Accurate Education – Marijuana (Cannabis): Terpenes – An Overview

Terpenes

 

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.

 

Cannabis is very aromatic, with different strains having their unique smells. 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 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 overall medical effects of cannabis. For more information about terpenes, see below.

 

See:

Marijuana – Legislative Update for Louisiana

Marijuana – Medical Use Overview

“Medical Marijuana” – Getting Started

Cannabis-Based Medications:

Over-the-Counter Cannabinoid Medications:

Marijuana – Cannabidiol (CBD)

 

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 & Terpenes – An Overview (coming soon)

Cannabinoids:

Marijuana – Cannabidiol (CBD)

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

cannabis-caduceus 

Terpenes

What are Terpenes?

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 are commonly used in the manufacturing of essential oils, natural flavorings and beauty products and are extensively used in fragrances and aromatherapy. They have been designated Generally Recognized as Safe (GRAS) by the US Food and Drug Administration (FDA). Terpenoids give the cannabis plant its characteristic scents.

 

Terpenoids are chemically related to the cannabinoids, sharing a common precursor, and have been proposed to exert therapeutic effects 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. Each terpene displays unique therapeutic effects that may contribute significantly to the entourage effects of cannabis-based products. Proposed synergistic effects of cannabinoid-terpenoid interactions include pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including MRSA – methicillin-resistant Staphylococcus aureus).There is an abundance of evidence for the clinical impact of terpenes in the field of aromatherapy.

 

Terpenes and terpenoids 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. Some of the commonly studied terpenes include limonene, myrcene, a-pinene, linalool, b-caryophyllene, caryophyllene oxide, nerolidol and phytol.

 

What do Terpenes do?

Terpenoids are quite potent, and affect animal and even human behavior when inhaled from ambient air at extremely low blood levels, <10 ng/mL. They contribute unique therapeutic effects that likely paricipate ine  the “entourage” effect of cannabis-based copounds. The “entourage” effect is a proposed synergistic pharmacologic effect created by the combination of the different constituents in cannabis, especially the different cannabinoids and terpenes. Four basic mechanisms of synergy have been proposed: (i) multi-target effects; (ii) pharmacokinetic effects such as improved solubility or bioavailability; (iii) agent interactions affecting bacterial resistance; and (iv) modulation of adverse events.

 

It is theorized that the synergy of cannabinoid-terpenoid interactions contribute to the medical benefits (and side effects) of cannabis with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus).

 

Scientific evidence is relatively convincing that the medical benefits of cannabis cannot be achieved by simple isolates of singular cannabinoids including THC and CBD. Evidence is present that non-cannabinoid marijuana plant components modulate the clinical effects of CBD and the intoxicating effects of THC. There is a great need for further research into the entourage effects generated by the cannabinoid-terpenoid synergy to expand our clinical applications of medical marijuana.

 

In fact, there is some evidence that several odors 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.

 

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, citrus fruits, and thyme as well as hops and lemongrass.

 

 The indica strains of cannabis commonly contain up to 0.5% or more of myrcene which is believed to contribute to sedative effects and aid in relaxation. Myrcene is a recognized sedative found in hops prepara- tions (Humulus lupulus) and is employed as a sleep aid  in Germany. Furthermore, myrcene acted as a muscle relaxant in mice, and potentiates barbiturate sleep time at high doses. Data supports the hypothesis that myrcene is a prominent sedative terpenoid in cannabis.

 

Interestingly, myrcene has been found to be analgesic in mice, but this action can be blocked by naloxone, perhaps via the a-2 adrenoreceptor, raising questions as to its mechanism of action.  Overall, myrcene may be useful in reducing inflammation and chronic pain and has been recommended as a supplement during cancer treatments.

 

Limonene

Limonene is the second most abundant terpene in cannabis, but it is not necessarily found in all strains. As the name itself implies, limonene has a citrus-like scent that resembles lemons and can be found in citrus fruits like lemons, limes, oranges and grapefruit which contain large amounts of this compound. Limonene is is highly non-toxic, highly bioavailable and rapidly metabolized, but it is accumulated and retained in adipose tissues and brain brain.

 

Proposed therapeutic benefits of limonene include mood enhancement and stress reduction as well as sedation. 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.

 

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. Linalool can also be found in lavender (Lavandula angustifolia), mint, cinnamon, and coriander. Just like those aromatic herbs used in traditional aromatherapy, linalool also reduces anxiety and provides sedation and relaxation. Interestingly, linalyl acetate, the other primary terpenoid in lavender, hydrolyses to linalool in gastric secretions.

 

Linalool has been found to have local anaesthetic effects equal to those of procaine and menthol and provides anti-nociceptive (anti-pain) benefits at high doses in mice. Linalool is also an  anticonvulsant. 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.

 

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. It has been proposed to offer benefit in patients suffering from arthritis, depression, seizures and insomnia. In fact, there is some evidence that linalool, present in lavender oil, improves sleep efficiency, increased total sleep time, elevated vigor the following morning and promotes sleep in patients with insomnia.

 

Caryophyllene or β-Caryophyllene (BCP)

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. Described as earthy and peppery, Caryophyllene is also found in black pepper (Piper nigrum), Copaiba balsam (Copaifera officinalis), clove,  cinnamon, oregano, hops and rosemary. Because carophyllene binds to CB2 receptors, some consider this terpene to be a cannabinoid. Carophyllene may help with pain, inflammation, alcohol addiction and depression. This compound is often used in topical anti-inflammatory ointments and salves.

 

Caryophyllene has demonstrated anti-inflammatory activity via prostaglandin PGE-1, 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 along with cannabis extract. It has been suggested to help relieve muscle spasms.

 

Early animal research in rats/mice have identified (−)-β-caryophyllene (BCP) as a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid. It has been shown to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Caryophyllene activitty as a selective full agonist at the CB2 cannabinoid receptor suggests this is the mechanism for its anti-inflammatory analgesic activity.

 

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.

  

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.

 

Pinene

Pinene is one of the most widely encountered terpenoids in nature, appearing in conifers, rosemary, sage and innumerable other plants, with an insect-repellent role. It is anti-inflammatory via prostaglandin PGE-1 and is a bronchodilator in humans at low exposure levels, suggesting benefit in asthma. Pinene acts as a broad- spectrum antibiotic and has also been shown to have prominent activity against antibiotic-resistant staph bacteria (MRSA). Claims have been made that it improves a person’s ability to focus their attention as well as to reduce perception of stress.

 

Carene (Delta 3-Carene)

Delta 3-carene (Carene): 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.

Humulene

Humuleneis often promoted for weight-loss as an appetite suppressant. Humulene is also said to have analgesic and anti-bacterial properties.

 

Terpinolene

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

 

Safety

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 by the US Food and Drug Administration (FDA) as food additives. Additionally, they are non-sensitizing to skin when fresh, but may cause allergic reactions. Terpenes are not associated with physical dependence (e.g. withdrawal and tolerance), nor associated with abuse or addiction.

 

Potential Conditions Responsive to Terpenes

In addition to the potentially direct clinical benefit that may be derived from the various cannabis-related terpenes, the Entourage Effect, or cannabinoid- terpenoid synergy might theoretically apply. The following is a list of conditions that, while highly speculative, might respond to a cannabinoid-terpenoid synergy:

  1. Anxiety
  2. Depression
  3. Insomnia
  4. Dementia
  5. Addiction

 

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). Addition of anxiolytic limonene and linalool could contribute to the clinical efficacy of a CBD extract.

 

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 psychopharmacological 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.

      

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.

 

 

 

 

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. 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

Terpenes: 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

 

Terpenes: Linalool:

  1. An olfactory stimulus modifies nighttime sleep in young men and women. – PubMed – NCBI
  2. Lavender and sleep – A systematic review of the evidence
  3. Lavender and the Nervous System – 2013
  4. Effects of odorant administration on objective and subjective measures of sleep quality, post-sleep mood and alertness, and cognitive performance – 2003

 

CBD – Anxiety

  1. Overlapping Mechanisms of Stress-Induced Relapse to Opioid Use Disorder and Chronic Pain – Clinical Implications – 2016
  2. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System – 2016
  3. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. – PubMed – NCBI
  4. Review of the neurological benefits of phytocannabinoids – 2018
  5. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders – 2017
  6. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. – PubMed – NCBI
  7. Evidences for the Anti-panic Actions of Cannabidiol – 2017
  8. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug – 2012
  9. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients – 2011

 

CBD – Interaction with THC

  1. Cannabidiol: a promising drug for neurodegenerative disorders? – PubMed – NCBI
  2. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis – 2015
  3. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  4. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI

 

 

  1.  

Medical Marijuana –Misc

  1. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  2. Cannabis and cannabis extracts – greater than the sum of their parts? – 2001
  3. Medical cannabis and mental health: A guided systematic review. 2016 – PubMed – NCBI
  4. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. – PubMed – NCBI
  5. Cannabis-conclusions – 2017 National Academy of Sciences
  6. Cannabis-chapter-highlights – 2017 National Academy of Sciences
  7. Cannabis-report-highlights – 2017 National Academy of Sciences
  8. Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Bene ts of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?-2004
  9. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. – PubMed – NCBI
  10. Cannabis use and cognitive function: 8-year trajectory in a young adult cohort. – PubMed – NCBI
  11. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. – PubMed – NCBI
  12. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI Pharmacogenetics of Cannabinoids – 2018
  13. Systematic review of systematic reviews for medical cannabinoids – 2018
  14. Adverse effects of medical cannabinoids – a systematic review – 2008
  15. Cannabimimetic effects modulated by cholinergic compounds. – PubMed – NCBI
  16. Antagonism of marihuana effects by indomethacin in humans. – PubMed – NCBI
  17. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  18. Clinical Pharmacodynamics of Cannabinoids – 2004
  19. Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. – 2017
  20. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  21. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  22. Pharmacology of Cannabinoids
  23. Current-status-and-future-of-cannabis-research-Clin-Researcher-2015
  24. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems – A Clinical Review – 2015

 

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

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