for their peculiar therapeutic effects. Cannabis sativa strains are commonly described as energetic, uplifting, creative, euphoric, spacey and better for daytime use. Cannabis indica strains are commonly described as relaxing, calming, and sedating with full body effects and better for nightime use. These effects are not purely due to CBD:THC ratios as there are no significant differences in CBD:THC ratios between sativa and indica strains. These different subjective effects are most likely due to varying amounts and ratios of cannabinoids, terpenes and probably additional phytochemicals.

 

Furthermore, due to the explosive market for mariuana there has been a huge flooding of the marijuana market with different strains, all with imaginative and mysterious names that offer no information as to their specific and peculiar benefits. Complicating this is the fact that there may be no consistency of constituent amounts or ratios from one batch of a strain to another, despite their same name. In addition, different people are likely to respond differently to the same cannabis constituents at different times and, still differently than another person’s response to the same constituents.

 

Despite these obvious, and perhaps overwhelming limitations, one may still assess different cannabis strains for their purported benefits and evaluate the breakdowns of their particular chemical constituents to determine if they might allow for predicting specific therapeutic benefits based on common constituents found in different cannabis strains that are known for their specific therapeutic benefits.  A 2017 study evaluated a number of high THC cannabis strains based on their terpene content, describing 5 major group characteristics:

    1. Terpinolene dominant
    2. beta-Caryophyllene dominant
    3. Limonene/myrcene dominant
    4. Limonene/myrcene/b-caryophyllene dominant,
    5. a-bisabolol/Myrcene dominant

 

Further study is required to determine how these groupings may correlate with therapeutic benefits. Based on the fact that the most common reasons that people turn to medical use of cannabis are for pain relief, anxiety relief and insomnia, these benefits will be reviewed first with respect to different cannabis strains.

 

Safety

Terpenes are commonly used in the manufacturing of essential oils, natural flavorings and beauty products and are extensively used in fragrances and aromatherapy. Terpenes, in the amounts found in cannabis and cannabis extracts, are believed to be safe and well tolerated with minimal or mild side effects such as sedation. All the terpenoids discussed here are Generally Recognized as Safe (GRAS) by the US Food and Drug Administration (FDA) as food additives. Additionally, they are non-sensitizing to skin when fresh, but they may cause allergic reactions. Terpenes are not associated with physical dependence (withdrawal) or tolerance nor are they associated with abuse or addiction. However, one should never consume or swallow concentrated terpenes or essential oils without appropriate dilution. If you’re at all unsure about the safety of a compound, do not orally consume it without consulting a medical professional.

 

Bioavailability

Bioavailability refers to the proportion of a drug or other substance which enters the blood circulation when introduced into the body via inhalation, through the skin or through ingestion. For example, the bioavailability of a substance introduced directly into the vein by injection is, by definition, 100%. The bioavailability of the terpenes in cannabis is not well studied yet but they are generally considered to have high bioavailability with inhalation and oral ingestion. Some monoterpenoids  including alpha- and beta-pinene, camphor, 3-carene, myrcene and limonene, may even have high bioavailability through the skin. Because terpenes are usually lipophilic (fat soluble), they are generally absorbed well from the gut and they will pass into the brain through the blood brain barrier.

 

When consumed, terpenes readily enter the blood but in general are metabolized and cleared from the blood quickly, within a few hours, and accumulation is unlikely. The majority of terpenes are metabolised in the liver and exhaled as CO2 or, mostly, eliminated as phase-II conjugates by the kidneys.

 

Conditions Potentially Responsive to Terpenes

Certain strains, or chemovars, of Cannabis sativa  as a whole plant product may worsen symptoms of mental health disorders in some people, particularly high THC, low CBD strains. Additionally, some strains can also increase the likelihood of developing mood or psychiatric illnesses . On the other hand,  a large body of pre-clinical and clinical evidence suggests that other strains offer a range of therapeutic benefits in psychiatric and neurological illnesses, including anxiolytic, anti-depressant, antipsychotic, neuroprotective, anti-inflammatory, anti-oxidant, and pro-cognitive effects.

 

The  following is a list of conditions that, while still highly speculative, might respond to terpenes or to a cannabinoid-terpene synergy:

  1. Pain
  2. Anxiety
  3. Depression
  4. Insomnia
  5. Dementia
  6. Addiction
  7. Oxidative Stress
  8. Inflammatory diseases – Respiratory inflammation, Atopic Dermatitis, Arthritis, and Neuroinflammation

 

Pain

Terpenes have a great deal of popular support for their pain benefits although most of the research that explores this is preclinical: animal or lab-based (in-vitro). The following terpenes are most commonly recognized for their benefits for pain:

 

(1) Beta-Caryophyllene

(2) Pinene

(3) Limonene

(4) Linalool

(5) Myrcene

(6) Eucalyptol

 

Pain – Cannabis strains and their terpenes, noted for their benefits for pain

While there are no rules, users tend to report more effective pain-relief with indica strains. In one survey, participants reported that indicas helped more than sativas when it came to headaches, joint pain, neuropathy, and spasticity. Users also reported indicas to be more helpful when it comes to sleep and sedation. While sativa-dominant strains don’t seem as popular for pain management, they  tend to have less sedative effects compared to indica strains. However, over the several decades of widespread cannabis breeding, the ability to distinguish indica strains from sativa strains has become vague and unreliable.

 

Upon review of many websites offering anecdotal reports of which cannabis strains are best for pain, the following strains seemed to be most popular for treating pain:

 

White Widow

White Widow is a potent, balanced sativa/indica hybrid strain, blending South American sativa and South Indian indica and is widely believed to be useful for chronic pain. Emerging in the Netherlands in the 1990s, the strain gained popularity in Dutch coffee houses. Many people believe this is one of the best choices for migraine headaches and is considered very effective for sleep. Its terpene profile is reported to include nerolidol (trans-nerolidol), limonene, myrcene, linalool and caryophyllene. One source identifies the following breakdown of the terpenes in White Widow where it is notable that this breakdown does not include nerolidol (trans-nerolidol), suggesting a lack of consistency in reports of cannabis strain constituents.

 

White Widow terpene profile (from industrialhempfarms.com):

Linalool (3.78%), alpha-Pinene (0.521%),, Myrcene (0.43%), Caryophyllene oxide (0.30%), Humulene (0.09%.beta-Pinene (<0.01%), Limonene (<0.01%), Terpinolene (<0.01%).

Total Terpenes 5.49%

Terpene product: White Widow Natural Terpene Blend

 

Blue Dream

Blue Dream is a blend of Blueberry (indica) with Haze (sativa) to create a sativa-dominant hybrid for treating pain. Blue Dream offers full-body relaxation with mental alertness and is reportedly effective for managing chronic pain without excessive sedation. Blue Dream has a reputation for being one of the best strains for relieving migraine headaches. It is also reported to improve depression and nausea. The THC content of Blue Dream ranges between 17-24% while its CBD content consistently ranges only from 0.1-0.2%. Its sweet berry aroma suggests prominent terpenes.

 

Blue Dream terpene profile (from industrialhempfarms.com):

Linalool (1.86%), alpha-Pinene (0.68%), Caryophyllene Oxide (0.40%), Caryophyllene (0.11%), Humulene (0.02%), Myrcene (<0.01%), beta-Pinene (<0.01%), Limonene (<0.01%), Terpinolene (<0.01%).

Total Terpenes: 3.07%

Terpene product: Blue Dream Natural Terpene Blend

 

Harlequin

Harlequin is sativa-dominant but very high in CBD with less than 10% THC, so there is less brain fog and euphoria while the CBD works on pain issues. Harlequin is considered by many to be the most effective for arthritis pain and also good for fibromyalgia and nerve pain, muscle and joint pain, menstrual cramps and nausea.

 

Harlequin terpene profile (from industrialhempfarms.com):

alpha-Pinene (0.309%), Myrcene (0.298%), Caryophyllene (0.238%), beta-Pinene (0.099%), Humulene (0.082%), Limonene (0.058%), Linalool (0.010%), Terpinolene (<0.002%), Ocimene (<0.002%).

Total Terpenes: 1.094%

Terpene product: Harlequin Natural Terpene Blend

 

Kush Strains (especially Master Kush)

There are many different varieties of Kush,” including purple Kush, OG Kush, Hindu Kush, and Bubba Kush to name some of the popular ones. Most of these strains are indica-based, originating from the Hindu Kush area of the Himalayas. Most are high in THC content. Master Kush is considered very potent. Bubba Kush is commonly found to be effective for pain, stress and depression, and is thought to be very effective for insomnia. The THC content of Bubba Kush ranges from 14-22%, and the CBD content ranges from 0.06-0.1%. Redwood Kush is known for its muscle relaxation properties. Afghan Kush is reported to be very effective for nerve pain but can be very sedating and it has a high CBD content.

 

OG Kush terpene profile (from industrialhempfarms.com):

Humulene (0.97%), alpha-Pinene (0.63%), Caryophyllene (0.34%), Terpinolene (0.10%), Myrcene (0.08%), Linalool (<0.01%), Caryophyllene oxide (0.96%), beta-Pinene (<0.01%), Limonene (<0.01%).

Total terpenes 2.13%

Terpene product: OG Kush Natural Terpene Blend

 

Hindu Kush terpene profile (from industrialhempfarms.com):

Humulene (0.66%), alpha-Pinene (0.26%), Caryophyllene (0.61%), Terpinolene (<0.01%), Myrcene (0.09%), Linalool (<0.01%), Caryophyllene oxide (<0.01%), beta-Pinene (<0.01%), Limonene (<0.01%).

Total terpenes 2.57%

 

Bubba Kush terpene profile (from industrialhempfarms.com):

Humulene (1.76%), Linalool (1.46%), Caryophyllene oxide (0.62%), Caryophyllene (0.4%), alpha-Pinene (<0.01%), Terpinolene (<0.01%), Myrcene (<0.01%),  beta-Pinene (<0.01%), Limonene (<0.01%).

Total terpenes 4.24%

 

AK-47

A sativa-dominant hybrid strain, AK-47 is a popular strains for treating chronic pain. It is reported to be derived from a variety of different strains, including South American, Mexican, and Thai sativa strains and the Afghani indica strain. While it derived from both sativa and indica, AK 47 is sativa dominant, and likely to be energizing. The terpenes in AK-47 are reported to consist mainly of Myrcene, Caryophyllene, d-Limonene, D-Alpha-Pinene, Alpha-Pinene and Beta-Pinene.

Terpene product: AK-47 Natural Terpene Blend

 

Jack Herer

Jack Herer is a cross between Shiva Skunk, Northern Lights #5 and a Haze hybrid that is sativa-dominant. It originated in the Netherlands in the 1990s, Jack Herer offers analgesia but less sedation than many of the indica-based strains. The THC content of Jack Herer ranges from 18-23%, and the CBD content ranges from 0.03 -0.2%. The terpenes in Jack Herer include pinene.

Terpene product: Jack Herer Natural Terpene Blend

 

 

OG Shark

OG Shark appears to be a lesser-known cannabis strain but in a study evaluating headache and chronic pain that is reviewed below, it ranked highest in preference by patients for treatment of chronic headaches and chronic pain.

 

Cannabinoids:

THC (21-25%),  THCA (22.8%), CBD (<0.1%), CBDA (0.1%)

Terpenes:

β-Caryophyllene (0.263%), β-Myrcene (0.194%), D-Limonene (0.191%), Linalool (0.136%),

Bisabolol (0.107%), Humulene (0.078%), Trans-Nerodiol (0.023%), α-Pinene (0.022%)

 

ACDC

ACDC has mixed reports of containing high levels of CBD but low levels of THC or high levels of both. It tends to produce little to no noticeable euphoria, or “high,” suggesting that the THC content is low. It helps to relieve pain and control stress.

 

ACDC terpene profile (from industrialhempfarms.com):

alpha-Pinene (<0.01%), Myrcene (<0.01%), Caryophyllene (<0.01%), beta-Pinene (<0.01%), Humulene (<0.01%), Limonene (<0.01%), Linalool (<0.01%), Caryophyllene Oxide (<0.01%), , Terpinolene (<0.01%).  Total Terpenes: <0.01%

Terpene product: ACDC profile (from trueterpenes.com) with prominent alpha-Pinene and Myrcene

 

 

Arthritis (Osteoarthritis)

Osteoarthritis (OA) is a degenerative joint disease characterized by inflammation and progressive loss of the joint (articular) cartilage that is associated with changes in the subchondral bone and other joint tissues. Although the mechanisms of joint tissure destruction in OA is not yet completely understood, pro-inflammatory cytokines, such as interleukin-1β (IL-1β), play a major role by inducing activity of cartilage-degrading enzymes in cartilage cells (chondrocytes). This enzymatic process, coupled with impaired repair responses, results in progressive cartilage loss, the hallmark of OA.

 

The terpenes myrcene, pinene and limonene have been found in preclinical research to have anti-inflammatory and anti-catabolic (breakdown) properties in human chondrocytes, although myrcene may show the greatest potential. Caryophyllene has also been identified as an agonist of the CB2 receptor which suggests it may also have anti-inflammatory benefis. Clinical studies are needed to identify how these benefits may be applied.

   

Headaches

A 2018 study evaluated the cannabis strains most commonly preferred for relief of headaches in chronic migraine patients and other types of chronic pain.  “OG Shark,” a sativa/indica hybrid strain, was identified as the most popular for both migraine patients as well as those with other chronic pain syndromes including arthritis. Among the most preferred 15 cannabis strains, there were no statistically significant differences in specific strain preferences found between patients with headache as their primary pain compared to those with other diagnoses of chronic pain or arthritis.

 

The OG Shark cannabis strain is reported to be a cross between Great White Shark and OG Kush cannabis strains and is a high THC/THCA (20+%), low CBD/CBDA (<1%) strain with β-caryophyllene followed by β- myrcene, limonene and linalool as the predominant terpenes. This is consistent with potent analgesic, anti-inflammatory, and anti-nausea properties of THC, along with documented anti-inflammatory and analgesic properties of β-caryophyllene, β-myrcene, limonene and linalool.

 

While OG Shark was identified as the most preferred strain for  headaches and pain, the following were the top 15 strains:

  1. OG Shark (29 patients; 8.9% of responders)
  2. Afghani (25; 7.7%)
  3. Skywalker OG (25; 7.7%)
  4. Lemon Sour Diesel (25; 7.7%)
  5. Jack Herer (24; 7.3%)
  6. Jean Guy (24; 7.3%)
  7. White Widow (24; 7.3%)
  8. Pink Kush (21; 6.4%)
  9. Master Kush (20; 6.1%)
  10. Sweet Skunk CBD (18; 5.5%)
  11. Headband (17; 5.2%)
  12. Island Sweet Skunk (17; 5.2%)
  13. Black Tuna (16; 4.9%)
  14. Warlock CBD (14; 4.3%)
  15. Cannatonic (14; 4.3%), Blueberry (14; 4.3%)

Click here  for an analysis of the constituents of these 15 preferred cannabis strains for pain

 

Anxiety

Abundant evidence supports the key role of the endocannabidiol system in moderating both depression  as well as anxiety, whether induced by aversive stimuli, such as post-traumatic stress disorder or pain. CBD’s anxiolytic effects are reasonably supported in the literature, especially regarding the belief that CBD reduces the side effect of anxiety that is associated with the use of THC (See Cannabidiol).

 

Terpenes are frequently promoted as having sedative and anxiety benefits. The following is a list of terpenes commonly believed to have sedative or anxiolytic effects:

  1. β-Caryophyllene
  2. Limonene
  3. Linalool
  4. Myrcene
  5. α-Pinene
  6. Phytol
  7. α-Terpineol
  8. Terpinolene

 

 

Anxiety – Cannabis strains and their terpenes, noted relative to their benefits for anxiety

 A 2018 publication evaluated (by surveys) the opinions of 442 patients using cannabis for medical purposes. Of these, 266 (60%) patients reported that they used cannabis to treat their anxiety whereas only 15% of these patients reported being diagnosed with a specific anxiety disorder.

 

Most Effective

The top four cannabis strains reported to be most effective for reducing anxiety were Bubba Kush,  Skywalker OG Kush, Blueberry Lambsbread and Kosher Kush. Three of these four are “Kush” varieties, which all share a similar chemotype with high levels of the terpenes: trans-nerolidol, myrcene, β-Caryophyllene, D-limonene and linalool. Kush strains contain genetics originating from the pure Indica strains found in the Kush mountain range in Central Asia, Afghanistan, Northern Pakistan and North-Western India.  “Hindu Kush” strains of Cannabis were brought to the United States in the mid-to-late 1970s.

Click here for a graph of weighted average terpene concentrations for the top four most effective cannabis strains for anxiety (taken from “Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype”).

 

Of note, while CBD has been identified as being effective for anxiety, in the strains identified in this study as being most effective for anxiety the cannabinoids cannabigerol (CBG) and cannabichromene (CBC) were measured at higher levels than CBD (0.68%, 0.13% and 0.075% respectively). It has been proposed that CBG may also have anxiolytic benefits.

 

Bubba Kush terpene profile (from industrialhempfarms.com):

Humulene (1.76%), Linalool (1.46%), Caryophyllene oxide (0.62%), Caryophyllene (0.4%), alpha-Pinene (<0.01%), Terpinolene (<0.01%), Myrcene (<0.01%),  beta-Pinene (<0.01%), Limonene (<0.01%).

Total terpenes 4.24%

 

Skywalker OG Kush terpene profile (from industrialhempfarms.com):

Humulene (1.77%), alpha-Pinene (0.88%), Myrcene (0.69%), Caryophyllene oxide (0.42%), Caryophyllene (0.37%),  Terpinolene (<0.01%), Linalool (<0.01%), beta-Pinene (<0.01%), Limonene (<0.01%).

Total terpenes 4.13%

 

Least Effective

Of the four cannabis strains considered least effective (but not necessarily ineffective), myrcene dominant strains and the terpinolene dominant strains were found to be less effective. These results could be due to different symptom etiology requiring different pharmacological interventions or may also arise from differences in personal biochemistry between patients with similar etiology.

For a complete analysis of weighted averages of all terpenes and cannabinoids for the top four most effective and least effective (for anxiety) cannabis strains in this study, click here (taken from “Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype”

 

Depression

While the possible benefits of THC on depression remain controversial, CBD- or CBG-predominant preparations have greater support. Research supporting benefit for depression treated solely with a citrus scent strongly suggests the possibility of synergistic benefit of a phytocannabinoid-terpenoid preparation with limonene.

 

Dementia

A recent study supports the concept that CBD, when present in significant proportion to THC, is capable of reducing or eliminating induced cognitive and memory deficits in normal subjects smoking cannabis.  Furthermore, CBD may also reduce b-amyloid in Alzheimer’s disease. The psycho-pharmacological effects of limonene, pinene and linalool could possibly offer benefits in mood in such patients.

 

Insomnia

The effects of cannabis on sleep remain inconclusive, but there may be benefits that can accrue in this regard, particularly with respect to symptom reduction permitting better sleep, as opposed to a mere hypnotic effect. Certainly, terpenoids with pain-relieving, anti-anxiety or sedative effects may supplement such benefits, particularly caryophyllene, linalool and myrcene.

 

In the same 2018 study referenced above regarding cannabis strain preferences, the following 15 cannabis strains were preferred by patients using cannabis for insomnia:

 

  1. Lemon Sour Diesel (20 patients; 13.8% of respondents)
  2. OG shark (15; 10.4%)
  3. Skywalker OG (13; 9%)
  4. Pink Kush (12; 8.3%)
  5. Jack Herer (10; 6.9%)
  6. White Widow (9; 6.2%)
  7. Afghani (8; 5.5%)
  8. Indica House Blend (7; 4.8%)
  9. Sweet Skunk CBD (7; 4.8%)
  10. Island Sweet Skunk (7; 4.8%)
  11. Black Tuna (7; 4.8%)
  12. Jean Guy (6; 4.1%)

    

Click here for a breakdown of the constituents of these 15 preferred cannabis strains for insomnia

 

Addiction

CBD has been proposed as a treatment for heroin, cocaine, and alcohol craving and addiction relapse although research remains inconclusive. It is theorized that terpenoids might provide adjunctive support including myrcene via sedation, pinene via increased alertness, and especially caryophyllene via CB2 agonism due to a newly discovered possible mechanism of action in addiction treatment. CB2 is expressed in dopaminergic neurons in the ventral tegmental area and nucleus accumbens, areas mediating addictive phenomena. Activation of CB2 in rats has been shown to inhibit dopamine release and cocaine self-administration. Caryophyllene, as a high-potency selective CB2 agonist would likely produce similar effects.

 

Oxidative Stress

Oxidative stress is a condition that results from an imbalance between the production of reactive oxidative species (ROS), such as free radicals, and their elimination by protective mechanisms. ROS are highly reactive chemicals that damage tissues, epecially proteins, lipids, and DNA/RNA. They are produced naturally by cells, especially when producing energy in the mitochondria. The excessive production of ROS causes tissue injury that leads to inflammation as well as irreversible damage to cells, possibly resulting in mutations, cancer and cell death. Terpenes may be protective by reducing the activity of enzymes involved in the production of ROS, or by protecting against oxidative damage by a wide range of ROS through several mechanisms of antioxidant activity including binding with, and neutralizing the ROS.

 

Due to their antioxidant behavior, terpenes have been shown to protect against different diseases, including neurodegenerative and cardiovascular diseases, cancer, diabetes, and aging processes. Many studies have demonstrated antioxidant properties of terpenes and terpenoids. D-Limonene has powerful antioxidative properties as does myrcene, pinene, d-limonene, terpinolene, humulene, linalool and β-caryophyllene and many others.

See: Antioxidants and Oxidative Stress, Oxidative Stress, Pain and Disease

   

Inflammation

Inflammation is a complex biological response to tissue damage as a consequence of wounds or infections or due to exposure to pathogens or other foreign substances. Initially inflammation is a normal part of the healing process. In some disease states, however, the immune system produces an inflammatory response in the absence of injury, foreign substances or infection. This response is characterized by an overproduction of inflammatory substances called cytokines.

 

In the inflammation pathway, triggered by pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α, the activated NF-κB translocates to the nucleus, and stimulates the production of pro-inflammatory genes. The general effect of the terpenes in most studies is reducing the pro-inflammatory cytokines expression and involve the inhibition of the NF-κB signaling pathway. Certain terpenes have been found to reduce inflammation by decreasing the release of pro-inflammatory cytokines. For example, some terpenes (D-limonene, terpinolene,  and linalool can reduce the expression of TNF-α, IL-1, and IL-6. The terpenes α-pinene, D-limonene, and myrcene decrease the expression of these cytokines in inflammatory cells called macrophages.

 

Neuroinflammation
Inflammation is a typical pathological feature involved in the progression of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease as well as depression. Additionally,  inflammation involving the nervous system is the foundation of central sensitization, the process in which acute pain becomes chronic. Microglia are inflammatory  cells in the central nervous system that produce pro-inflammatory cytokines and ROS. When activated, they produce pro-inflammatory cytokines such as IL-1β, IL-16, TNFα, and TGF-β1.

 

Certain terpenes have been shown to suppress microglia-mediated inflammation involved in acute or chronic neurodegenerative diseases. Studies strongly suggest that linalool has neuroprotective activity, acting in NF-κB activation and preventing its nuclear translocation. D-limonene is also involved in neuroinflammation regulation process by reducing the inflammatory response and decreasing the levels of inflammatory cytokines such as IL-1, IL-6 and TNF- α.

See: Neuroinflammation

 

Respiratory Inflammation

Respiratory conditions associated with inflammation include asthma, allergic rhinitis, bronchitis, pneumonia and, recently, COVID-19. Several animal studies have shown the beneficial effects of some volatile terpene compounds via the anti-inflammation response to airway inflammation in allergic asthma. In the mouse asthma model, inhalation of limonene significantly reduced the levels of various proinflammation-related molecules as well as airway fibrosis, indicating that limonene has the potential to reduce airway remodeling. Lab studies suggest that terpeneol may improved lung function as well as enhance airway smooth muscle relaxation. Inhalation of α-Pinene has been shown to be a bronchodilator in human volunteers at low exposure levels.

 

Allergic rhinitis, a disorder of the upper airways caused by an inflammation of the nasal membranes, and often coexising with asthma, has been shown to respond to α-Pinene. However, adverse effects of inhaled terpene on airways has also be found. Oxidation products of α-pinene and d-limonene have been shown to cause irritation both in the upper airways and lungs in mice.

 

Individual Terpenes

While the over 200 different terpenes found in the cannabis plant have been much less researched compared to THC and CBD, they do show promise for their ability to provide therapeutic benefits. Below are some of the most frequent terpenes:

 

Myrcene

Myrcene is the most abundant terpene in cannabis, making up as much as 65% of total terpene profile in some strains. Myrcene has an earthy, musky aroma, similar to cloves. It also has a fruity, red grape-like aroma. Myrcene can also be found in foods such as mango and citrus fruits, as well as thyme, sweet basil, bay leaves, hops, parsley and lemongrass. Mango contains significant amount of myrcene, so eating it before consuming cannabis may strengthen the effects of THC and increase its absorption rate.

 

Strains that contain 0.5% or more of myrcene are usually indicas with sedative and anxiolytic effects. Myrcene has also been reported to be useful in reducing inflammation and chronic pain. Strains that are rich in myrcene are Skunk XL, White Widow, and Special Kush. Myrcene is a recognized sedative found in hops preparations (Humulus lupulus) and is employed as a sleep aid  in Germany. Furthermore, myrcene acted as a muscle relaxant in mice.  Myrcene is a prominent sedative and potentiates sleep at high doses.  If the level of myrcene is >0.5% it may result in a “couch lock,” or heavy sedative effect, while low levels of myrcene (<0.5% myrcene) can produce a higher energy.

 

Interestingly, myrcene has been found to be analgesic in mice, and this action can be blocked by naloxone, raising questions as to its mechanism of action as related to opioids. β-myrcene is known to facilitate the analgesic effect of THC and CBD by stimulating the release of endogenous opioids through an α2-adrenergic receptor-dependent mechanism.

 

Like pinene, myrcene has significant anti-inflammatory effects via prostaglandin E2 and is also believed to act as a muscle relaxant and therefore may be useful in reducing chronic pain. Myrcene has protective effects in cartilage, suggesting potential anti-arthritic activity and the ability to halt, or at least slow down cartilage destruction and arthritis progression.

See:

Relative concentrations of β-myrcene in essential oils and some natural products – 1

Relative concentrations of β-myrcene in essential oils and some natural products – 2

Relative concentrations of β-myrcene in essential oils and some natural products – 3

Relative concentrations of β-myrcene in essential oils and some natural products – 4

β-myrcene content in various plant essential oils

International standards regarding β-myrcene content in various plant essential oils

The above tables are from: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans – 2019

 

Limonene

Limonene is the second most abundant terpene in cannabis, but it is not necessarily found in all strains. Strains that have “lemon” or “sour” in their name are usually rich in limonene. High levels of limonene can be found in strains like O.G. Kush, Sour Diesel, Super Lemon Haze, Durban Poison, Jack Herer, and Jack the Ripper. As the name itself implies, limonene has a citrus-like scent that resembles lemons and can be found in the rinds of all citrus fruits, including lemons, limes, oranges and grapefruit which contain large amounts of this compound. Limonene is non-toxic, highly bioavailable and rapidly metabolized. It is accumulated and retained in adipose tissues and brain brain.

 

Limonene does not interact with CB1 or CB2 receptors but even though it has a low affinity for cannabinoid receptors, this monoterpene boosts up the level of serotonin and dopamine, thereby inducing the anxiolytic, anti-stress, and sedative effects of the CBD.

 

Proposed therapeutic benefits of limonene include  anti-inflammatory, gastro-protective, anti-nociceptive, anti-tumor, and neuroprotective activity, mood enhancement and stress reduction as well as sedation and immune-stimulation. Studies of citrus oils in mice suggest it to be a powerful agent for reducing anxiety, with studies demonstrating increased serotonin in the prefrontal cortex and dopamine in the hippocampus mediated via serotonin receptor, 5-HT1A. Confirmatory evidence in humans was found in a clinical study in which hospitalized depressed patients were exposed to citrus fragrance in ambient air demonstrated subsequent normalization of depression and successful discontinuation of antidepressant medications in 9/12 patients.

 

The reported antioxidant and free radical scavenging properties of Citrus lumia oil, which is highly-concentrated in monoterpenes (e.g., 48.9% D-limonene and 18.2% linalool), suggests an important preventive role in oxidative stress. Overall, limonene has therapeutic potential for diseases associated with inflammatory and oxidative-stress processes.

 

Linalool

With its spicy and floral notes, linalool is one of the most abundant terpenes in the majority of cannabis strains and, together with myrcene, produces that pungent floral and spicy scent that makes cannabis smell the way it does. Some well known linalool strains are Amnesia Haze, Special Kush, Lavender, LA Confidential, and OG Shark.

 

Linalool is abundant in in lavender (Lavandula angustifolia), bergamot and sweet basil but can also be found in ylang-ylang, mint, cinnamon and coriander. Essential lavender oil contains 37.3% linalool and 41.6% linalyl acetate but also contains moderate levels of beta-caryophyllene, (Z)-beta-ocimene, (E)-beta- ocimene, and lavandulyl acetate. It is frequently used in aromatherapy for the skin, anxiety, stress, pain, and to improve sleep. Linalyl acetate, the other primary terpenoid in lavender, hydrolyses to linalool in the stomach.

 

A  study by Dugo et al. evaluated bergamot oil and found that it contains linalyl acetate (15.6–41.4%), linalool (1.7–26.0%) and limonene (10.5–45.8%) as the major constituents; along with with β-pinene (0.08–11.0%) and γ-terpinene (3.7–11.4%). However the amount of terpenes found in lavender or bergamot oil can vary greatly based on the origin, latitude, growing year and harvest period. 

 

Linalool is a major and common terpenoid contained in most herbal essential oils and teas, including both green and black teas, including Earl Grey tea. Bergamot oil is one of the key flavorings found in Earl Grey tea. 

 

Oral intake of linalool from food and beverages is estimated to be up to 1-5 mg/day, including the dietary intake of linalool from natural sources such as vegetables and spices.  Linalool occurs in apple, citrus juices, berries, grapes, guava, celery, peas, potatoes, tomatoes, cinnamon, cloves, cassia, cumin, ginger, mustard, nutmeg, pepper, thymus, cheeses, grape wines, butter, milk, rum, cider, tea, passion fruit, olive, mango, beans, coriander and rice.

 

Most studies evaluating linalool’s therapeutic benefits are preclinical, laboratory-based or animal-based, with limited human studies. It has been proposed linalool offers benefit in patients suffering from arthritis, depression, seizures and insomnia.

 

Linalool – Anxiety, Sedation and Relaxation

Just like those aromatic herbs used in traditional aromatherapy, linalool also reduces anxiety and provides sedation and relaxation.  There is evidence that lavender oil, containing linalool, improves sleep efficiency, increased total sleep time, elevates vigor the following morning and promotes sleep in patients with insomnia. It is believed that the modulation of glutamate and GABA neurotransmitter systems are the likely mechanisms for the sedative, anxiolytic and anticonvulsant properties of linalool.  Multiple articles listed below demonstrating linalool’s benefits regarding anxiety and sleep may be downloaded for review.

 

Evidence suggests that the effectiveness of linalool is equal to commonly prescribed anti-anxiety medications including lorazepam (Ativan) and paroxetine (Paxil)) and often with less side effects; however, well-designed clinical trials are required to confirm this.

 

Like pinene, linalool is a monoterpene with a low molecular weight and is highly lipophilic, suggesting that it may pass the blood brain barrier to exert effects on brain function. Linalool does not appear to bind to either endogenous cannabinoid receptor CB1 or CB2 and has no affinity for GABAA-benzodiazepine receptor. Findings suggest linalool may block NMDA receptors.

 

Inhalation of lavender oil (predominantly linalool and linalyl acetate) has a long history of traditional use and effectiveness for anxiety and sleep. Animal and human studies have demonstrated that linalool has anxiolytic properties, possesses stress-relieving effects and improves quality of sleep.

 

Oral: intake of linalool, in the form of lavender essential oil (Silexan™) capsules wa demonstrated to be effective for anxiety in a meta-analysis published in 2019. Five studies with a total of 524 participants received treatment with Silexan™ 80 mg and 121 participants taking silexan 160 mg. Silexan™ 80 mg was observed to be effective for anxiety, equivalent to that of paroxetine (Paxil), a prescription SSRI (selective serotonin reuptake inhibitor). Overall, Silexan™ 160 mg was found to be more effiective than Silexan™ 80 mg. Silexan™ contains primarily linalool (36.8%) and linalyl acetate (34.2%). Minor components of Silexan™ include monoterpene alcohol lavandulol, its ester lavandulyl acetate, and bicyclic monoterpenoids borneol, eucalyptol (1,8-cineole) and camphor.

 

OTC Products

Lavender oil is available in a number of over-the-counter (OTC) medications directed at treating anxiety and to promote relaxation and calm. As noted above, Silexan™ is a formulation of lavender oil that has been studied and found to be effective for these conditions and can used to supplement marijuana products. Although Silexan™ does not seem to be available directly, it is found in different brands of OTC meds, such as Nature’s Way “CalmAid®” in 80mg softgels to be dosed at 80-160 mg/day. Other OTC products similarly available list “lavender oil,” 80mg) but not specifically as Silexan™ and may provide identical benefits,

 

Inhalation vs Oral: Unfortunately, a systematic review published in 2017 identified no studies that met the author’s criteria that meaningfully established comparative effectiveness of oral Silexan compared to inhaled lavender essential oil as aromatherapy for sleep latency, sleep duration, sleep quality, disturbed sleep or anxiety in adults.

 

  

Linalool – Pain

Topical exposure to linalool has been found to have local anaesthetic effects equal to those of procaine and menthol and provides anti-inflammatory and analgesic benefits at high doses in mice. In traditional Chinese medicine, frankincense (Boswellia carterii) is commonly used for topical treatment of pain and inflammation. A study carried out to investigate the antinociceptive and anti-inflammatory action of frankincense found three of its main componentes, linalool, α-pinene and 1-octanol, showed consistent evidence of their anti-inflammatory and analgesic effects.

 

Further investigation of the mechanism of action  of lavender oil found that it inhibites the endocannabinoid degradation enzymes FAAH (fatty acid amide hydrolase) and MAGL (monoacylglycerol lipase). While FAAH and MAGL can synthesize or degrade endocannabinoids depending on body needs, FAAH inhibition is beneficial in CNS and pain disorders by conserving endocannabinoids and enhancement of endocannabinoid signaling including  the endogenous cannabinoid N-arachidonoylethanolamide (AEA; also known as anandamide). AEA directly affects specific brain regions related to emotionality, behavior planning, and motivation (hippocampus, striatum, and frontal cortex).

 

 

Inhalation exposure to linalool in animals has been shown to significantly decrease pain response. Additionally, linalool has been associated with decreased morphine opioid use after inhalation in a study of post-operative pain with gastric banding in morbidly obese surgical patients. Linalool acts on neurogenic and inflammatory pain, and that its antinociceptive effect may be related to reduced peripheral and central nerve excitability. It is believed that linalool’s analgesic benefits are possibly related to inhibition of substance P release or a blocking effect on its receptor neurokinin-1 (NK-1). 

 

Ingestion of linalool for use in the treatment of painful and inflammatory disorders appears to be limited due to poor oral availability. Interestingly though, oral linalool has been found to be effective for anxiety and relaxation.

 

Linalool – Antioxidative Activities

Linalool has been traditionally used for medicinal purposes due to its potent antioxidative activities. Linalool decrease ROS as well as improve mitochondrial function and morphology through different pathways, directly reducing the cell death rate due to oxidative stress. Studies have shown that α-pinene, β-caryophyllene and linalool up-regulate Nrf2 activity to protect cells from oxidative damage. Nrf2 (nuclear factor erythroid 2) is a transcription factor that is involved in cellular responses to oxidative damage and inflammation. See: Nrf2 Activators

Recent research suggests that linalool may also have activity in triglyceride metabolism to improve dyslipidemia by reducing lipid peroxidation levels and plasma triglyceride concentrations.

 

β-Caryophyllene (BCP)

β-Caryophyllene (or just “caryophyllene”) is one of the most common terpenoids found in cannabis and is frequently the predominant terpenoid overall in cannabis extracts, particularly if they have been processed under heat for decarboxylation. In nature, β-caryophyllene is usually found together with small amount of its isomers α-caryophyllene and γ-caryophyllene or in a mixture with its oxidation product, β-caryophyllene oxide. Described as earthy and peppery, Caryophyllene is also found in black pepper (Piper nigrum), Copaiba balsam (Copaifera officinalis), clove,  cinnamon, oregano, basil, hops and rosemary. Cannabis strains with prominent amounts of  Caryophyllene include Super Silver Haze, Skywalker and Rock Star.

 

Amount of Caryophyllene in the essential oils of other substances

Of naturally occurring sources, the essential oil of West African black pepper (Piper guineense) has the highest concentration of caryophyllene at 58%.

  • Cannabis, Hemp, Marijuana (Cannabis sativa): 3.8–37.5%
  • Cloves (Syzygium aromaticum): 1.7–19.5%
  • 
Hops (Humulus lupulus): 5.1–14.5%
  • 
Basil (O. micranthum): 4.0–19.8%
  • 
Oregano (Origanum vulgare): 4.9–15.7%
  • 
Black Pepper (Piper nigrum): 7%
  • 
Lavender (Lavandula angustifolia): 4.6–7.5%
  • 
Rosemary (Rosmarinus officinalis): 0.1–8.3%
  • 
True Cinnamon (Cinnamomum zeylanicum): 6.9–11.1%
  • Ylang-ylang (Cananga odorata) [3.1–10.7%]

 

β-Caryophyllene as a CB2 Agonist

Cannabis contains over 65 cannabinoid-like natural products. Δ9-tetrahydrocannabinol (THC), Δ8-tetrahydrocannabinol, and cannabinol (CBN) that activate cannabinoid receptor types 1 (CB1) or 2 (CB2). The CB1 receptor is responsible for psychoactive euphoric effects and analgesic effects, as well as other therapeutic effects whereas CB2 receptor inhibits inflammation and edema and has analgesic effects. In the gastrointestinal tract, CB2 receptor agonists have been shown to reduce inflammation in colitis. The CB2 receptor is also a potential target for the treatment of atherosclerosis and osteoporosis. CB1 and CB2 cannabinoid receptors are present on free nerve-endings as part of the endocannabinoid system (ECS). These can be activated by topical cannabinoid therapy to provide therapeutic benefits.

 

Some consider β-Caryophyllene to be a cannabinoid because it strongly binds to CB2 receptors as a functional agonist although it does not bind to CB1 receptors. The CB2 receptor is the peripheral receptor for cannabinoids, which is mainly expressed in immune tissues and has been shown to modulate immune cell functions.The CB2 receptor mediates anti-inflammatory responses induced by β-caryophyllene.

 

The Anti-Inflammatory Properties of β-Caryophyllene

Our understanding of the therapeutic benefits offered by Carophyllene is based almost entirely on laboratory (in vitro) and animal studies. The anti-inflammatory properties of BCP have been extensively shown in different mouse models of disease. Carophyllene may help with pain and is proposed to reduce inflammation by reducing levels of IL-1β, IL-6, through activity at  prostaglandin PGE-1 and at the NLRP3 inflammasome. Studies have also shown that β-Caryophyllene up-regulates Nrf2 activity to protect cells from oxidative damage. Nrf2 (nuclear factor erythroid 2) is a transcription factor that is involved in cellular responses to oxidative damage and inflammation. See: Nrf2 Activators.

 

Carophyllene is also thought to be effective against neuro-inflammation by reducing activity of glial cells.This compound is often used in topical anti-inflammatory ointments and salves. β-Caryophyllene’s anti-inflammatory activity is comparable in potency to phenylbutazone, etodolac and indomethacin. In contrast to NSAIDs, however, caryophyllene protects the stomach lining  and has been claimed to be effective in treating duodenal ulcers in the United Kingdom. It has been suggested to help relieve muscle spasms and there is some evidence for benefit in alcohol addiction and depression.

 

β-Caryophyllene: Pain

Early animal research in rats/mice have identified β-caryophyllene (BCP) as a selective full agonist at the cannabinoid receptor type 2 (CB2). It has been shown to exhibit analgesic effects in neuropathic pain associated with chemotherapy, diabetes, and chronic nerve damage.  Analgesia produced by BCP is mediated by activation of CB2 receptors, which stimulates the local release from keratinocytes (superficial skin cells) of the endogenous opioid β-endorphin. When combined with morphine, a synergistic, increased analgesic benefit of low dose BCP was found.

 

β-Caryophyllene: Cold Weather and Wild Giant Pandas

The TRPM8 receptor on sensory nerves in the skin become activated upon exposure to cold, triggering the sensation of feeling cold.  This receptor may be triggered environmentally by exposure to cold or chemically by exposure to compounds such as menthol.  β-caryophyllene inhibits cold-activation of these receptors and suppresses the perception of feeling cold which helps to improve cold tolerance at low temperatures.

In fact, studies have shown that in cold weather, giant pandas roll in fresh horse manure which is rich in β-caryophyllene as a means of adapting to the cold!  As of yet I have not found studies to assess how effective topical β-caryophyllene may be in humans for tolerating cold weather, or reducing the impact of cold weather on pain. I will be looking…

 

β-Caryophyllene: Alcohol and Cocaine Abuse

Research also suggest that CB2 receptors play a major role in alcohol reward and the CB2 receptor system may be involved in alcohol and cocaine dependence via modulation of dopamine reward pathways. In mice, β-caryophyllene has been shown to reduce voluntary alcohol intake as well as decrease cocaine self-administration. It may therefore represent a potential pharmacological target for the treatment of alcohol and cocaine abuse.

β-Caryophyllene: Paclitaxel-induced Peripheral Neuropathy (PINP)

Painful peripheral neuropathy is a common side effect of paclitaxel (PTX), a chemotherapy medication used to treat a number of types of cancer. However, currently employed analgesics have several side effects and are poorly effective. β-caryophyllene (BCP), a selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain is not yet known. A 2017 study in mice receiving PTX indicated that BCP reduced nerve pain sensitivity to mechanical stimulation (allodynia) induced by the PTX possibly through CB2-activation in the CNS and inhibition of inflammatory cytokines. These results suggest that BCP might be useful in treating the nerve pain associated with PINP.

 

β-Caryophyllene: Depression and Stress

β-caryophyllene shows promise for treating depression and stress related mental illnesses due to its direct binding to CB2 receptors.

  

Caryophyllene: Multiple Sclerosis

Multiple sclerosis (MS) is a severe inflammatory demyelinating disease of the central nervous system (CNS). It affects over two million people worldwide although the cause of MS is  not completely understood. However, studies with MS patients suggest that the demyelination associated with MS in the CNS results from a T cell-mediated autoimmune response. Due to growing research indicating that some of the constituents found in cannabis possess anti-inflammatory properties and may suppress certain functions withing the immune response, research is focusing on cannabis use to treat MS.

In an investigation published in 2017 to evaluate the therapeutic potential of BCP in an experimental animal model of multiple sclerosis (MS),  it was found that BCP significantly reduces both the clinical and pathological features of the animal model. The mechanisms underlying BCPs immunomodulatory effect appears to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes and pro-inflammatory cytokines. Furthermore, it reduce axonal demyelination  through the activation of CB2 receptor. The study has important implications for clinical research and strongly supports the effectiveness of BCP as a possible molecule to target in the development of effective treatment for MS.

 

β-Caryophyllene: Other Potential Therapeutic Benefits

BCP is believed to be a neuroprotective, antidiabetic, antioxidant, and anticonvulsive agent as well as to reduce neuroinflammation, improve lipid profiles, alleviate endometriosis, and show promise for interstitial cystitis, substance abuse disorders, and protection against nonalcoholic fatty liver disease.

 

Caryophyllene: Products

Despite its promising biological activities, β-caryophyllene is characterized by high lipophilicity and poor solubility in water-based media such as biological fluids, which limits its bioavailability and absorption into cells. The poor solubility of this terpene in aqueous fluids can hinder its uptake into cells, resulting in inconsistent therapeutic effects, thus limiting its application. β-caryophyllene’s absorption is good when it is delivered in an oil-based medium but new products are being developed in which the β-caryophyllene is enveloped in a fatty layer (liposomal) to enhance its bioavailabity when delivered in aqueous media.

 

Topical β-caryophyllene Products

Because β-caryophyllene is generally considered safe, it is available in over-the-counter (OTC) products. A particularly useful formulation for β-caryophyllene is in topical creams because there are many CB2 receptors as well as TRPM8 receptors in the skin allowing for effetive treatment of nerve pain and cold sensitiviy respectively.

 

There are growning numbers of commerical topical products now available, including Entourage Bio-Therapeutics, which also contain CBD but are THC-free. In addition to OTC products, prescription cannabis-based products that also contain THC are available in LA, including “Soothe” by Ilera.

 

Direct Effects™ Topical β-Caryophyllene

As part of a patent process regarding topical therapy with β-Caryophyllene, it was reported that 30 mg of β-caryophyllene applied to the back of neck, spinal regions or at peripheral areas of neurological dysfunction provided relief and benefit for the following conditions within 10 to 15 minutes of topical application:

    • Muscle Tension & Spasm
    • Peripheral Neuropathic Pain
    • Post-Herpetic Neuralgia/Zoster

    • Tinnitus/Ringing in Ears

    • Trigeminal Neuralgia

    • Blepharospasm

 

It was reported that the duration of therapeutic effect ranged from a few hours to an entire day, depending on condition treated; and its severity and duration. The only side effects reported were occasional tingling and slight transient burning sensation following topical cream application. There was a rare headache. Rash or irritation at the site of application was experienced in less than 5% of patients treated. Because of its non-systemic nature, no systemic side effects or drug-drug interactions were observed.

 

Caryophyllene: In Food

β-caryophyllene is commonly ingested with vegetables, and an estimated daily intake of 10–200 mg of this terpene could be a dietary factor to benefit inflammatory and other pathophysiological processes.

 

Humulene (obsolete name: α-caryophyllene)

Humulene (previously termed α-caryophyllene) is an isomer of β-caryophyllene and plays a significant role in many of the distinguishing characteristics between different cannabis strains like White Widow, Headband, Girl Scout Cookies, Sour Diesel, Pink Kush and Skywalker OG. It is also found in herbs and spices such as hops, clove, basil, sage, ginger, spearmint, and ginseng as well as some fruits and vegetables. It has strong anti-inflammatory properties comparable to dexamethasone systemically and topically, as well as analgesic properties.  There are anecdotal reports that it causes weight loss and appetite suppression and it is often promoted for weight-loss as an appetite suppressant. Humulene is also said to have analgesic and anti-bacterial properties.

 

Alpha-pinene (α-pinene)

Pinene is one of the most most commonly occurring terpene in nature. In nature, two structural isomers of this terpene exist, α-pinene and β-pinene  Pinenes are found in cannabis strains like Jack Herer, Strawberry Cough, Blue Dream, Island Sweet Skunk, Dutch Treat and Romulan. They are also found in pine needles, conifers, and many herbs such as parsley, basil, and dill. These terpenes are also the major constituents of turpentine, and are abundant in rosemary and lavender. α-pinene is the main compound found in frankincense (Boswellia frereana), myrtle, juniper, camphor, and conifers.

 

Pinene acts on multiple neurologic pathways, including GABAergic, cholinergic, dopaminergic, serotoninergic, adrenergic, noradrenergic neurotransmitter systems. It acts in multiple regions of the brain inckuding the hippocampus, frontal cortex, striatum and midbrain.

 

Pinene’s low molecular weight and high lipophilicity suggests it likely penetrates the blood brain barrier and studies indicate that pinene can enter the brain following oral ingestion or inhalation .  α-pinene and β-pinene do not appear to have an appreciable binding affinity for CB1 or CB2 receptors. The mechanisms underlying α-pinene-induced pain benefits are unclear but may involve GABAA and μ-opioid receptors However, the ability of pinene to reduce pain in inflammatory states and exert longer-lasting analgesia suggests that pinene has a broader mechanism of action than only activity on the opioid receptors.

 

Extensively investigated for its medicinal properties, alpha-pinene has been found to have sedative, hypnotic, and anxiolytic properties along with significant anti-inflammatory and analgesic benefits. Pinene also plays an insect-repellent role in plants and is a bronchodilator in humans at low exposure levels, suggesting benefit in asthma. It is an acetylcholinesterase inhibitor that may reduce short-term memory impairment from THC. Claims have been made that it improves a person’s ability to focus their attention as well as to reduce perception of stress.

 

Anti-inflammatory and Analgesic Effects

As noted above, pinene is one of the dominant terpenes found in cannabis strains known to benefit chronic pain. Alpha-pinene’s anti-inflammatory and analgesic benefits take place through inhibition of COX-2.

 

SARS-CoV

Essential oils have been evaluated for their inhibitory activity against SARS-CoV replication in the lab. L. nobilis oil, containing beta-ocimene, 1,8-cineole, alpha-pinene, and beta-pinene as the main constituents appears to have antiviral activity against SARS-CoV. Pinene also acts as a broad-spectrum antibiotic and has also been shown to have prominent activity against antibiotic-resistant staph bacteria (MRSA). These properties likely contribute to the disinfectant properties of Pine-Sol,® a multi-surface cleaner.

 

Antioxidant

Studies have shown that α-pinene, β-caryophyllene and linalool up-regulate Nrf2 activity to protect cells from oxidative damage. Nrf2 (nuclear factor erythroid 2) is a transcription factor that is involved in cellular responses to oxidative damage and inflammation. See: Nrf2 Activators

 

Arthritis

Pinene is anti-inflammatory via prostaglandin PGE-1 and its antioxidant and anti-inflammatory effects in human chondrocytes (cartilage cells), suggests potential benefit in arthritis. It is thought to have analgesic benefits as well.

 

Anxiety and Sleep

Pinene exerts its effects on the brain through its ability to act as a positive modulator of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA)A receptor subtype by binding to the benzodiazepine site to improve sleep. It significantly increases the duration of non-rapid eye movement sleep (NREMS), and reducing sleep latency (time to fall asleep).

  
β-Pinene

Related to α-pinene, β-Pinene is another important monoterpene present in different strains of Cannabis. β-pinene has antimicrobial, antiseptic and antioxidant activity. It also may have anti-depressant-like and sedative-like properties. The mechanisms for these benefits are unknown but theorized to be related to the serotonergic  adrenergic and/or dopaminergic systems. α-pinene and β-pinene inhibis the activity of acetylcholinesterase in the brain and are thought to aid memory and minimize cognitive dysfunction induced by THC intoxication.

 

Overall, existing pre-clinical studies still require replication in human trials while the effectiveness and safety of pinene remain unknown. Nevertheless, with initial research demonstrating their psychopharmacological and anti- inflammatory effects, pinene isomers may be of use treating anxiety and depression, while their combination of anti- inflammatory and analgesic properties suggest they may be suitable fot treating chronic pain, but further research is needed.

 

 

Carene (Delta 3-Carene)

Delta 3-carene (Carene) is a terpene found in basil, bell peppers, rosemary, and cannabis that promotes the drying up of excess liquid and has anti-inflammatory effects. Side effects often associated with this terpene are dry mouth and red eyes. Carene has a pungent and pleasant earthy aroma that is piney in resemblance. This terpene is thought to stimulates memory and help memory retention.

 

Eucalyptol (Cineole)

Also known as cineole, eucalyptol is the primary terpene of the eucalyptus tree. It is also found in tea tree, rosemary, sweet basil, wormwood, tea trees, mugwort, bay leaves and common sage. Most cannabis strains do not contain large amounts of eucalyptol, usually only making up around 0.06% of a strains complete terpene profile. Eucalyptol can be found in the cannabis strains Super Silver Haze and Headband.

 

It has been proposed to improve memory and cognitive learning and because of its cholinesterase inhibitory activity, it has potential for use in Alzheimer’s disease and protection against amyloid beta-induced inflammation. Eucalyptol has antioxidative, anti-inflammatory and analgesic properties and has been suggested as a potential long-term therapy in the prevention of COPD exacerbations and asthma and inflammatory bowel disease. It helps treat nasal and sinus inflammation and secretions and is used as a nasal decongestant and cough suppressant.

 

Terpinene

Terpinene is considered an anti-inflammatory, antimicrobial, analgesic, and anticancer agent.

 

Terpinolene

Terinolene can be found in apples, cumin and lilac. It is purported to be sedating and calming, often found in cannabis indica.

 

Terpineol

Terpineol is found in pine trees, lilacs, eucalyptus, and lime blossoms, and has a pleasant scent, similar to lilac, and is a common ingredient in perfumes, cosmetics, and flavors. Terpineol can be found  in Girl Scout Cookies, Jack Herer, and OG Kush strains. Animal and preclinical studies sugges it has anti-inflammatory, analgesic and antioxidant properties and it may have anxiolytic and sedative effects. There is no evidence that terpineol interacts with CB receptors.

 

Nonetheless, terpineol shows different pharmacological properties that include analgesic, antifungal, anti-inflammatory, and antidiarrheal. Terpineol has been investigated in different animal models of pain and research suggests that terpineol may have analgesic benefit by activation of descending inhibitory pain system. Its analgesic effect is reversed by naloxone (opioid antagonist), and ondansetron (5-HT3 serotonin antagonist) suggesting multiple modes of action. Terpineol has been demonstrated to be a safe and effective drug for control of sarcoma-induced cancer pain in mice.

 

Regarding it anti-inflammatory properties, terpineol has also been investigated for the treatment of allergic inflammation and asthma. Terpineol decreases leucocyte migration and TNF levels and suppresses the production of inflammatory mediators (e.g., NF-κB, p38, ERK, and MAPK signaling pathways) in human macrophages.

 

Terpineol properties go beyond the above. It has been shown to have bactericidal and antifungal properties and strong anti-proliferative activity on cancer. Terpineol is a versatile compound with a wide variety of beneficial effects which could lead to the development of new antibiotics, antifungal, and anticancer agents.

 

Nerolidol (trans-nerolidol)

Nerolidol (trans-nerolidol) is a secondary terpene found in many herbs and spices including lavender, lemon grass, ginger, jasmine, tea tree, oranges, and it is present at low levels in the peels of citrus fruit. Cannabis strains like Island Jack Herer, Sweet Skunk, and Skywalker OG are rich in nerolidol. Nerolidol has sedative properties and is useful in insomnia. The mechanism of action for proposed analgesic activity of trans-nerolidol involves the GABAergic system, but not the opioidergic system.

 

 

Alpha-bisabolol (α-bisabolol, bisabolol, levomenol)

Alpha-bisabolol (also known as levomenol and bisabolol) has a pleasant floral aroma and can also be found in chamomile flowers. This terpene is used primarily in the cosmetics industry, but the pharmacological attributes of α-bisabolol include wound healing, gastroprotection, antitumor, antioxidant, analgesic and anti-inflammatory properties. While animal and preclinical studies support the folk use of herbs and plants containing bisabolol for pain and inflammation, human studies are lacking. Alpha-bisabolol can be found in cannabis strains like Harle-Tsu, Pink Kush, Headband, OG Shark, and ACDC.

 

Commercial Products

 

Terpene Products

Commercial terpene products are availabe for use as supplements to be used independently or in combination with cannabis-based products, including THC and CBD.  Some companies promote their products by claiming the constituents in their terpene products are formulated to simulate the same terpene blends of specific cannabis strains.  Upon investigation, it was not possible to find on their website evidence to confirm their claims regarding their blends, probably to protect their proprietary interests. Links to some of these products are available here for educational purposes but are not meant to recommend or endorse the products. It should also be emphasized that these terpene products do not contain THC, CBD or other cannabinoids.

 

CBD Products

In addition to commercial terpene products, there are many CBD products that contain terpenes. CBD products with terpenes are labeled as “broad spectrum” when the constituents have no THC and “full spectrum” when they contain THC at levels up to a 0.3%. Unfortunately, CBD products frequently do not identify their specific terpenes and their concentrations, again, probably to protect their proprietary interests.

See: CBD

 

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

 

References:

   

Terpenes – Overviews

  1. Therapeutic and Medicinal Uses of Terpenes – 2019
  2. Terpenes:Terpenoids in Cannabis – Are They Important? – 2020
  3. Advances in Pharmacological Activities of Terpenoids – 2020
  4. Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant – 2020
  5. The Cannabis Terpenes – 2020
  6. The “Entourage Effect” – Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – 2020
  7. Cannabis Essential Oil – A Preliminary Study for the Evaluation of the Brain Effects – 2018
  8. A Systematic Review of Essential Oils and the Endocannabinoid System – A Connection Worthy of Further Exploration – 2020
  9. Efficacy of Essential Oils in Pain – A Systematic Review and Meta-Analysis of Preclinical Evidence – 2021

 

Terpenes – Aromatherapy

  1. Aromatherapy and Aromatic Plants for the Treatment of Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease Clinical Evidence and Possible Mechanisms – 2017
  2. Corrigendum – A question of scent – lavender aroma promotes interpersonal trust -2015
  3. Odors enhance slow-wave activity in non-rapid eye movement sleepOdors enhance slow-wave activity in non-rapid eye movement sleep
  4. Essential Oils and Animals – Which Essential Oils Are Toxic to Pets?
  5. Essential Oils and Pets
  6. Herbs and Their Uses for Animals – Patchouli and Pets
  7. Reactivating memories during sleep by odors – odor specificity and associated changes in sleep oscillations – 2014
  8. Increasing Explicit Sequence Knowledge by Odor Cueing during Sleep in Men but not Women – 2016
  9. Effects of odorant administration on objective and subjective measures of sleep quality, post-sleep mood and alertness, and cognitive performance – 2003
  10. An Olfactory Stimulus Modifies Nighttime Sleep in Young Men and Women – 2005
  11. Massage with or without aromatherapy for symptom relief in people with cancer. – PubMed – NCBI
  12. Aromatherapy hand massage for older adults with chronic pain living in long-term care. – PubMed – NCBI
  13. A Systematic Review of Essential Oils and the Endocannabinoid System – A Connection Worthy of Further Exploration – 2020
  14. Human olfactory receptors – novel cellular functions outside of the nose,” – 2017
  15. The diversified function and potential therapy of ectopic olfactory receptors in non-olfactory tissues – PubMed – 2017
  16. How does your kidney smell? Emerging roles for olfactory receptors in renal function,” – 2017

 

Terpenes – CB2 Receptor

  1. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain – an updated review – 2021
  2. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – 2014
  3. The CB2 receptor and its role as a regulator of inflammation – 2016

 

Terpenes – Synergy with Cannabinoids:

  1. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  2. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  3. Entourage Effect 2.0
  4. Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype – 2018
  5. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity – 2019
  6. Absence of Entourage – Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors – 2019
  7. Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors – 2020
  8. The “Entourage Effect” – Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – 2020

 

Terpenes – Marijuana Strains

  1. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  2. Terpenoid Chemoprofiles Distinguish Drug-type Cannabis sativa L. Cultivars in Nevada – 2018
  3. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity – 2019
  4. Identification of Terpenoid Chemotypes Among High (−)-trans-Δ9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars 0 2017
  5. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018

 

Terpenes – Routes of Use:

  1. The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application – 2020
  2. Antiviral effect of phytochemicals from medicinal plants – Applications and drug delivery strategies – 2020
  3. Cannabinoid Delivery Systems for Pain and Inflammation Treatment – 2018

 

Terpenes – Bioavailability

  1. Bioavailability and Pharmacokinetics of Natural Volatile Terpenes in Animals and Humans – 2000
  2. Bioavailability of Bioactive Compounds
  3. SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene – 2018

 

Terpenes – Arthritis

  1. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015

 

Terpenes – Anxiety

  1. Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype – 2018
  2. The “Entourage Effect”: Terpenes Coupled With Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – PubMed – 2019
  3. Medicinal cannabis for psychiatric disorders – a clinically-focused systematic review – 2020
  4. A Systematic Review of the Anxiolytic-Like Effects of Essential Oils in Animal Models – 2015
  5. A Systematic Review on the Anxiolytic Effect of Aromatherapy during the First Stage of Labor – 2019
  6. A Systematic Review on the Anxiolytic Effectsof Aromatherapy in People with Anxiety Symptoms – 2011
  7. Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression – PubMed – 2020
  8. Effect of Aromatherapy on Dental Anxiety Among Orthodontic Patients – A Randomized Controlled Trial – 2019
  9. Essential Oils and Their Constituents – An Alternative Source for Novel Antidepressants – 2017
  10. Essential Oils and Their Constituents Targeting the GABAergic System and Sodium Channels as Treatment of Neurological Diseases – 2018
  11. Possible Use of Phytochemicals for Recovery from COVID-19-Induced Anosmia and Ageusia – 2021
  12. The calming effect of roasted coffee aroma in patients undergoing dental procedures – 2021
  13. The Effect of Lavender Aroma on Anxiety of Patients Having Bone Marrow Biopsy- 2020
  14. The-Effects-of-Essential-Oils-and-Terpenes-in-Relation-to-Their-Routes-of-Intake-and-Application-2020
  15. Therapeutic Effect and Mechanisms of Essential Oils in Mood Disorders – Interaction between the Nervous and Respiratory Systems – 2021
  16. Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats – 2019

 

Terpenes – Infectious Diseases

  1. Phytochemical Analysis and in vitro Antiviral Activities of the Essential Oils of Seven Lebanon Species – 2008
  2. Antiviral effect of phytochemicals from medicinal plants – Applications and drug delivery strategies – 2020
  3. Essential Oils and Coronaviruses – 2020

 

Terpenes – Pain:

  1. Analgesic-like Activity of Essential Oils Constituents – 2011
  2. Analgesic-Like Activity of Essential Oil Constituents – An Update – 2017
  3. Medicinal Plants of the Family Lamiaceae in Pain Therapy – A Review – 2018
  4. Analgesic Potential of Essential Oils – 2016
  5. Medicinal Plants of the Family Lamiaceae in Pain Therapy – A Review – 2018
  6. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  7. Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant – 2020
  8.  The Molecular Mechanisms That Underpin the Biological Benefits of Full-Spectrum Cannabis Extract in the Treatment of Neuropathic Pain and Inflammation – PubMed – 2020
  9. Cannabis-based medicines and the perioperative physician – 2019
  10. Cannabis‐based medicines for chronic neuropathic pain in adults – 2018
  11. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain – An Update on Current Evidence and Cannabis Science – 2018
  12. Role of Cannabinoids and Terpenes in Cannabis-Mediated Analgesia in Rats – PubMed – 2019
  13. Antinociceptive effect of inhalation of the essential oil of bergamot in mice – 2018
  14. Analgesic Potential of Essential Oils – 2016
  15. Analgesic-Like Activity of Essential Oil Constituents – An Update – 2017

 

 

Terpenes – Headaches:

  1.  Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain – An Update on Current Evidence and Cannabis Science – 2018
  2. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018

 

Terpenes – Inflammation:

  1. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015 
  2. Cannabis sativa L. and Nonpsychoactive Cannabinoids – Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer – 2018
  3. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  4. Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases – 2020
  5.  The Molecular Mechanisms That Underpin the Biological Benefits of Full-Spectrum Cannabis Extract in the Treatment of Neuropathic Pain and Inflammation – PubMed – 2020
  6. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015
  7. Cannabis, Cannabinoids, and the Endocannabinoid System—Is there Therapeutic Potential for Inflammatory Bowel Disease? – 2019
  8. Therapeutic Applications of Terpenes on Inflammatory Diseases – 2021

 

 Individual Sources of Terpenes

 

Terpenes – Bergamot

  1. The Anxiolytic Effect of Aromatherapy on Patients Awaiting Ambulatory Surgery – A Randomized Controlled Trial – 2013
  2. Antinociceptive effect of inhalation of the essential oil of bergamot in mice – 2018
  3. Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats – 2019
  4. Bergamot – Natural Medicines – Professional.pdf
  5. Citrus bergamia essential oil – from basic research to clinical application – 2015
  6. Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent – 2020 Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs – PubMed – 2019
  7. Possible involvement of the peripheral Mu-opioid system in antinociception induced by bergamot essential oil to allodynia after peripheral nerve injury – PubMed – 2018
  8. Peripherally injected linalool and bergamot essential oil attenuate mechanical allodynia via inhibiting spinal ERK phosphorylation – PubMed – 2013
  9. Neuropharmacology of the essential oil of bergamot – PubMed – 2010
  10. Effect of Harvesting Time on Volatile Compounds Composition of Bergamot (Citrus × Bergamia) Essential Oil – 2019
  11. Chemical Composition and Biological Activities of Essential Oils from Peels of Three Citrus Species – 2020
  12. Chemical_Composition_of_Bergamot_Citrus_Bergamia_Risso_Essential_Oil_Obtained_by_Hydrodistillation – 2010
  13. Cannabinoid Signaling in the Skin – Therapeutic Potential of the “C(ut)annabinoid” System – 2019
  14. Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain – PubMed – 2016

 

Individual Terpenes

Terpenes: β-Caryophyllene:

  1. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis – 2017
  2. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. – PubMed – NCBI
  3. Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion – 2018
  4. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. – PubMed – NCBI
  5. Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation? – 2016
  6. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice – 2012
  7. β‐caryophyllene and β‐caryophyllene oxide—natural compounds of anticancer and analgesic properties – 2016
  8. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – 2014
  9. Toxicological Evaluation of β-Caryophyllene Oil: Subchronic Toxicity in Rats. – PubMed – NCBI 2016
  10. The cannabinoid CB₂ receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic… – PubMed – NCBI – 2014
  11. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain – 2013
  12. SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene – 2018
  13. β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway – 2011
  14. Why wild giant pandas frequently roll in horse manure – 2020
  15. Beta-caryophyllene is a dietary cannabinoid – 2008
  16. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. – 2006
  17. The menthol receptor TRPM8 is the principal detector of environmental cold – PubMed – 2007
  18. Molecular basis of peripheral innocuous cold sensitivity – 2018
  19. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception – PubMed – 2013
  20. NON-CANNABIS THERAPY – Cannabinoid Therapy Without Using Cannabis: Direct Effects™ Topical β-Caryophyllene

 

Terpenes: Linalool:

  1. GS12-linalool
  2. Linalool – 1997
  3. The “Entourage Effect”: Terpenes Coupled With Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – PubMed – 2020
  4. An olfactory stimulus modifies nighttime sleep in young men and women. – PubMed – NCBI
  5. Lavender and sleep – A systematic review of the evidence – 2012
  6. Lavender and the Nervous System – 2013
  7. Effects of odorant administration on objective and subjective measures of sleep quality, post-sleep mood and alertness, and cognitive performance – 2003
  8. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. – PubMed – NCBI – 2000
  9. Odors enhance slow-wave activity in non-rapid eye movement sleep – 2016
  10. A question of scent – lavender aroma promotes interpersonal trust – 2015
  11. Is Lavender an Anxiolytic Drug? A Systematic Review of Randomised Clinical Trials – 2012
  12. Efficacy of Silexan in subthreshold anxiety – meta-analysis of randomised, placebo-controlled trials – 2019
  13. Essential oil of lavender in anxiety disorders – Ready for prime time? – 2017
  14. Linalool is a PPAR ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome – 2014
  15. A Review of the Potential Use of Pinene and Linalool as Terpene-Based Medicines for Brain Health – Discovering Novel Therapeutics in the Flavours and Fragrances of Cannabis – 2021
  16. The Efficacy of Lavender Aromatherapy in Reducing Preoperative Anxiety in Ambulatory Surgery Patients Undergoing Procedures in General Otolaryngology – 2017
  17. Efficacy, Safety and Tolerability of Aroma Massage with Lavender Essential Oil – an Overview – 2020
  18. Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide – 2017
  19. Exploring Pharmacological Mechanisms of Lavender (Lavandula angustifolia) Essential Oil on Central Nervous System Targets – 2017
  20. Linalool Ameliorates Memory Loss and Behavioral Impairment Induced by REM-Sleep Deprivation through the Serotonergic Pathway – 2018
  21. Effects of lavender on anxiety, depression and physiologic parameters – Systematic Review and Meta-Analysis – 2021
  22. Lavender and sleep – A systematic review of the evidence – 2012
  23. Lavender and the Nervous System – 2013
  24. A question of scent – lavender aroma promotes interpersonal trust – 2015

 

 

Terpenes, Linalool:Silexan

  1. A Multi-Center, Double-Blind, Randomised Study of the Lavender Oil Preparation Silexan in Comparison to Lorazepam for Generalized Anxiety Disorder – 2010
  2. Is Lavender an Anxiolytic Drug? A Systematic Review of Randomised Clinical Trials – 2012
  3.  An Orally Administered Lavandula Oil Preparation (Silexan) for Anxiety Disorder and Related Conditions- An Evidence Based Review – 2013
  4. Lavender oil preparation Silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine – 2014
  5. Silexan in anxiety disorders – Clinical data and pharmacological background – 2017
  6. Effectiveness of Silexan Oral Lavender Essential Oil Compared to Inhaled Lavender Essential Oil Aromatherapy for Sleep in Adults- A Systematic Review – 2018
  7. Silexan in anxiety disorders Clinical data and pharmacological background – PubMed – 2018
  8. Efficacy and safety of lavender essential oil (Silexan) capsules among patients suffering from anxiety disorders – A network meta-analysis – 2019
  9. Efficacy of Silexan in subthreshold anxiety – meta-analysis of randomised, placebo-controlled trials – 2019
  10. Therapeutic effects of Silexan on somatic symptoms and physical health in patients with anxiety disorders – A meta- analysis – 2020
  11. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of ‘subsyndromal’ anxiety disorder a randomized, double-blind, placebo controlled trial – PubMed – 2010
  12. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder – PubMed – 2009
  13. No Abuse Potential of Silexan in Healthy Recreational Drug Users – A Randomized Controlled Trial – 2021

 

Terpenes – Limonene

  1. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015
  2. Neuroprotective Potential of Limonene and Limonene Containing Natural Products – 2021

 

Terpenes: Myrcene

  1. β-MYRCENE – IARC MONOGRAPHS
  2. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015

 

Terpenes: Pinene

  1. A Review of the Potential Use of Pinene and Linalool as Terpene-Based Medicines for Brain Health – Discovering Novel Therapeutics in the Flavours and Fragrances of Cannabis – 2021

 

 

Medical Marijuana – Product Evaluation

  1. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018
  2. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  3. Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements – 2020

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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