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The science
Hemp is one of the oldest plants people have grown on purpose, and the archaeological record is now chemical rather than anecdotal. Cannabis recovered from a 2,700 year old tomb in the Turpan basin has been analysed and found to carry the plant's active compounds. In the Pamir mountains, braziers from a cemetery of roughly 2,500 years ago held residues rich in those same compounds, the earliest clear evidence of deliberate use for their effect. Written records of medical use run back through the Chinese, Indian and Middle Eastern traditions, and in our own era cannabis entered the United States Pharmacopeia in 1850 and stayed there for almost a century.
None of those cultures knew why it worked. They only knew that it did. What none of them could see is that the reason sits inside us.
A receptor that responds to cannabinoids was identified in 1988. A second was described in 1993, and in 1992 researchers isolated the first of the cannabinoids the body makes for itself. That sequence is set out in the reviews linked below. What emerged is one of the body's broad regulatory networks, with receptors through the nervous system, the immune system, the gut and the skin, and its role is balance. The body's own cannabinoids are present in human breast milk, which is to say the system is at work from the first days of life.
So the plant is not acting on us from outside. It is speaking a language the body already uses.
Because the system was only identified in 1988, almost all of the research on it has been done since. That is recent for any field of biology. More than 29,000 papers on cannabis and cannabinoids had been published by 2021, the large majority of them in the previous twenty years, which places this among the most studied plant families in modern science.
The strongest of that work is set out below, each study with its limitations stated alongside its findings. It begins with a clinical practice guideline in the BMJ built from 32 randomised trials and 5,174 people.
Sources: ancient cannabis analysed from the Yanghai tombs, Russo and colleagues, Journal of Experimental Botany, 2008, full text. Residues from the Pamir braziers, Ren and colleagues, Science Advances, 2019, open access. The discovery of the cannabinoid receptors and of the cannabinoids the body makes for itself, Pertwee, British Journal of Pharmacology, 2006, full text. Where those receptors are found in the body, Zou and Kumar, International Journal of Molecular Sciences, 2018, open access. Endocannabinoids in human milk, Gaitán and colleagues, Nutrients, 2018, open access. Publication counts, bibliometric analysis, Journal of Cannabis Research, 2022, open access.
Cannabis was an official medicine in the United States for almost a century. It entered the United States Pharmacopeia in 1850 and doctors prescribed it as a matter of routine. As late as 1916, forty percent of the official preparations in that Pharmacopeia were crude plant extracts.
The 1937 Tax Act did not ban medical use outright. It required every physician and pharmacist who prescribed or dispensed it to register with federal authorities and pay an annual tax. The American Medical Association opposed the bill. Its legislative counsel, Dr William Woodward, told Congress that the measure
loses sight of the fact that future investigation may show that there are substantial medical uses for Cannabis.
He was ignored. Cannabis was struck from the Pharmacopeia five years later, in 1942. By 1950 crude plant extracts had fallen from forty percent of official preparations to nine percent. Medicine moved to synthetic molecules, and in 1970 the Controlled Substances Act placed cannabis in Schedule I, the category defined as having no accepted medical use.
The commercial logic followed the law. A naturally occurring compound cannot itself be patented in the United States, so there is no exclusivity waiting at the end of a clinical trial that costs tens of millions of dollars to run. A synthetic molecule can be patented. That is where the investment went, and it has stayed there.
So this research is younger than it should be. Not because the plant was tested and failed, but because for the better part of a century it was barely tested at all. That gap is closing quickly.
Hemp and cannabis come from the same species, Cannabis sativa L. The line between them is legal rather than botanical, and it is drawn at one compound. The 2018 Farm Bill defines hemp as:
the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.
Above that line the plant remains a federally controlled substance. At or below it, the plant is hemp, and the 2018 Farm Bill removed hemp from the Controlled Substances Act entirely. Reset ECS is made from hemp, tested by an accredited laboratory, with every certificate published in full.
Sources: Pharmacopeia dates and the share of plant extracts, Americans for Safe Access historical timeline. Dr Woodward's testimony to Congress, transcript, 4 May 1937. Patentability of isolated natural products, Wong and Chan, Chinese Medicine, 2014. Hemp definition, US Food and Drug Administration.
Starting with the strongest evidence available, and stating the limitations of each study alongside its findings.
The strongest evidence that exists on this question. An international panel worked from four linked systematic reviews covering 32 randomised clinical trials and 5,174 participants, 3,812 with chronic non-cancer pain and 1,362 with cancer pain. They graded the evidence as high certainty that non-inhaled cannabis or cannabinoids produce an important improvement in pain for a proportion of people living with chronic pain, high certainty of improvement in physical function, and moderate certainty of improvement in sleep quality.
A phase III double blind placebo controlled randomised trial of a cannabinoid formulation delivered through the skin, in 100 people with painful diabetic peripheral neuropathy. Mean neuropathic pain scores fell from 25.60 to 5.57 in the treatment group against 25.24 to 22.85 on placebo, a between group difference of 17.27 points at twelve weeks, p below 0.001 across every measured dimension. Adverse events occurred in ten percent of both groups and were mild, dermatological and fully reversible.
Transdermal cannabidiol, applied to the hand, in people with hand osteoarthritis. Current, average and maximum pain all fell by roughly two points on a ten point scale, each at p below 0.0001, and grip strength in the treated hand increased significantly. Participants also reported improvements in fatigue, stiffness and anxiety. When treatment stopped, pain and grip strength drifted back toward baseline, which is itself evidence the effect was attributable to the treatment.
What the research shows about the tissue a topical actually reaches, and what happens in it.
Skin has its own endocannabinoid system. This review documents cannabinoid receptors throughout human skin: CB1 in differentiated cells, CB2 predominantly in basal undifferentiated sebocytes, with receptors also present in epidermal keratinocytes, melanocytes, hair follicles, mast cells, fibroblasts and sweat gland cells. It describes that system as involved in barrier maintenance and regeneration, sebum and lipid balance, keratinocyte proliferation and differentiation, pigmentation, and inflammatory and immune regulation.
Read it in Molecules ↗Phytocannabinoid formulations tested on human keratinocytes and human dermal fibroblasts, the two cell types that make up skin and the tissue beneath it. Under oxidative and chemical stress the formulations significantly reduced inflammation, downregulating IL-6, TNF-α and IL-36G in both cell types. They also modulated genes governing the extracellular matrix, including elastin, fibronectin, EGFR and TIMP3, which is the structural scaffolding of tissue. The authors report improved barrier function and good tolerance, and attribute the effects to CB1, CB2 and GPR55 signalling.
The mechanism underneath the findings above.
A review of how cannabidiol acts on the nitric oxide system, which sits at the centre of inflammatory signalling. The pattern reported is selective rather than blunt: CBD reduces inflammation-driven inducible nitric oxide synthase while maintaining or enhancing the endothelial form that supports healthy blood vessel function, lowering oxidative stress in the process. The authors describe suppression of the inflammatory pathway partly through inhibition of NF-κB.
Where the individual cannabinoids in a broad spectrum formulation bind, and why that differs from a single isolated compound.
Eight cannabinoids tested at the CB1 and CB2 receptors, first in cells and then in animals. Every compound showed activity at one or both receptors. CBG and CBC behaved as weak partial agonists at both with greater selectivity for CB2 and stronger activity there. CBDV showed little activity at CB1 but measurable affinity at CB2. This is the evidence that the minor cannabinoids in a broad spectrum formulation are doing something, rather than being along for the ride.
Read it in Scientific Reports ↗CB1 and CB2 are not the whole story. This review sets out cannabinoid activity at the transient receptor potential ion channels, which are involved in sensing temperature, pressure, irritation and inflammatory signals. CBD acts at TRPV1, TRPV2, TRPA1 and TRPM8 and acts most strongly of the phytocannabinoids tested at TRPV1 and TRPM8. CBG is active across TRPV1 to TRPV4 and TRPA1. CBN shows activity at TRPV2, TRPV4 and TRPA1.
Read it in Frontiers ↗The acid forms, CBDA and CBGA, are normally destroyed by heat and lost. This review covers what is known about them. CBDA is reported to engage 5-HT1A serotonin receptors and to selectively inhibit COX-2, the same enzyme targeted by common anti-inflammatory drugs, at low micromolar levels. CBGA is reported to modulate TRPV1 and TRPM8 ion channels, block store operated calcium entry in immune cells, and inhibit cholinesterase enzymes.
Read it in Journal of Cannabis Research ↗