Cannabis. Cannabis is a Schedule I drug but has been used in medicine for at least 3,000 years. Recent neuroscience research18 has discovered that cannabinoid 1 receptors (CB1Rs) bind not only endogenous cannabinoids (endocannabinoids), such as anandamide16, but also Δ9-tetrahydrocannabinol (THC), the psychoactive ingredient of cannabis that makes users 'stoned'. Of particular interest for neuroscience is that CB1Rs are widely distributed in high density throughout the brain; indeed, they are the most densely expressed of the whole G protein-coupled receptor family19.

A Pubmed search for terms related to cannabinoid receptors or endocannabinoid receptors produces many fewer hits than Pubmed searches for two other G protein-coupled receptors, namely dopamine receptors and serotonin receptors. In part, this may be due to the relative newness of these discoveries on cannabis receptors, but it may also reflect the possibility that the illegal status of cannabis and the need for licences plus safe holding inhibits research.

Despite the fact that cannabis has long been used in medicine and that its use has been recommended by eminent doctors (including the physician to Queen Victoria20), cannabis was put into Schedule I of the United Nations convention in 1961 on the basis of it having no medical use. This action was clearly a political rather than a scientific decision and one that has persisted since in both the United States and United Kingdom (but not in, for example, the Netherlands) despite further evidence of clinical value, as discussed below. The justification for the continued illegal status of cannabis includes claims of harms such as lung disease associated with smoking the substance, schizophrenia and addiction21. Such harms undoubtedly exist, but they are frequently exaggerated by scientists and the media. Overall, cannabis is less harmful than other popular drugs, such as alcohol22.

Self-reports reveal that cannabis is commonly smoked as self-medication to improve sleep and reduce anxiety symptoms23, and there is growing interest in its possible use24 in attention-deficit hyperactivity disorder. Plant-derived THC also has utility in the treatment of pain and spasticity in conditions such as multiple sclerosis and AIDS11,12. Other products of the cannabis plant, such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), have a pharmacology that is quite different from that of THC and may have utility in the treatment of seizure disorders, anxiety, psychosis25 and addiction26. Although CBD is not a scheduled substance in the United Nations, US or UK systems, THCV is Schedule 1-controlled in the United Kingdom. The reason for this is unclear (THCV is not scheduled in the United Nations conventions); it cannot be on the basis of any pharmacological similarity to THC. Indeed, the actions of THCV may reverse the impairing effects of THC27. Partly because of its Schedule I status, THCV has been little studied in humans.

Medical use of marijuana has developed in the United States in the past decade and is now allowed in 17 states. It has recently been legalized for personal use in both Washington and Colorado. Nevertheless, for researchers, access to cannabis is limited, as it remains listed as a Schedule I drug. Moreover, the only source for research-grade cannabis in the United States is the National Institute on Drug Abuse (NIDA), and obtaining it for a clinical trial requires submission of US Food and Drug Administration (FDA)-approved protocols to a special 'ad hoc' Public Health Service interdisciplinary review process. Furthermore, the regulations governing the sale of marijuana to privately funded researchers explicitly state that the purpose of their research cannot be to develop the marijuana plant itself into an FDA-approved prescription medicine but must be to develop isolated cannabinoids in non-smoking delivery systems (presumably to avoid harms from smoking)28.

In the United Kingdom, a solution of cannabis extracts containing THC and other cannabinoids, called Sativex (GW Pharmaceuticals), presented a problem for the UK authorities because THC is a Schedule 1 drug and therefore cannot be prescribed. Rather than deciding that cannabis preparations should not be in Schedule 1, Sativex was put into Schedule 4 and is now licensed for the treatment of pain and spasticity in multiple sclerosis. This decision to classify it in Schedule 4 was justified on the (pharmacologically meaningless) grounds that it was in an alcoholic solution and therefore different from other forms of THC. The decision is also inconsistent with the provisions of the 1961 United Nations convention4. Here, cannabis and cannabis resin are not only included in Schedule I but are also listed in the more restrictive Schedule IV of that convention4, according to which its use does not extend to the medical treatment of people. The decision to list Sativex in Schedule 4 of the UK regulations can be seen as a pragmatic response to a messy legal situation, but it also demonstrates how current regulations impair therapeutic development. How can any producer of other cannabinoid therapeutics be sure that similar special exemptions will be made for them?

A number of synthetic cannabimimetic agents acting at the CB1R have been developed, but most will probably never be licensed as medications because they are put in Schedule I in both the United Kingdom and the United States. Moreover, despite these synthetic cannabimimetics being widely available to the general public on the black market29, their potential addictive and therapeutic properties cannot be studied by anyone other than a Schedule I-licensed researcher. The proliferation of these new cannabimimetics with unknown toxicity was probably driven by the laws against cannabis — one of many examples of where once a drug has been made illegal, a more potent and so potentially more dangerous one takes its place. Synthetic cannabinoid agonists present two problems. First, they are often more potent than cannabis: that is, they have a higher affinity for the CB1R. Second, because of the way they are packaged (with inert vegetable material), users may inadvertently consume an overdose in a way that is much less likely to occur with cannabis or cannabis resin. It has been suggested that regulatory agencies “...curb regulation aimed at any CB receptor agonists as Schedule I, as this ignores their medicinal properties.” (Ref. 30) One such potential application of substituted naphthoylindoles (that is, typical cannabinoid agonists, which are currently listed as Schedule 1 in the United Kingdom) is in the treatment of glioblastomas31.

MDMA-type stimulants. Many derivatives of amphetamine have been investigated for clinical purposes, as they have various interesting mood-altering properties. The most well-known of these derivatives is MDMA. Although first synthesized 100 years ago, it came into unofficial therapeutic use in the 1970s. Originally known as 'empathy', it was used in the United States as an adjunct to psychotherapy32,33 owing to its ability to facilitate interpersonal communication34. Before the neuroscientific mechanisms of this property could be investigated, it entered youth culture in the dance/rave scene, where dealers changed the name to 'ecstasy'. The huge media backlash against this culture focused on the drug, with exaggerated claims of harm. Early stories focused on whether MDMA could produce a type of neurological damage that had been observed in rats35, but despite years of study, there is no good evidence that occasional use has adverse neurological sequelae36. A number of deaths resulting from MDMA use were typically associated with hyperthermia37, as users often danced for prolonged periods of time and failed to hydrate adequately. When the cause of these deaths became known among users, rave clubs in the United Kingdom began to offer 'chill-out' rooms and promote adequate hydration. Amazingly, in the United States, the DEA attempted to criminalize such harm reduction strategies and used them as evidence that the promoters knew that drugs were being used at their events, thus justifying DEA raids (R. Doblin, personal communication).

In the 1980s, MDMA and related compounds were Schedule I-controlled in the United Kingdom and United States and were also added to the United Nations 1971 convention on the grounds of harm. However a recent analysis showed that the publicly held view that MDMA has a relatively high fatal toxicity is incorrect38. MDMA use has also been claimed to lead to brain damage and memory impairment, although the evidence for these adverse effects has been questioned36. Indeed, a critical appraisal of the harms of ecstasy suggested that they are less than those associated with other popular recreational activities, such as horse riding39.

Since MDMA was banned, a small group of MAPS members has campaigned to maintain interest in the potential therapeutic value of MDMA. They argue for its use as an adjunct to psychotherapy and run scientific symposia on this topic. They also completed a small scientific clinical proof-of-concept study in the United States40, which was the first controlled clinical study of MDMA. It was conducted in patients with treatment-resistant PTSD, a severely disabling condition. They found that about 80% of MDMA-treated patients showed clinical benefits, whereas only about 20% of the placebo-treated group did. The patients were followed up for over 1 year, and the majority of MDMA-treated subjects continued to have symptomatic relief, with no subjects reporting harm from the treatment41. These results require replication by other research groups in other countries, which will be difficult under current regulations.

Current best practice in treatment for PTSD aims at extinction of the memories so that they no longer intrude into consciousness, but this approach requires the patient to relive the trauma and then overcome it. For many patients, the traumatic memories are so powerful and distressing that they cannot tolerate the emotions resulting from the recall, and so cannot complete the therapy. MDMA has the ability to reduce the brain responses to threats42, which may allow patients to engage fully in the treatment. The seemingly unique ability of MDMA to enhance empathy and trust makes it a powerful (and arguably necessary) tool for studying the neuroscience of these states, but there is no other published imaging study.

There are other potential clinical uses for MDMA beyond psychotherapy for PTSD that include helping with end-of-life anxiety and couples therapy. It has been suggested that the pro-empathy actions of MDMA might help people with autism43. Recently, MAPS made a grant available to test this hypothesis. Other perhaps less obvious possibilities include the treatment of the disabling dyskinesias associated with L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease. Animal models of Parkinson's disease suggest that 5-hydroxytryptamine (5-HT) dysregulation is involved in these dyskinesias, and the dyskinesia-reducing effect of MDMA is probably due to its enhancement of 5-HT levels44. Other studies suggest that MDMA facilitates the recovery of cognitive function after minimal brain trauma in mice45. This, to some extent, reprises results from older studies that used other stimulants in the treatment of brain injury46 — another research area hampered by the illegal status of the possible treatments.

A more recent and equally controversial amphetamine analogue is mephedrone (also known as 4-methylmethcathinone). This drug was first synthesized in 1929, but was little used until the 2000s, when it was resurrected in Israel as an octopamine analogue to provide a biological control approach for aphids on plants (hence the slang name 'plant food'). It became widely used in Israel by young people, and although there were no reported deaths or serious harms, it was banned by the Knesset. Soon after, it spread to the United Kingdom as a 'legal high', where it went by various names such as MCAT, drone and miaow-miaow. It became very popular as it was sold in pure form (in contrast to MDMA, which was often of particularly poor quality) and, being legal, could be readily ordered over the Internet.

As with MDMA, many media articles claimed that mephedrone has dangerous adverse effects. Coupled with unfounded police suggestions that it had led to deaths, this resulted in mephedrone being banned despite the lack of any real evidence of harm47. It was subsequently discovered that the rise in recreational mephedrone use in the United Kingdom in fact had some unexpected benefits, particularly a spectacular fall in the number of deaths due to cocaine use by over 20% in 1 year48. This surprising finding could be explained by the fact that many cocaine users switched from cocaine to mephedrone, which is less toxic. Mephedrone thus seems to have saved more lives than it claimed, suggesting it has potential as a substitute for cocaine, like methadone is for heroin. Its illegal status and the fact that many analogues of mephedrone were banned under the same legislation means that this potential is now unlikely to be investigated, let alone realized.

Psychedelics. Psychedelic is a term that covers a range of drugs, but literally, it means 'mind manifesting'. Psychedelic drugs occur widely in nature: for example, in magic mushrooms (psilocybin), peyote cactus (mescaline), plant roots (ibogaine) and plant bark and certain grasses (dimethyltryptamine).

Although many scientists saw LSD as an important new tool for understanding the brain, it was never used as such because LSD was banned in the 1960s, before the emergence of modern brain science. The banning appeared to be largely driven by political concerns — namely, that American youths were using it and as a result declined to fight in Vietnam. Nevertheless, the ban was justified by claims of harms such as people dying while trying to fly or having enduring psychotic experiences49. Recent analyses suggest, however, that LSD is less harmful than most other controlled drugs1,2.

LSD received much attention for its clinical uses. Between the 1950s and mid-1960s, there were more than 1,000 clinical papers discussing 40,000 patients, several dozen books and six international conferences on LSD-assisted psychotherapy50. Because research was stopped so early, the methods and tools were not available to examine the neurobiological basis for the efficacy of LSD. Some findings were remarkable, however. A recent meta-analysis of six studies (published before LSD was banned) into its clinical efficacy for the treatment of alcoholism found LSD-assisted psychotherapy to be at least as effective as any other available treatment51. In addition, LSD has been shown to help patients with a terminal illness come to terms with dying52. A MAPS-sponsored study of LSD in subjects with anxiety associated with end-of-life issues was recently completed in Switzerland; the results await publication.

The banning of LSD led people to search for other psychedelics that were free from the threat of legal sanctions. The most popular was psilocybin, which was (when in magic mushrooms) legal in the United Kingdom until the Drugs Act of 2005 (Ref. 53). Although magic mushrooms are largely used recreationally, many individuals report using them for self-treatment of disorders such as obsessive-compulsive disorder (OCD). However, only one clinical trial has investigated psilocybin as a potential treatment for OCD54. That study showed marked decreases in OCD symptoms to variable degrees in all nine subjects during one or more of the testing sessions. Unfortunately, the disproportionate cost of the obtaining the drug precluded a larger follow-up study.

Another use for psychedelics is in cluster headaches, a severe pain syndrome for which treatment options are limited and which is associated with high suicide rates. Magic mushrooms and LSD are regularly used by sufferers55, but their effectiveness in reducing pain in this condition has not been formally studied, presumably owing to their Schedule I status.

A couple of small scientific studies of psilocybin validate the view that it has therapeutic value. One study found that psilocybin administration can have profound effects on attitudes and behaviour in healthy subjects, with many subjects rating it as one of the five most significant experiences in their lives56. These effects were enduring; a follow-up study 2 years later revealed that the subjects still found the experience profoundly meaningful57. A study in cancer sufferers showed that, in a fashion similar to the value of LSD in terminal illness52, psilocybin helped people make sense of their predicament and cope with it better15.

Psychedelics have a particularly important role in the study of consciousness because they produce such profound changes in this state; indeed, one could argue that the psychedelic state is a major challenge for neuroscience to explain. Psychedelics act as agonists at the 5HT 2A receptor, which is most highly expressed in the cortex, particularly on layer 5 pyramidal cells, but also on fast-spiking regulatory interneurons58. Layer 5 neurons are thought to control top-down cortical processing of sensations59 and possibly emotions that are disturbed in conditions such as schizophrenia and depression. Studying the role of these receptors is impossible without using psychedelics as, to our knowledge, all 5-HT 2A agonists have psychedelic effects. Some 5-HT 2A agonists are not, as yet, controlled and therefore can be used in preclinical studies with relative ease. However, no safety data exist for these agonists, and therefore they cannot be used for studies in humans. Studies in animals have found that 5HT 2A agonists produce excitation of layer 5 pyramidal cells and associated interneurons60, and in humans, 5HT 2A antagonists block the psychotomimetic effects of psilocybin61. Thus, the banning of psychedelics not only impairs research into their potential therapeutic value but also hampers basic neuroscience research.

Despite the interesting preclinical neuroscience findings listed above, very few studies using psychedelic drugs to investigate human brain function have been conducted in the 50 years since psychedelics were banned. In one recent functional MRI study, intravenous administration of psilocybin revealed a profound and unpredicted reduction in brain activity, particularly in the default-mode network, and a decoupling of the integrity of this system62. This effect was shown to be of neuronal origin, as it was replicated using magnetoencephalography, a technique that has sufficient temporal resolution to allow analysis of cortical neuronal circuits by dynamic causal modelling. This study showed that the main action of psilocybin was on layer 5 pyramidal neurons63.

In some subjects in this study, psilocybin exposure was associated with enhanced mood several weeks later64, which is consistent with findings from other studies15,57. Interestingly, psilocybin exposure was associated with an enhancement of visual association cortex activation in response to positive memories, which might help to explain the positive mood outcomes64. The psychosis-like state induced by psilocybin could also be used to test new antipsychotics, as the default-mode uncoupling it produces is similar to that observed in individuals with prodromal schizophrenia65.

These findings have implications for the treatment of mood disorders, and the UK MRC has funded a trial of psilocybin-augmented psychotherapy for treatment-resistant depression. However, the trial has been unable to begin because no supplier of trial quality (good manufacturing practice (GMP)) psilocybin has been found. (Current UK Medicine regulations require GMP production of substances for clinical trials but allow neuroscience experiments to be performed with chemically pure non-GMP products.) Even if the trial does start and has a positive outcome, roll-out of psilocybin into wider clinical research and treatment will be almost impossible in either the United Kingdom or United States without a change in the law, because any doctor wishing to prescribe the drug treatment would need to obtain a Schedule I licence — at great cost and time, as explained above.

Table 2 summarizes the actual and potential uses and neuroscience interests for many of the substances discussed here.