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UPDATE:  On the advice of experts, the UK Home Secretary Sajid Javid has announced that specialist physicians will be allowed to prescribe cannabis-derived medicinal products by the autumn. Before that can happen, the Department for Health and Social Care and the Medicines and Health products Regulatory Agency need to come up with a definition of what constitutes a cannabis-derived medicinal product.

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THEY say that to see the future, you should go to California. So when the Golden State legalised medical cannabis in 1996, we should have seen what was coming.

Sure enough, where California led, others followed. Today more than half the citizens of the US have legal access to medical cannabis of one form or another, as do those of a further 44 countries. The United Nations recently convened a special meeting to assess the state of knowledge on medical cannabis, the first time it has ever looked at the drug since blanket prohibition almost six decades ago. As a published in 2017 by the US National Academies of Science, Engineering, and Medicine concluded, “this is a pivotal time in the world of cannabis policy and research”.

The UK is the latest front line, with public controversy leading to a review of strict prohibition, and the likelihood that the country will join the list of those allowing the medical use of cannabis in some form. Whether that is a good idea is hard to call, not least because the term “medical cannabis” covers a multitude of possibilities. At one end are freewheeling US states like California and Colorado, where it is all but indistinguishable from recreational use. At the other are tightly controlled systems that closely resemble mainstream medicine. Both have their pros and cons. So if you are going to design a system of legalised medical cannabis, what should it look like?

Cannabis has been used medicinally for centuries, but it was not widely known in the West until the 1840s. By the 1850s, it was sanctioned as a painkiller, sleep aid and anticonvulsant. But growing concerns about the potential for abuse led to a gradual retreat. In 1961, the UN put cannabis on schedule 1 of its Single Convention on Narcotic Drugs, the strictest level of prohibition and a global diktat to criminalise cannabis for all uses.

Modern moves to legalise the medical use of cannabis began in San Francisco in the early 1990s, initially driven by AIDS activists who argued that it could alleviate the nausea and wasting associated with the late stages of the disease. The movement quickly blossomed into Proposition 215, a state-wide referendum that legalised use, possession and cultivation of medical cannabis.

That small bud has now grown into a rambling weed of medical marijuana legalisation across the US and beyond (see graphic, below). Currently 34 US states and territories have legalised it, and an estimated 2.3 million Americans use it medicinally. Other countries where the use of medical cannabis is legal include Canada, Australia and Germany. The UK’s debate has been sparked by the case of 12-year-old Billy Caldwell, whose cannabis oil, bought in Canada to control his rare form of epilepsy, was confiscated on his return to the country. The outcry has prompted a Home Office review of the law.

But what might the country be buying into? Smoke or ingest cannabis and you are flooding your nervous system with at least 400 compounds, about 100 of which are classed as cannabinoids. This means that they interact with an important signalling network spread throughout the nervous and immune systems. The endocannabinoid system consists of a group of neurotransmitters that latch onto receptors modulating things including pain, appetite, mood and learning, and which are also involved in brain development and maturation.

This is how cannabis exerts its wide-ranging biological effects, although, with so many compounds sloshing about, it is not clear exactly what is going on. Nobody knows which cannabinoids activate which receptor, or how they interact. Especially mysterious are “entourage effects”, meaning certain cannabinoids are only active in the presence of others.

That alone is enough to rule whole cannabis out as an orthodox medicine, at least within existing systems. Regulatory agencies such as the US Food and Drug Administration (FDA) only stamp their approval on single, highly purified active compounds or, at a push, a mixture of two or three.

Yet, in many places, patients can ask for a prescription for “whole” cannabis – in other words the flowers, buds and leaves – which they are free to consume, and in some cases grow, as they please. This anomalous state of affairs has sent global production and consumption of cannabis for medical use soaring (see graphic, below), but is largely a result of persistent lobbying rather than careful scientific research. In the US and Canada, much of what passes for medical cannabis is actually a smokescreen to legalise recreational use, says at the Institute of Psychiatry, King’s College London.

That is not to say that cannabis or its constituents have no role in medicine. Despite being classified as a schedule 1 drug by the UN and the FDA, meaning it has no accepted medical use, there is convincing evidence that it helps with a number of conditions.

That number is three. Or seven, depending on how you count them.

The shorter list is as follows: pain, spasticity from multiple sclerosis, and nausea and vomiting caused by chemotherapy. According to the National Academies report, these are the only conditions for which there is “conclusive or substantial” evidence of effectiveness.

The longer list also includes appetite loss caused by AIDS and cancer and two rare forms of epilepsy, on the basis that cannabis-based drugs have been approved to treat them.

But the range of other conditions for which cannabis has been claimed to be effective reads like a medical encyclopaedia. There are more than 80 of them, including some of the world’s most burdensome diseases – cancer, depression, Alzheimer’s, hepatitis C and addiction – plus everything else from asthma and chronic kidney failure to autism and Tourette’s syndrome.

Many of these conditions have found their way onto official lists of conditions that are eligible for a cannabis prescription, despite there being no scientific evidence that cannabis is effective against them. California, for example, includes anorexia, arthritis, cancer, glaucoma and migraine. Several US states have recently included post-traumatic stress disorder. Illinois lists 40 qualifying conditions. Across all US states with legal medical marijuana, a total of 53 are recognised, says , an addiction psychiatrist at Harvard Medical School. Some US states with medical cannabis also allow doctors to prescribe cannabis for “any other illness for which marijuana provides relief”, which opens the door to it being prescribed for almost anything.

For many people with these conditions, access to medical cannabis makes their quality of life immeasurably better. “I’ve worked with many people who are medical users of cannabis and I’ve seen some truly remarkable effects,” says , president of UK campaign group CLEAR Cannabis Law Reform.

However, the lack of scientific and regulatory rigour both worries and irks mainstream medics. It is not clear why the approval process for medical cannabis should be any different from that for other drugs, says of Yale School of Medicine: evidence supporting its use should come from large, double-blind, randomised, placebo-controlled clinical trials.

Murray agrees. “My view would be that they should just go through the regular medicines approval system.”

The Wild West system is made worse by the variety of cannabis preparations, recommended doses and methods of administration. Besides the buds, leaves and flowers of whole cannabis, there are resins, oils, waxes, tinctures, creams and patches. Cannabis can be smoked, vaped, eaten, drunk, popped under the tongue, applied to the skin and inserted into the anus or vagina. Some is cultivated by commercial farms, but much is home-grown.

And it is often not clear what is being ingested. Different cannabis strains vary widely in their constituents, especially in their ratio of the two most abundant cannabinoids: delta-9-tetrahydrocannabinol (THC), which is powerfully psychoactive, and cannabidiol (CBD), which is not. That’s true even for medical-grade cannabis grown under controlled conditions. The Canadian grower Tilray, for example, sells products with specified amounts of THC and CBD, but they all come with a disclaimer that THC and CBD levels may vary considerably. This is a serious problem, says D’Souza. “Patients will have to experiment with different strains and doses to achieve the desired effects.”

The use of whole cannabis also opens people up to some of the well-known risks that recreational users face. One is dependence, which despite cannabis’s reputation as a non-addictive drug is a real risk. According to Murray, about 1 in 11 people who try cannabis become dependent on it. People also become tolerant to the drug and need to escalate doses to get the same effect.

“The average cannabis user is about twice as likely as a non-user to develop a psychotic disorder”

Next on the checklist of concerns is psychosis. Cannabis consumption is a proven risk factor for short-term psychotic breaks as well as chronic psychoses including schizophrenia. “We can say with absolute certainty that cannabis carries severe risks,” says , registrar of the UK Royal College of Psychiatrists. A body of research by his group and others suggests that the average cannabis user is about twice as likely as a non-user to develop a psychotic disorder.

These risks seem to be caused by THC, and are exacerbated by heavy consumption, especially early in life. For that reason, they are mainly a worry for recreational users, says Murray, who tend to be young and consume more. The cannabis plant makes both THC and CBD from the same precursor chemical, and the more there is of one, the less there is of the other. The black market is increasingly dominated by high-THC “skunk” cannabis, which many users say gives them a better high. Since the 1970s, the , from about 6 to 14 per cent, and it now contains little or no CBD. CBD seems to counteract the addictive and psychotic effects of THC; it may be a useful antipsychotic medicine in its own right and is the active ingredient in the “cannabis oils” recently approved to treat rare forms of epilepsy. Contrary to popular belief, these conditions do not respond to THC.

Addiction and psychosis ought to be a minor problem for medical cannabis. Some strains are bred to have high CBD and low THC content, and others are close to 50/50. But even in this market there is evidence of a consumer preference for high THC varieties. For example, Dutch grower Bedrocan’s most commonly used whole cannabis contains 22 per cent THC and almost no CBD. A recent study found that .

As yet there is little sign of an actual problem. Medical cannabis has been freely available in California for more than two decades, and there is no hint of an epidemic of addiction or mental health problems. Ditto in the Netherlands, which effectively legalised cannabis decades ago. Nor is there much evidence that medical cannabis increases the rate of traffic accidents or is a gateway to other, more harmful drugs, common complaints of opponents of legalisation. The opposite, in fact: US states where medical cannabis is legal have significantly lower rates of death from addiction to opioid painkillers (see “Cannabis vs opioids”).

But little is known about the long-term effects of using cannabis, especially on those who start as adolescents and young adults. This issue really worries some researchers. There is growing evidence that the endocannabinoid system has a pivotal role in neural development, guiding the generation, growth and maturation of brain cells and the process of synaptic pruning, a major event in brain maturation occurring mainly in adolescence that weeds out unnecessary connections.

The effects of flooding this system with powerful chemicals such as THC are not well-known, but animal studies and studies of teens who use cannabis regularly hint that it can lead to long-lasting emotional, cognitive and behavioural problems, including a drop in IQ. Given that brain development continues into the mid-20s, this suggests that medical marijuana should be prescribed sparingly to people under 25, says D’Souza.

Perhaps the answer is to rein cannabis in and allow only treatments that have satisfied the normal standards of evidence. This is the principle used in less freewheeling jurisdictions, where the prescription of medical cannabis dovetails more-or-less seamlessly with orthodox medicine. Patients are diagnosed in the normal way, then prescribed standardised drugs based on compounds in cannabis or extracted from it. Many countries, for example, allow Sativex – an oral cannabis extract containing roughly equal amounts of THC and CBD – for muscle spasticity and pain associated with muscular dystrophy.

This approach would annoy the cannabis lobby, but arguably would be no great loss to medicine. For the conditions for which good evidence exists, medical cannabis does not necessarily mean smoking a joint or drinking cannabis tea. All can be – and often are – successfully treated with synthetic cannabinoid pharmaceuticals or standardised cannabis extracts.

Some may not require cannabis at all. A recent review carried out in Germany, where medical cannabis use is soaring after a ruling that health insurers must cover the cost, concluded that . Where cannabis was the right choice, synthetic cannabinoids were better, cheaper and easier to administer than herbal cannabis.

That doesn’t impress some advocates of medical cannabis, who argue that the whole plant is more effective for the very reason it is seen as problematic: it contains a cocktail of interacting ingredients rather than just one purified molecule. “It can’t be regarded in the same simplistic sense as single-molecule medicines, that is why it is so difficult to come up with a way of regulating it,” says Reynolds.

And it is true, says Hill, that our current medical exploitation of cannabinoids is poor. Thus far, mainstream pharmacology has only explored THC and, to a lesser extent, CBD. “We’ve got 100-plus cannabinoids,” says Hill. “Maybe the other cannabinoids, or combinations of cannabinoids, can do better than what we’ve got”.

“There may be a lot of mileage in cannabis products,” says Murray. The fact that the evidence is lacking may simply reflect a dearth of research, which is perhaps no surprise given that the drug is listed on schedule 1 and is expensive and complicated to study.

Performing large and high-quality clinical trials of whole cannabis is possible, but difficult. The lack of standardisation is a problem, and the characteristic taste and odour makes it almost impossible to find a placebo. A review by the World Health Organization found only 12 placebo-controlled trials of whole cannabis; most were small and inconclusive.

That said, the existing system does not stop new cannabis-based drugs from coming on to the market. Epidiolex, recently approved in the US to treat two rare forms of childhood epilepsy, is essentially purified CBD extracted from cannabis plants, and similar to the cannabis oil confiscated from Billy Caldwell.

All the indications are that the UK will opt for a conservative, but evidence-based approach, perhaps legalising the prescription of cannabis-based pharmaceuticals for a narrow list of conditions, but not medical weed. To many, that would be welcome progress from the rigid prohibition of the past without opening the back door to full legalisation.

“I’m not against medical cannabis, there’s merit in it,” says Murray. “But it can also be a foot in the door towards recreational cannabis.” Nine US states and the District of Columbia, plus Canada and Uruguay, have gone all the way and legalised recreational cannabis after experimenting with medical use for a few years. That is a whole different debate, but where California leads, others follow. Whatever the UK decides to do about medical cannabis, much of the world will be heading towards the Californian model.