Alternative supplements for the endocannabinoid system

In integrative medicine, one of the key strategies to improve patient health outcomes is to deliver more personalized care by providing alternative options for preventative and therapeutic treatments. Cannabidiol (CBD) has become an increasingly popular ingredient for therapeutic and recreational purposes; however, there are several alternative ingredients that provide similar benefits via comparable mechanisms of action in the body.

This article will provide an overview of the endocannabinoid system (ECS), how CBD interacts with the ECS, and several ingredients that can be used as safe and effective alternatives.

Potential alternatives to CBD include palmitoylethanolamide, certain essential oils, valerian, ginger, and echinacea.

The endocannabinoid system and CBD

The ECS is composed of cannabinoid receptors, the receptors’ ligands (i.e., molecules that bind to receptors that send biological signals), and numerous enzymes that up- or down-regulate the ECS itself. (46)(47)(51)(59)(79)

The two most well-known cannabinoid receptors are cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). The predominant CB1 form is most highly expressed in the central nervous system (i.e., brain and neurons) and skeletal muscle, but another isoform can be found in the liver, pancreas, and adipose tissues. In comparison, the main CB2 form is expressed in immune T cells and in nerve endings exclusively found in the peripheral nervous system. Other isoforms may be found in the brain, testes, and spleen. (31)(46)(47)(51)(79)

The two primary endocannabinoids (i.e., ligands that are created by the body) in the ECS are N-arachidonoylethanolamine (AEA), otherwise known as anandamide, and 2-arachidonoylglycerol (2-AG). In vivo and in vitro studies have shown that these metabolic derivatives of arachidonic acid (an omega-6 polyunsaturated fatty acid) work by binding to and activating CB receptors. Anandamide primarily binds to and activates CB1, but only binds to CB2 with a relatively low activation. In comparison, 2-AG activates both CB1 and CB2 making it the primary agonist (i.e., the primary molecule that causes signaling) of CB receptors. (46)(47)(51)(59)(79)

Though the specific mechanisms are beyond the scope of this article, endocannabinoids also interact with several other types of receptors and signaling pathways of the body, ultimately leading to the homeostatic modulation of several neurological and physiological processes including:

• Appetite and metabolism
• Embryo implantation and fertility
• Locomotion and muscular contraction
• Memory and sleep
• Mood, motivation, and reward
• Neurogenesis and neuroprotection
• Perception of pain and inflammation
• Prenatal and postnatal development
• Regulation of the immune system (31)(46)(67)

Cannabidiol

Cannabidiol is one of the major non-psychoactive phytocannabinoids found in the plant Cannabis sativa. Phytocannabinoids are phytochemicals (or chemical constituents of plants) that interact with the ECS. (52)

In vivo and in vitro studies have shown that CBD may have indirect antagonistic or agonistic effects with regards to the various receptors involved with endocannabinoids and other systems in the body. The current consensus is that while CBD does not directly activate or antagonize CB1 or CB2 receptors, it can play an indirect role in their activation by increasing the availability of 2-AG or by inhibiting uptake of anandamide, leading to greater or prolonged activation of endocannabinoid receptors. Additionally, CBD broadly interacts with numerous receptors of other signaling systems, which can provide overlapping functions, such as in pain, inflammation, sedation, anxiety, and neuroprotection. (31)(36)(48)(59)(72)

CBD has been an increasingly adopted ingredient for a variety of indications. According to a 2019 consumer report by The CBD Insider (n= 1,055), approximately 30% of the population in the United States currently uses CBD. The top five reasons that it is used are to improve:

• Aches/discomfort (58%)
• Relaxation (50%)
• Muscular soreness and recovery (41%)
• Sleep (39%)
• Mood (38%) (71)

Accordingly, the top five medical conditions for which CBD is used in descending order of frequency includes:

• Chronic pain
• Arthritis/joint pain
• Anxiety
• Depression
• Insomnia or other sleep disorders (15)

However, patient concerns, perceptions, and other reasons related to the regulatory state of CBD in the United States may lead to non-adoption or lack of adherence to a practitioner’s recommendations to use CBD. Individuals who do not use CBD or decide to discontinue its use, may cite various reasons including:

• Concerns about safety, testing, and legal status
• Development of tolerance or side effects
• High costs
• Lack of efficacy or belief in a lack of efficacy
• Lack of ingredient, product, or brand knowledge (71)

Ultimately, this may require practitioners to recommend alternative ingredients that may provide similar preventative and therapeutic benefits as CBD through their mechanisms of action within the ECS.

The following section will provide details on cannabimimetics and natural ingredients that may be used as alternatives to CBD products.

Cannabimimetics and CBD Alternatives

Cannabimimetics are natural substances or ingredients that can interact with the ECS in a similar manner to endocannabinoids or phytocannabinoids. They may interact with CB and other receptors, or may modulate the enzymatic activities that increase or decrease the availability of endocannabinoids. (32)(41)(47)

The following section provides an overview of several of the most common cannabimimetics, and other ingredients that can be used as alternatives to CBD.

1. Palmitoylethanolamide

Palmitoylethanolamide (PEA) is a lesser-known endocannabinoid naturally produced by the body. (56) While this means that PEA is not strictly speaking a cannabimimetic by definition, PEA is believed to exert its wide effects through the interaction of numerous receptors and enzymes of the ECS. Several of these mechanisms increase the activity and expression of various cannabinoid receptors leading to the reduction of inflammation and immune system activation. (56)

PEA has become an increasingly recognized and evidence-based metabolite in immunomodulation, pain and inflammation, and neurological conditions. Meta-analyses and systematic reviews show that PEA may reduce the prevalence of acute, chronic, and neuropathic pain. (8)(21)(40)(55) The use of 150 to 300 mg twice per day for eight weeks led to significant reductions in pain, stiffness, and function scores in knee osteoarthritis patients, with secondary improvements in anxiety scores. (68) A post-hoc analysis of the same dosing structure for three weeks in patients with low back pain from sciatica also showed improvement in pain and function scores. (17)

PEA also has pain applications in the gut where 200 mg of PEA and 20 mg of polydatin twice per day for 12 weeks reduced abdominal pain in patients with irritable bowel syndrome. (45) Similar to CBD, PEA has been shown to reduce intestinal permeability in healthy humans. (16)

Recent evidence also suggests that PEA may reduce the average time to fall asleep. In one trial, patients with sleep disturbances reduced their sleep onset latency from 43 minutes to 23 minutes after eight weeks when using a 350 mg formulation of PEA one hour before sleep. Significant benefits were observed after use for one month compared with placebo. (60) Though sleep quality and duration did not improve in this trial, these measures did improve in patients that were experiencing neuropathic pain in another study. (22)

2. Essential oils

A wide variety of essential oils isolated from various botanicals have shown ECS activity. A systematic review of preclinical trials identified the following essential oils and compounds with ECS activity:

• Beta-caryophyllene activates CB2 and is found in many sources including Copaiba species, guava leaf, black pepper, lemon balm, clove, and ylang-ylang.
• Lavender inhibits enzymes that degrade anandamide and 2-AG and has moderate beta-caryophyllene levels.
• Atlas cedarwood activates CB1 and CB2.
• Mastic increases PEA and oleoylethanolamide (OEA), which are two minor endocannabinoids.
• Chir pine activates CB2. (41)

Beta-caryophyllene is also known to increase enzymes involved in anti-inflammatory pathways. (39)(57)

Lavender

Lavender’s essential oils are well studied for their applications in aromatherapy and as topicals for relieving various types of pain. A meta-analysis also showed a significant reduction in pain scores in patients undergoing cardiac surgery (1) or during needle insertions. (30)(77) Furthermore, a systematic review summarized that within 30 to 60 minutes of inhalation, lavender aromatherapy can significantly reduce pain intensity in women undergoing labor. (70) One trial showed that lavender aroma therapy improved the efficacy of acupoint stimulation by reducing the pain intensity in patients with low back pain by 39%. (25) Other indications include the reduction of pain severity in osteoarthritis, (54) migraine, (63) and dysmenorrhea. (6)

Lavender is also widely used for its effects on anxiety and depression. Meta-analyses highlight that lavender can reduce anxiety and depression in menopausal and older women. (61)(62) A meta-analysis also showed a significant reduction in anxiety scores in patients undergoing cardiac surgery. (1) Furthermore, a systematic review summarized that within 60 minutes of inhalation, lavender aromatherapy can significantly reduce anxiety in women undergoing labor. (70) One trial showed that ingestion of a specific lavender product at a dose of 80 mg per day for ten weeks improved anxiety by 45% compared with placebo in patients with general anxiety disorder (44) and to a similar extent as the benzodiazepine lorazepam. (75)

The use of lavender’s essential oils have also demonstrated positive associations with improvement in sleep quality in individuals with mild sleep disturbances. (49) The improvement in sleep may be secondary to the improvements observed on anxiety; (65) however, potential applications include in patients experiencing anxiety staying in intensive care units (43) or undergoing hemodialysis. (66)

Ultimately, lavender’s effects may be induced by increasing anandamide and 2-AG levels by inhibiting enzymes that degrade each, respectively. (41)

Melissa officinalis

Melissa officinalis (lemon balm) is a medicinal herb with calming properties containing the CB2 activator, beta-carophyllene. The use of 500 mg of a lemon balm extract twice per day for 14 days led to a reduction in the number of anxious episodes in patients with heart palpitations as well as the frequency of these palpitations. (4) Using 3,000 mg per day of Melissa officianalis for eight weeks also led to a reduction in scores for depression, anxiety, stress, and sleep disturbance in chronic stable angina patients. (37)

Additionally, 1,200 mg as lemon balm essence was provided to adolescents with premenstrual syndrome, which led to the improvement of psychosomatic symptoms, anxiety, sleeping disorder, and social function disorder. (38)

Guava leaf

As the essential oils of guava leaf also contain beta-carophyllene, it may also be used as another alternative ingredient to CBD. Guava leaf extract (334 mg) three times per day for 12 weeks reduced pain and stiffness scores in patients with knee pain. (42) Additionally, 500 mg of a specific extract (QG-5®) every eight hours over three days reduced the duration of abdominal pain in patients with acute diarrhea. (50)

3. Valerian

Valerian officinalis is a medicinal botanical often used for its anxiolytic effects. It may induce CBD-like effects by activating the GABA-A receptor and possibly by increasing CB2 activity. (33)(64)

The use of 150 mg of valerian’s main constituents for four weeks has shown to reduce anxious mood, tension, fear, cognitive or concentration disturbances, and depressed mood or behavior subscales of the Hamilton Anxiety Scale in patients with generalized anxiety disorder. This was shown to have similar efficacy as the strong and commonly prescribed anti-anxiety drug diazepam. (5)

Valerian can also reduce anxiety caused as a side effect of pharmacological therapies. Large single doses of 1,500 mg have also been shown to reduce anxiety when used prior to operations in infertile women undergoing invasive imaging. (29) The use of 530 mg of valerian one hour before sleep for four weeks to patients with HIV using antiretroviral therapies improved anxiety scores and sleep quality. (2)

Valerian officinalis is also widely used for improving sleep-related disorders. Meta-analyses and systematic reviews indicate that the use of valerian products increase the likelihood of self-reports of improved sleep quality by 37 to 80% (11)(23) by reducing sleep latency and time awake after sleep onset, ultimately improving sleep duration. (34) In a triple-blind, randomized, controlled trial, menopausal women with receiving 530 mg of a valerian extract twice per day for four weeks improved the quality of sleep. (69) Similarly, 450 mg of a valerian extract per day, one hour before bed for eight weeks reduced reports of sleep disturbance, fatigue, and drowsiness in patients undergoing cancer therapy. (10) Additionally, 800 mg of dry valerian root ingested one hour before bed for eight weeks has been shown to reduce symptom severity and sleepiness in patients with restless leg syndrome. (18) Finally, valerian has also been shown to be effective in improving sleep quality and duration, while reducing sleep latency and wake times in pediatric populations with sleeping difficulties when ingested as 500 mg of Valeriana edulis over the course of two weeks. (24)

4. Ginger

Ginger has demonstrated broad anti-inflammatory and pain-mitigating effects as well as anti-nausea and vomiting effects. Ginger may produce these effects by altering receptor activities in a similar manner to CBD. (3)(73)(78) Ginger may reduce pain when it is used at doses ranging between 750 to 2,000 mg per day during the first three to four days of the menstrual cycle in women with dysmenorrhea, (19) providing similar efficacy as NSAIDs. (14) Ginger may also reduce pain and disability severity in osteoarthritis when provided at doses of 500 to 1,000 mg per day in studies ranging between three to 12 weeks. (7)(9) This may be particularly mitigated by ginger’s ability to reduce serum TNF-α and IL-1β. (53) Studies have shown that ginger can reduce muscle pain related to exercise and the exercise-induced inflammatory response. (74) Doses of 2,000 mg per day have been shown to reduce muscular pain 24 to 48 hours after exercise when used for up to 11 days in healthy subjects. (12)(13)

5. Echinacea

Echinacea species are well known for their immunomodulatory effects and are widely used to treat the common cold. It has been proposed that echinacea’s immunomodulatory activity may be partially explained by the agonistic interaction between its alkylamide constituents and CB2. Furthermore, echinacea can increase the availability of endogenous cannabinoids by inhibiting enzymes that degrade endocannabinoids. Levels of anti-inflammatory markers TNF-α and IL-2 in T cells may be altered through these interactions. (26)(27)(28)(58)

Echinacea has also been shown to reduce inflammatory cytokines TNF-ɑ, IL-8, and (less consistently) IL-6, while increasing the anti-inflammatory cytokine IL-10 in human volunteers. (20)(76) One trial showed that a standardized extract of echinacea twice per day for seven days reduced anxiety scores compared with placebo. (35)

The bottom line

The ECS plays a crucial role in almost all homeostatic functions of the body. CBD has gained popularity for use in pain management, sleep, and stress, and may have powerful effects on these aspects of health through its interaction with the ECS. However, not all patients have access to or are comfortable with using CBD products. The good news for these patients is that many other natural ingredients can help in these areas of well-being by having similar functions in the ECS. With this knowledge, patients can benefit from the effects of CBD, even without using it.