Cannabinoids and cannabis have become popular for cancer treatment in the community [69]. An uncountable number of anecdotal responses and testimonials after using cannabis oil for malignant diseases (extracts rich in THC or CBD oil) suggest anticancer effects [70,71,72,73,74,75]. The usual dosages are 1 g, up to 2 g per day. However, such reports must be interpreted with caution. Not only do they lack proper medical documentation, but, conversely, the story of the many others who were unsuccessful in their efforts to combat their tumour with cannabinoids remains unknown. In addition, the extracts that have been used often lack appropriate characterization, therefore the results may not be reproducible. Although not an ideal form of evidence, they are nonetheless, to some extent, resources for identifying possible effects.

In contrast to the large number of reports in social media, only 16 articles were identified in the scientific medical literature describing nearly 180 cases. To date, CBD, CBD combined with THC, pure THC, as well as poorly characterized cannabis or hemp extracts, have been used for the treatment of malignant diseases in man. These articles reported measurable benefits, such as tumour regression and/or extension of survival. Although representing ‘real-world data’, the selection of cases responding, the paucity of similar cases, the heterogeneity of the data, the lack of head-to-head comparisons or of an independent ‘blinded’ assessment for possible confounders, and a sufficiently long follow-up in the majority of cases are factors limiting overall conclusions on efficacy (Table 3).

Treatment with pure CBD has been reported in only five articles, all of which are case reports. Brain tumours were the primary cancer described in these publications.

The largest collection of cases described the results from 119 patients with various cancers, most of which were metastatic [76]. Data were routinely collected, as part of a treatment programme with synthetic CBD, over a 4-year period. A minority of 28 patients received CBD as the sole treatment. Breast, prostate and colorectal cancer were the most often reported cancers, with 39, 16 and 13 patients, respectively; 8 other patients had non-Hodgkin's lymphoma and 7 had a diagnosis of GBM. One-third of the patients had a history of previous, self-initiated use of cannabis extracts, intriguingly without a response. CBD (10–30 mg twice daily for a minimum of 6 months) was administered according to a ‘3 days on, 3 days off’ schedule. In some cases, nabiximols was used in conjunction with CBD (two sprays twice daily, equivalent to 10.8 mg THC + 10 mg CBD/day).

Clinical responses were reported in 92% of the 119 cases with solid tumours, including a reduction in circulating tumour cells (test performed before and after treatment in the majority of patients). A number of patients had relevant scans. The authors noted that patients receiving continuous dosing did not do as well as those receiving this on/off pulsed regimen, unfortunately without supporting details. Some of the patients reverted to cannabis oil bought on the internet, and following this, 80% of these cases relapsed. According to the authors, <6 months of treatment had little effect; these patients were defined as ‘unassessable’ and were excluded. Such a selection can cause bias. Patients with < 6 months of treatment may have had, for example, progressive disease or may have reverted to preparations from the internet because of the lack of a clear effect. However, many interesting aspects remain unanswered in that article, such as response criteria, number of patients who were stable/progressive when CBD was started or who had been treated for <6 months (with reasons), or characteristics of patients who relapsed. It is therefore difficult to attribute the therapeutic success solely to CBD.

The publication describes six cases in more detail—four with breast cancer, one with prostate cancer and one female patient with oesophageal cancer, all receiving treatment with CBD alone and who demonstrated the most impressive response. In addition, the case of a 5-year-old boy with an anaplastic ependymoma, a rare form of brain tumour, who had exhausted standard treatment (twice surgery, chemotherapy, radiotherapy) and who experienced a reduction of his tumour by ~60% with CBD, is briefly described [76]. An updated description of this particular case, based on a publicly accessible interview with his father, is of interest as treatment was switched from pulse dosing with pure CBD to daily dosing with an extract. Details are provided below.

The boy, named William (as has been revealed from interviews with his father), has received much publicity over the years (e.g., https://www.theextract.co.uk/health/pain/interview-father-of-tumour-sufferer/). In 2014, at the age of slightly above 1½ years, William was diagnosed with an anaplastic ependymoma, Grade 3, of the 4th ventricle, the size of a golf ball. The tumour was resected, and chemotherapy, maintained for 9 months, was started. In late 2015, about 1 year after chemotherapy, the tumour was growing again and was surgically removed for a second time, followed by a 6-week course of radiotherapy. Around March 2016, the tumour had resumed growth and the family looked desperately for alternative treatments. Via a private clinic, the child received synthetic CBD oil at a dosage of only 5 mg CBD once daily for 3 days on and then 3 days off in parallel with a ketogenic diet. Not only did the child become more alert, but the magnetic resonance imaging (MRI) scan showed that the tumour had shrunk by more than two-thirds in comparison with 6 months earlier. However, in late 2018, the tumour had grown again slightly, and even significantly more 3 months later. In March 2019, the child underwent surgery for the third time, followed by further chemotherapy. At this time, the low-dose pulse treatment with synthetic CBD was stopped and replaced with a CBD extract (30 mg daily of a ‘full spectrum CBD oil’, likely containing 5.6% CBD, however the exact composition is unknown). Since then, the scans are stable and no growth of the tumour has been observed (latest update January 2021, ~7 years after diagnosis; https://makewilliamwell.com/).

Highly purified phyto-CBD (99.8%, mainly 200 mg twice daily) concomitant to standard radiochemotherapy with temozolomide was used in the treatment of 15 unselected, consecutive patients with GBM (see the study by Likar et al. [77]). Seven (46.7%) patients have now been living for at least 24 months, and four (26.7%) for at least 36 months; this is more than twice as long as has been previously reported in the literature. The mean overall survival is currently 24.2 months (median 21 months) and the 1-year survival rate 87%. The same authors had previously reported improved survival in a smaller cohort of nine consecutive patients with brain tumours (six with GBM grade IV) [78]. As with the previous case series, the heterogeneity of the patient population, the relatively small number of patients, and the lack of a control group are factors limiting definite conclusions.

Another publication describes the case of two male patients with brain tumours—one with GBM and the other with a grade III oligodendroglioma. Both patients underwent a partial surgical resection of tumours (both tumours were MGMT-methylated, with a mutation of IDH-1, indicative of chemotherapeutic resistance and enhanced cancer cell growth). The first patient developed temozolomide resistance and was administered chemoradiation with six cycles of PCV (procarbazine, lomustine, and vincristine) associated with a CBD regimen (300–450 mg/day; capsules made with hemp oil with < 0.3% THC). Pseudoprogression (increased oedema, inflammation, extensive contrast enhancement and hypoperfusion), a marker of treatment response, was resolved within a short period. The second patient, also relapsing after temozolomide, was treated with a similar regimen of six cycles of PCV associated with CBD (100–200 mg/day). The patient also demonstrated a marked remission, which the authors considered as uncommon in both cases [79].

Pancreatic cancer is another example of a very aggressive and ‘orphan’ cancer, with an incidence of about 5/100,000. Pure phyto-CBD (99.8%, 200 mg twice daily) concomitant with standard chemotherapy improved the survival of nine consecutive, unselected patients with advanced, metastatic pancreatic cancer [80]. Whereas the overall survival reported in the literature for metastatic disease is 5.9 months [81], the mean overall survival of patients receiving CBD as additional treatment was almost twice as long (11.5 months). As noted previously, a collection of cases, widely differing in their characteristics, diagnosed at various stages of disease, and who also received other medications, does not have the same level of evidence as the results from controlled clinical trials that aim to include an homogeneous population. This limits definite conclusions regarding the therapeutic contribution of CBD.

Several other articles describe cases that have been treated with ‘CBD oil’, assumed to be extracts with CBD as the predominant cannabinoid. Compared with pure CBD, the lack of an appropriate characterization of the components of such extracts, as well as of the amounts administered, renders conclusions about the potential effects of CBD/cannabinoids even more difficult. Moreover, it cannot be excluded that patients who turn to cannabinoids may also take other alternative medicines, often without telling their physicians or only doing so long after initiation.

An 81-year-old female with a metastatic, low-grade, ovarian carcinoma, accidentally diagnosed during surgery (CA125 value 77 U/mL) received one drop of CBD oil (composition not reported) sublingually each evening concomitant with laetrile 500 mg four times daily. Chemotherapy was declined. The CA125 value dropped from borderline 46 U/mL after surgery to 22 U/mL after 1 month of CBD [82]; treatment was maintained. Assuming a volume of at least 35 µL per drop and a concentration of 10% CBD, 1 drop contains about 3.5 mg of CBD. Repeated computed tomography (CT) imaging showed a dramatic reduction in the patient’s disease burden, with near complete resolution of all previously identified lesions 7 months after surgery. CA125 values remained low at around 12 U/mL. The authors related this striking response to her intake of CBD. It was very likely tumour resection (CA125 value had considerably dropped after surgery) had a major effect on the further course of the disease, irrespective of CBD.

An 81-year-old male with biopsy-confirmed adenocarcinoma of the lung was administered a regimen with 2% CBD oil (1.32 mg CBD twice daily) 11 months after diagnosis. The tumour was progressive at that time. CBD, which was the sole therapy, was increased to 6 mg twice daily after 1 week. CT imaging 4 months later revealed near total resolution of the left lower lobe mass and a significant reduction in the size and number of mediastinal lymph nodes (stable according to a CT control 2 months later) [83].

Another article reported the case of a subject with terminal, biopsy-confirmed lung cancer. The patient, a 53-year old male, had a history of intense alcohol and drug abuse and repeated injuries to his spine after multiple car accidents. He suffered from very severe pain, insomnia, post-traumatic stress disorder, anxiety and depression, with a loss of bladder control in parallel. In a last attempt to save or improve his life, the patient joined Alcoholics Anonymous, where one of his fellow members advised him to inhale vaporized cannabis oil. To his surprise, he was not only able to stop substance abuse but also his lung cancer disappeared within about 3 months of inhaling vaporized cannabis oils (composition unknown) on a daily basis. He died from cardiac failure about 1 year later [84].

A similar observation has recently been published [85]. A female in her 80s was diagnosed with non-small cell lung cancer (tumour size 41 mm, with no evidence of local or further spread). As the patient refused treatment, she received only regular CT scans every 3–6 months. Surprisingly, a progressive shrinking of the tumour was observed over time, which reached a diameter of 10 mm 32 months after diagnosis, despite the fact that the patient continued to smoke (estimated 68 packs of cigarettes/year). Discussions with the physicians revealed that the patient had taken 0.5 mL of ‘cannabis oil’ two to three times daily since her diagnosis (20% CBD, 19.5% THC, 24% THCA, according to the supplier), i.e. ~200–300 mg of CBD and THC per day. Other treatments the patient has been prescribed (for mild chronic obstructive pulmonary disease, osteoarthritis, and high blood pressure) cannot explain the shrinkage of the tumour by 76%.

Although no direct effects on the tumour have been reported, the case of an 11-year-old female with a pilocytic astrocytoma located in the medulla oblongata, diagnosed at the age of 4 years and treated with chemotherapy, has also been reviewed. Cerebellar pilocytic astrocytoma are a less malignant form of brain tumour, but, due to their location, they are usually accompanied by a range of neuropsychological sequelae; in this particular case, by mood instability, irritability, memory deficits, fatigue, nausea, decreased appetite and dysarthria. Multiple courses of chemotherapy in the past had left residues, which presented as a cyst. MRI showed stable conditions for 5 years from the time CBD was started, as well as during the entire period of treatment with CBD thereafter. Parents self-initiated treatment with over-the-counter CBD of unknown composition (likely ‘CBD oil’), which considerably improved symptoms but was stopped for financial reasons; this was followed by worsening of irritability, fatigue and reduced appetite. Pharmacy-grade CBD (purity 99.8%, 200 mg/day for 3 months) was reintroduced, this time under medical surveillance, and improvement in, most notably, cognitive functions, working memory, behaviour and quality of life was observed [86].

The first clinical study in humans was a pilot phase I trial with THC in 9 patients who had recurrent GBM. All of these patients had previously not responded to standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression at the time they received pure THC locally. An aliquot of a THC solution (100 mg/mL in ethanol) was dissolved in 30 mL of physiological saline solution supplemented with 0.5% (w/v) human serum albumin and infused into the resection cavity, at days 3–6 after surgery. After 20–40 mg on Day 1, the dose was progressively increased for 2–5 days up to 80–180 mg/day. The median duration of an administration cycle was 10 days; five patients received more than one cycle. In three of these five patients, a temporary reduction in tumour proliferation was observed. THC administration was well tolerated without overt psychoactive effects. Median survival of the cohort from the beginning of THC administration was 24 weeks [87].

In a two-part clinical study, six patients with recurrent GBM received standard chemoradiotherapy treatment, as described by Stupp et al. [88], followed by dose-intense temozolomide combined with nabidiolex (a 1:1 CBD:THC oromucosal spray) to assess the maximum tolerated dose (12 sprays per day) and the safety of the combined treatment. In part two, 12 patients were randomized to CBD:THC (daily dose up to 32.4 mg THC + 30 mg CBD, i.e. 12 sprays) and 9 patients were randomized to placebo (mean age 58 years, baseline median Karnofsky score 90 in both treatment groups). Median time from diagnosis of recurrence to the start of treatment (Day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo groups, respectively); however, there were relatively more males in the placebo group (5/12 vs. 8/9). The median number of days of dosing with CBD:THC or placebo was similar (155 days [range 50–356] and 134 days [range 13–359], respectively. Median survival in the CBD:THC treatment was >550 days, and 369 days in the placebo group (difference not significant); 1-year survival was 83% in the CBD:THC group and 56% in the placebo group (p = 0.042). Progression-free survival at 6 months was 42% in the CBD:THC group and 33% in the placebo group (not significant ). Overall, the most common treatment-related adverse events were dizziness (11/18 patients) and nausea (7/18 patients) [89].

Although not planned as a therapeutic study, the effects observed with nabiximols in patients with a leukemic indolent B-cell lymphoma without treatment indication is of interest. Fifteen patients received the maximum tolerated dose containing 18.9 mg THC and 17.5 mg CBD as a single dose, and the effects on lymphocyte counts were measured after 2, 4, 6, 24 and 168 h in comparison with a non-treatment control day. A significant time-dependent decrease in lymphocyte counts (clonal B cells and lymphocytes to a similar extent) was observed with the nadir usually at 4 h after drug administration. A week after administration of nabiximols, all non-malignant lymphocytes had returned to baseline levels, but the clonal B cells had significantly increased. This transient decrease was not due to increased cell death, as measured by activated caspase-3, but was very likely to be a ‘homing’ of lymphoma B cells from blood into secondary lymphoid organs where they receive prosurvival signals. Therefore, the authors advise caution with nabiximols in patients with indolent leukemic lymphomas [90].

A recent publication presents the case of a pregnant patient with Hodgkin’s lymphoma (HL) who self-initiated topical and oral therapy with THC-rich cannabis oil (exact composition unknown) at 26 weeks of her second pregnancy. HL had been diagnosed 5 years previously. At that time, chemotherapy with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) for 6 months, and radiotherapy (20 sessions of 20 Gy), achieved incomplete remission, with lymphoma tissue about 2 cm in diameter persisting in the thorax. Radiochemotherapy was poorly tolerated and the patient refused further treatment.

During the patient’s first pregnancy, an MRI scan revealed an HL of about 15 × 13 cm with left lung involvement, posterior and anterior mediastinal extension with anterior right pleural–pulmonary determination and extension to the anterior right ribs. Chemotherapy was refused. A healthy developed male was born by caesarean section at 37 weeks.

While still breastfeeding, the patient became pregnant again. As termination of the pregnancy was refused by the patient, disease progressed further, with terrible chest pain and numerous complications. At 26 weeks of pregnancy, the patient began topical cannabis oil application on the supraclavicular tumour and oral treatment with cannabis oil of unknown composition but obviously rich in THC, between 1 and 5 mL, three times daily. Remarkably, this not only reduced pain significantly but also the dimensions of her supraclavicular tumour, and improved the patient’s quality of life. Although the patient’s condition worsened, she delivered a male newborn, weighing 2380 g, by caesarean section at 34 weeks’ gestation. Postpartum, the mother’s disease progressed to HL stage IVB. Since her second pregnancy in 2015, the patient has received various treatments with chemo- and immune therapeutics, as well as a bone marrow autologous stem cell transplant. As at December 2019, the patient was still alive and possibly continued to use cannabis.

Also of particular interest is the case of a 14-year-old female with terminal acute lymphoblastic leukaemia (ALL) with a Philadelphia chromosome mutation, a very aggressive form of ALL, diagnosed in March 2006. When standard treatment options were unsuccessful, the patient received a bone marrow transplant 6 months after diagnosis. Six months later, aggressive chemotherapy was again initiated along with imatinib mesylate, a tyrosine kinase inhibitor, 500 mg orally twice daily. Nine months after the transplant, the presence of premature blast cells was observed. In February 2008, 23 months after diagnosis, another tyrosine kinase inhibitor, disatinib, was administered at 78 mg twice daily with no additional rounds of chemotherapy. Five months later, cerebellitis was noted after conducting a CT scan, and 10 treatments of radiation therapy were administered to the brain. Almost 3 years after diagnosis, blood was noted in the patient’s stools and a blood cell count revealed the presence of blast cells. All treatment was then suspended. Within about 2 weeks, the patient’s blast cell counts rose from 51,490 to 194,000. At this time, the patient’s family decided to administer a THC-rich extract (‘Rick Simpson oil’), in increasing daily doses. Blast cells decreased from a peak of 374,000 to 61,000 after 15 days; common adverse effects of THC, such as an increase in euphoria symptoms, a disoriented memory, an increase in alertness, and decreased use of morphine for pain were observed in parallel. The original extract had been consumed after 2 weeks and a new extract from a new cannabis cultivar was started. However, with the same dose as before, a decreased response in terms of the adverse effects of euphoria and appetite was noted; blast cells began to increase again to a peak of 66,000. After increasing the daily dose, blast cell counts decreased rapidly. Four weeks later, the second extract had been consumed and a new, third and fourth batch of another cannabis cultivar was started, with more pronounced adverse effects that necessitated a reduction in dose. As blast cells began to increase, dosages were also increased. The level of blast cells could be maintained at around 0.5–0.6 per thousand. This extract was used up after 25 days, 68 days after the initial administration of cannabis oil. At this time, blast cells had increased again to 79,000. A new batch, batch number 5, was administered and blast cells decreased very rapidly as before. However, on Day 78, gastrointestinal bleeding occurred and the patient passed away. Neutropenic colitis with perforation was diagnosed as the cause of death, very likely resulting from the aggressive chemotherapy the patient had received previously [48].

Another case report describes a 44-year-old male with a painful, non-healing malignant, exophytic wound (recurrence of squamous cell cancer of the right buccal cavity treated surgically and with radiochemotherapy 3 years earlier). Despite using high-dose hydromorphone, pregabalin, and dexamethasone, the patient continued to experience continuous (background) generalized right hemifacial pain along with volitional incident pain (wound-related procedural pain) occurring with wound dressing changes, rated by the patient as 9 out of 10 on a daily average. After starting to inhale medical cannabis (MC; THC 7.25% + CBD 8.21%, 0.5–1.0 g/day, vaporized every 2–4 h and 15 min before the patient’s daily wound dressing change), the patient’s pain improved significantly. He was able to discontinue pregabalin and dexamethasone while reducing hydromorphone to approximately 25% of his pre-MC dosage. Despite continued vaporizing, the patient’s malignant wound increased in size. Therefore, topical treatment with 1–2 mL of MC (THC 5.24% + CBD 8.02%) dissolved in sunflower oil, applied both externally and intrabuccally four times daily on the entire malignant wound, was started. With this treatment, the size of the patient’s malignant wound decreased by about 5% over the following 4 weeks. Unfortunately, the initial success was not maintained. After acute hospitalization for hypovolaemia and interruption of MC, the patient passed away.

Grotenhermen [7] reported the successful topical treatment of a basal cell carcinoma with a THC-rich cannabis extract (exact composition not reported). The patient, a 74-year-old male, had a recurrent basal cell carcinoma on his nose, diagnosed and surgically treated 13 years earlier, followed by resection, skin transplant and radiation on two further occasions. After topical application of a THC-rich extract four times daily, the tumour completely disappeared within 2 weeks. Ten months later, the patient was still free of recurrences. Impressive pictures were presented by Grotenhermen at the Cultiva Congress in Vienna, October 2017.

Such observations with extracts have inherent limitations, on the one hand due to the insufficient characterization of components and their dosages, and on the other hand, because of the limited information provided with most of these case reports. Nonetheless, the number of observations cannot be completely ignored as these articles were written by medical professionals. In line with in vitro and in vivo results of experiments with various cannabinoids, anticancer effects in man seem to be at least plausible. In short, 16 articles report the anticancer effects of CBD and other cannabinoid preparations against various malignancies in approximately 180 patients; 5 publications report the use of pure CBD, and 11 others report the use of (medical) cannabis, THC or extracts. Remarkably, oral daily doses of CBD for adults varied widely over a range of 20–600 mg/day, which is within the range of human-equivalent doses used in animal experiments.

Five of 16 publications independently reported positive effects on brain tumours. As no comparative trials between cannabinergic products exist in man in contrast to preclinical studies, a therapeutic advantage for a specific substance, combination or product cannot be delineated. A majority of patients with GBM has been treated with CBD concomitant with standard radiochemotherapy. A closer look at the survival data shows that those patients who received CBD 200 mg/day have survived for a mean of 10.5 months (four patients) compared with a mean of 24.2 months for the entire cohort of 15 patients [77].

All articles described some benefit, such as an extension of survival or tumour regression; however, bias in reporting patients who improved with cannabinoids cannot be excluded, particularly for case reports. Currently, there is no unambiguous evidence for a definite long-term ‘cure’, as maintained in social media. Conversely, no prominent harmful effects have been reported in any of these articles. As for extracts, it has to be kept in mind that each has its own characteristics in terms of composition, anticancer potency and adverse reactions [91]. Caution is therefore advised as results may not be reproducible with another extract.