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How much cbd oil do i take for testicular cancer

Cannabis and Cannabinoids (PDQ®)–Patient Version

Questions and Answers About Cannabis and Cannabinoids

Cannabis, also known as marijuana, is a plant first grown in Central Asia that is now grown in many parts of the world. The Cannabis plant makes a resin (thick substance) that contains compounds called cannabinoids. Some cannabinoids are psychoactive (affects your mind or mood). In the United States, Cannabis is a controlled substance and has been classified as a Schedule I agent (a drug with a high potential for abuse and no accepted medical use).

Hemp is a mixture of the Cannabis plant with very low levels of psychoactive compounds. Hemp oil or cannabidiol (CBD) are made from extracts of industrial hemp, while hemp seed oil is an edible fatty oil that contains few or no cannabinoids. Hemp is not a controlled substance.

See the General Information section of the health professional version of the Cannabis and Cannabinoids summary for more information on medicinal Cannabis products.

Clinical trials that study Cannabis for cancer treatment are limited. To start a clinical trial with Cannabis in the United States, researchers must file an Investigational New Drug (IND) application with the FDA, have a Schedule I license from the U.S. Drug Enforcement Administration, and have approval from the National Institute on Drug Abuse.

By federal law, possessing Cannabis (marijuana) is illegal in the United States unless it is used in approved research settings. However, a growing number of states, territories, and the District of Columbia have passed laws to legalize medical and/or recreational marijuana. (See Question 3).

Cannabinoids, also known as phytocannabinoids, are chemicals in Cannabis that cause drug-like effects in the body, including the central nervous system and the immune system. Over 100 cannabinoids have been found in Cannabis. The main psychoactive cannabinoid in Cannabis is delta-9-THC. Another active cannabinoid is cannabidiol (CBD).

Cannabinoids may help treat the side effects of cancer and cancer treatment.

Although federal law prohibits the use of Cannabis, the map below shows the states and territories that have legalized Cannabis for medical use. Some other states have legalized only one ingredient in Cannabis, such as cannabidiol (CBD), and these states are not included in the map. Medical marijuana laws vary from state to state. Enlarge A map showing the U.S. states and territories that have approved the medical use of Cannabis.

Cannabis may be taken by mouth (in baked goods or as an herbal tea) or may be inhaled. When taken by mouth, the main psychoactive part of Cannabis (delta-9-THC) goes through the liver and is changed into a different psychoactive chemical (11-OH-THC).

When Cannabis is smoked and inhaled, cannabinoids quickly enter the bloodstream. The psychoactive chemical (11-OH-THC) is made in smaller amounts than when taken by mouth.

Clinical trials are studying a medicine made from an extract of Cannabis that contains specific amounts of cannabinoids. This medicine is sprayed under the tongue.

In laboratory studies, tumor cells are used to test a substance to find out if it is likely to have any anticancer effects. In animal studies, tests are done to see if a drug, procedure, or treatment is safe and effective in animals. Laboratory and animal studies are done before a substance is tested in people.

Laboratory and animal studies have tested the effects of cannabinoids in laboratory experiments. See the Laboratory/Animal/Preclinical Studies section of the health professional version of Cannabis and Cannabinoids for information on laboratory and animal studies done using cannabinoids.

No ongoing studies of Cannabis as a treatment for cancer in people have been found in the CAM on PubMed database maintained by the National Institutes of Health.

Small studies have been done, but the results have not been reported or suggest a need for larger studies.

  • An oral spray of Cannabis extract given with temozolomide to treat recurrentglioblastoma multiforme.
  • CBD taken by mouth to treat acute graft-versus-host disease in patients who have undergone allogeneic hematopoietic stem cell transplantation.

Cannabis and cannabinoids have been studied as ways to manage side effects of cancer and cancer therapies.

Nausea and vomiting

Cannabis and cannabinoids have been studied in the treatment of nausea and vomiting caused by cancer or cancer treatment:

  • Delta-9-THC taken by mouth: Two cannabinoid drugs, dronabinol and nabilone, approved by the U.S. Food and Drug Administration (FDA), are given to treat nausea and vomiting caused by chemotherapy in patients who have not responded to standardantiemetic therapy. Clinical trials have shown that both dronabinol and nabilone work as well as or better than other drugs to relieve nausea and vomiting.
  • Oral spray with delta-9-THC and CBD: Nabiximols, a Cannabis extract given as a mouth spray, was shown in a small randomized, placebo-controlled, double-blinded clinical trial in Spain to treat nausea and vomiting caused by chemotherapy.
  • Inhaled Cannabis: Small trials have studied inhaled Cannabis for the treatment of nausea and vomiting caused by chemotherapy.

Newer drugs given for nausea caused by chemotherapy have not been compared with Cannabis or cannabinoids in cancer patients.

There is growing interest in treating children for symptoms such as nausea with Cannabis and cannabinoids, but studies are limited. The American Academy of Pediatrics has not endorsed Cannabis and cannabinoid use because of concerns about its effect on brain development.


The ability of cannabinoids to increase appetite has been studied:

  • Delta-9-THC taken by mouth: A clinical trial compared delta-9-THC (dronabinol) and a standard drug (megestrol, an appetite stimulant) in patients with advanced cancer and loss of appetite. Results showed that delta-9-THC did not help increase appetite or weight gain in advanced cancer patients compared with megestrol.
  • Inhaled Cannabis: There are no published studies of the effect of inhaled Cannabis on cancer patients with loss of appetite.

Pain relief

Cannabis and cannabinoids have been studied in the treatment of pain:

  • VaporizedCannabis with opioids: In a study of 21 patients with chronic pain, vaporized Cannabis given with morphine relieved pain better than morphine alone, while vaporized Cannabis given with oxycodone did not give greater pain relief. Further studies are needed.
  • Inhaled Cannabis: Randomized controlled trials of inhaled Cannabis in patients with peripheral neuropathy or other nerve pain found thatinhaled Cannabis relieved pain better than inhaled placebo. A retrospective study of patients who received an anticancer drug for gastrointestinal cancers found that those who also inhaled Cannabis had less nerve pain, including those who took Cannabis before they began the anticancer drug.
  • Cannabis plant extract: A study of Cannabis extract that was sprayed under the tongue found it helped patients with advanced cancer whose pain was not relieved by strong opioids alone. In another study, patients who were given lower doses of cannabinoid spray showed better pain control and less sleep loss than patients who received a placebo. Control of cancer-related pain in some patients was better without the need for higher doses of Cannabis extract spray or higher doses of their other pain medicines. Adverse events were related to high doses of cannabinoid spray.
  • Delta-9-THC taken by mouth: Two small clinical trials of oral delta-9-THC showed that it relieved cancer pain. In the first study, patients had good pain relief, less nausea and vomiting, and better appetite. A second study showed that delta-9-THC could relieve pain as well as codeine. An observational study of nabilone also reported less cancer pain along with less nausea, anxiety, and distress when compared with no treatment. Neither dronabinol nor nabilone is approved by the FDA for pain relief.
  • Non-specific Cannabis products: A randomized controlled trial studied patients with advanced cancer who used Cannabis in addition to opioids early in treatment compared to patients who added Cannabis later in treatment. Patients who were given Cannabis later showed an increase in opioid use during the 3-month study. Opioid use was stable in patients who began Cannabis use earlier. There were no changes in symptoms or adverse effects between the two groups. Over 100 different Cannabis products were given during the study.

Anxiety and sleep

Cannabis and cannabinoids have been studied in the treatment of anxiety.

  • Inhaled Cannabis: A small case series found that patients who inhaled Cannabis had improved mood, improved sense of well-being, and less anxiety. In another study, 74 patients newly diagnosed with head and neck cancer who were Cannabis users were matched to 74 nonusers. The Cannabis users had lower anxiety or depression and less pain or discomfort than the nonusers. The Cannabis users were also less tired, had more appetite, and reported greater feelings of well-being.
  • Oral Cannabis oil: A randomized controlled trial studied two different doses of oral Cannabis oil in patients with brain cancer that could not be removed by surgery or had come back. Physical side effects such as sleep were noted to be better in the 1:1 ratio dose group. Both doses were well tolerated without any adverse effects.

Side effects of Cannabis and cannabinoids can include:

  • Fast heartbeat.
  • Low blood pressure.
  • Muscle relaxation.
  • Bloodshot eyes.
  • Slow digestion.
  • Dizziness.
  • Drowsiness.
  • Depression. . .

Both Cannabis and cannabinoids may be addictive. Symptoms of withdrawal from cannabinoids include:

  • Being easily annoyed or angered.
  • Trouble sleeping.
  • Unable to stay still. .
  • Nausea and cramping (rare).

These symptoms are mild compared with symptoms of withdrawal from opiates and usually go away after a few days.

Studies on cancer risk from Cannabis use

Studies on the risk of various cancers linked to Cannabis smoking have shown the following:

  • Lung cancer: Because Cannabis smoke contains many of the same substances as tobacco smoke, there are concerns about how inhaled Cannabis affects the lungs. A cohort study of men in Africa found that there was an increased risk of lung cancer in tobacco smokers who also inhaled Cannabis. A population study of lung cancer patients found that low Cannabis use was not linked to an increased risk of lung cancer or other aerodigestive tract cancers.
  • Testicular cancer: A 1970 study interviewed over 49,000 Swedish men aged 19 to 21 years about their personal history of using Cannabis at the time they enlisted in the military and then followed them for up to 42 years. The study did not find a link between those who had “ever” used Cannabis and testicular cancer, but did find that “heavy” use of Cannabis (more than 50 times in a lifetime) was linked to more than twice the risk of testicular cancer. The study was limited by the way data was gathered and did not note whether the testicular cancers were seminoma or nonseminoma types or whether Cannabis use also occurred after enlistment.
  • Bladder cancer: A review of bladder cancer rates in Cannabis users and non-users was done in over 84,000 men who took part in the California Men’s Health Study. After more than 16 years of follow-up and adjusting for age, race, ethnic group, and body mass index, rates of bladder cancer were found to be 45% lower in Cannabis users than in men who did not report Cannabis use.

Larger studies that follow patients over time are needed to find if there is a link between Cannabis use and a higher risk of testicular germ cell tumors.

Studies on Cannabis use and impact on cancer treatment

Few studies have been done to find out how Cannabis interacts with conventional treatment. A retrospective observational study in Israel showed that Cannabis reduced the effect of immunotherapy. A prospective observational study of immunotherapy and Cannabis in patients with metastatic cancer reported that the Cannabis users did not benefit from immunotherapy as much as those who did not use Cannabis.

The U.S. Food and Drug Administration (FDA) has not approved Cannabis or cannabinoids for use as a cancer treatment.

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Cannabis is not approved by the FDA for the treatment of any cancer-related symptom or side effect of cancer therapy.

Two cannabinoids (dronabinol and nabilone) are approved by the FDA for the treatment of nausea and vomiting caused by chemotherapy in patients who have not responded to antiemetic therapy.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the use of Cannabis and cannabinoids in the treatment of people with cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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The best way to cite this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cannabis and Cannabinoids. Bethesda, MD: National Cancer Institute. Updated . Available at: Accessed . [PMID: 26389314]

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General CAM Information

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

Evaluation of CAM Therapies

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

Questions to Ask Your Health Care Provider About CAM

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

  • What side effects can be expected?
  • What are the risks related to this therapy?
  • What benefits can be expected from this therapy?
  • Do the known benefits outweigh the risks?
  • Will the therapy affect conventional treatment?
  • Is this therapy part of a clinical trial?
  • If so, who is the sponsor of the trial?
  • Will the therapy be covered by health insurance?

To Learn More About CAM

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

  • NCCIH Clearinghouse
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  • TTY (for deaf and hard of hearing callers): 1-866-464-3615
  • E-mail: [email protected]
  • Website:

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

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  • Silver Spring, MD 20993
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  • Website:

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

  • Who Cares: Sources of Information About Health Care Products and Services
  • Fraudulent Health Claims: Don’t Be Fooled
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  • Federal Trade Commission
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  • Washington, DC 20580
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  • Updated: February 18, 2022

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Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis

The aetiology of testicular cancer remains elusive. In this manuscript, we review the evidence regarding the association between cannabis use and testicular cancer development.


In this systematic review and meta-analysis, we reviewed literature published between 1 st January 1980 and 13 th May 2015 and found three case–control studies that investigated the association between cannabis use and development of testicular germ cell tumours (TGCTs).


Using meta-analysis techniques, we observed that a) current, b) chronic, and c) frequent cannabis use is associated with the development of TGCT, when compared to never-use of the drug. The strongest association was found for non-seminoma development – for example, those using cannabis on at least a weekly basis had two and a half times greater odds of developing a non-seminoma TGCT compared those who never used cannabis (OR: 2.59, 95 % CI 1.60–4.19). We found inconclusive evidence regarding the relationship between cannabis use and the development of seminoma tumours. It must be noted that these observations were derived from three studies all conducted in the United States; and the majority of data collection occurred during the 1990’s.

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The cannabis plant has been ingested or inhaled by humans for more than 4000 years [1]. In the 2014 United Nations World Drug Report, it was estimated that some 178 million 15–64 year-olds worldwide use cannabis at least once per year – making it the most consumed illicit drug by a factor of five [2]. Substantial variability in the consumption of cannabis has been observed between (and within) populations – with prevalence considerably higher in the Americas, Europe and Oceania compared to Asia and Africa [2].

Testicular cancer is the most common cancer among young men, with peak incidence occurring between 15 and 40 years of age [3] and the highest rates of disease found among men who can trace their ancestry to Northern Europe [4]. Rates of testicular cancer appear to be increasing rapidly over time [5] – and yet the primary exposures involved in its aetiology remain poorly understood [6].

In recent years, at least three case–control studies reported associations between cannabis exposure and testicular germ cell tumour (TGCT) development [7–9]. A recent meta-analysis of these studies showed that those who used cannabis for longer than 10 years were 50 % more likely to develop testicular cancer than those who never used cannabis (summary odds ratio [OR]: 1.50, 95 % CI 1.08–2.09) [10]. However, this review was limited in two ways: firstly, it did not assess the quality of the case–control studies – an important step toward understanding potential sources of bias introduced by the authors; and secondly, it did not differentiate between seminoma and non-seminoma tumour types [10] – which is also important, since a) non-seminoma tumours are typically diagnosed seven [11] to ten [12] years earlier than seminoma tumours, and may differ in terms of risk factors; and b) each of the studies showed a stronger association for non-seminoma tumours than for seminoma tumours. This review aims to address these issues.


In order to summarise the current evidence regarding the strength of association between cannabis exposure and testicular cancer, a systematic review and meta-analysis of the literature were undertaken. The review was performed in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [13].

Search strategy

All articles published between 1 st Jan 1980 and 13 th May 2015 were eligible for inclusion. No limits were set in terms of language used or study design. A search of electronic databases was conducted on 13 th March 2015 using the following databases: Cinahl, Cochrane Library, Embase, Medline, ProQuest Central, ProQuest Dissertations and Theses, Scopus and Web of Science. Using a Boolean approach, we searched the electronic databases for any possible combination of the keywords listed in Table 1.

The reference lists of those studies which were considered eligible for inclusion (see below) were scanned for additional relevant studies. Two international experts in the field of testicular cancer and/or cancer epidemiology were contacted via email, and given a list of those studies which met our inclusion criteria. They were asked to identify any studies that had been missed by our search.

Study inclusion

References were collected and logged in EndNote vX7.1 (Thomson Reuters, New York, U.S.A.). Duplicate records were removed prior to further analysis. Abstracts were screened by one reviewer (JG) to remove irrelevant studies, with a 10 % random sample of these verified by a second reviewer (VS). Any disagreements about inclusion were resolved by referral to a third reviewer (DS). The full text of all remaining papers was obtained and assessed by two reviewers (JG and VS) to identify those which met our inclusion criteria.

Studies included in the final analysis were those that reported associations between cannabis and testicular cancer. Studies were only included if data were provided from which summary associations (odds ratio or relative risks) and their 95 % confidence intervals could be calculated, or if these summary associations were provided by the authors themselves. All manuscripts that were considered relevant during the abstract screening process but ineligible for inclusion in our final analysis are listed in the supplementary material, along with justification for why they were ultimately excluded (Additional file 1).

Data extraction

For each included study, one reviewer (JG) extracted meta-data, which was then verified by a second reviewer (VS). Meta-data included: study design, year of publication, location of study, sample size (cases/controls) sources of data, exclusion criteria, adjustment for confounding, methods of cannabis exposure measurement, and estimate of the association between outcome and exposure (Table 2).

Table 2 Papers included in meta-analysis of association between cannabis use and testicular cancer development, with study meta-data

Assessment of study quality

The assessment of study quality and potential for bias is an essential feature of any systematic review. However, there remains no gold standard measure of study quality for observational research. In the absence of such a gold standard, it has been recommended that any tools used to measure study quality should be as specific as possible to the given topic, and involve a simple checklist as opposed to a scale or score [14]. Given these factors, we assessed study quality and potential for bias using the criteria outlined in the Newcastle-Ottawa Quality Assessment Scale [15, 16], but did not determine a quality score [17]. Two reviewers (JG and JS) independently assessed study quality against these criteria, with disagreements resolved by referral to a third reviewer (DS).

Statistical analysis


Our search strategy resulted in the initial identification of 149 records. Forty-nine duplicate records were removed, leaving 100 unique studies. A further 84 records were removed as a result of abstract screening, which left a total 16 records for full-text screening to determine eligibility for analysis. No further records were added by scanning the reference list of the 16 records (Fig. 1).

Flow chart of systematic review investigating association between cannabis exposure and testicular cancer development

Following full-text screening, 10 records were removed due to either lack of primary data or lack of relevance to the topic. A further 3 records were removed due to their primary data being formally published elsewhere – for example, primary data from a PhD thesis that was subsequently published in a peer-reviewed journal (Additional file 1). Following systematic review and exclusions, a total of 3 relevant case–control studies were found [7–9]. No cohort studies were found. Our invited experts both advised that they were unaware of any additional published studies of relevance to this review.

Meta-data for included studies

Meta-data for each of the included studies are presented in Table 2. Each of the included studies were conducted in the United States, with the earliest recruitment occurring in 1986 [8] and the most recent occurring in 2006 [9]. A total of 719 cases with testicular germ cell tumours (TGCT) participated across the three studies, along with a total of 1419 controls. In all studies, cases were identified from local cancer registries and confirmed via review of pathology reports. In terms of histological type, two of the three studies separated the cohort into seminoma and non-seminoma sub-groups [8, 9], while the other study additionally separated non-seminoma tumours into non-seminoma and mixed-type sub-groups [7].

Controls were either randomly derived from the community [8, 9] or the friend of cases [7]. All three studies matched on age, while two of the three studies matched on region of residence [8, 9]. Two of the three studies also matched cases and controls on race and/or ethnicity [7, 8]. Two of the three studies [7, 9] frequency-matched controls to cases, while one study individually-matched controls to cases [8].

Cannabis exposure was measured using self-report, either via face-to-face interview [8, 9] or self-completed paper-based questionnaire [7]. Each of the included studies asked the participant to report ever-use of cannabis, the duration of use and the frequency of use – with one study also asking about age at first use [9].

With respect to adjustment for confounding – in addition to the covariates used to match controls to cases – all three studies adjusted for history of cryptorchidism, two of the studies additionally adjusted for use of alcohol and tobacco. [7, 9] One study also adjusted for other drug use (including amyl nitrate and cocaine), religiosity and education level [8].

Assessment of study quality

The assessment of study quality against the Newcastle-Ottawa criteria is presented in Table 3. Case definition was adequate for all included studies, with registry records independently validated via review of pathology records. In terms of case representativeness, two of the included studies restricted their participants to those aged between 18 and 44–50 – with such practice being common in the testicular cancer context since a) the vast majority of cases occur within this age band, and b) it is thought that the aetiology of tumours that occur in younger or older populations differs to those that occur among this 18–50 year age group. One study (Lacson et al. [8]) further restricted their study groups to those aged 18–35.

Table 3 Assessment of the quality of studies included in current meta-analysis against the Newcastle-Ottawa criteria [16]

Each of the included studies derived their controls from the community, although one study used the friend of cases as controls [7], which may have reduced the representativeness of the control sample in that study. All controls had no history of testicular cancer. Each of the studies measured cannabis exposure in the same way (via self-report), although one asked about hashish exposure specifically as well as cannabis. For those studies in which person-to-person interview was conducted [8, 9], there is no record that interviewers were blinded as to the case/control status of the participant.

In order to maximise the comparability of cases and controls, each of the studies matched controls to cases – or adjusted in their regression modelling – for what could be considered the two strongest confounding variables (age and history of cryptorchidism).

Two of the included studies reported highly-differential response rates for cases and controls. One of these studies reported the highest response rate among cases (response rate: cases 67.5 %, controls 43.3 %) [9], while the other reported the highest response rate among controls (cases 38.2 %, controls 73.3 %) – the latter study deriving their controls from friends of cases [7]. The remaining study reported high and near-identical response rates between cases and controls (cases 81.0 %, controls 78.7 %) [8].

Meta-analysis results

In terms of overall association, our meta-analysis was inconclusive regarding the association between ever-use of cannabis and development of TGCT (pooled odds ratio [OR], ever-use compared with never use): 1.19, 95 % CI 0.72–1.95), and for the association of former use with TGCT (OR: 1.54, 95 % CI 0.84–2.85). We observed that current use of cannabis increased the odds of TGCT development by 62 % (OR: 1.62, 95 % CI 1.13–2.31). Frequency of cannabis was associated with TGCT development, with weekly (or greater) use appearing to nearly doubling the odds of TGCT development (OR: 1.92, 95 % CI 1.35–2.72). There was also evidence of an association between the duration of cannabis use (> = 10 years vs. never use) and TGCT development (OR: 1.50, 95 % CI 1.08–2.09).

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There was insufficient evidence to conclude that cannabis use was associated with seminoma development (Fig. 2). However, there was evidence of an association between cannabis use and non-seminoma development – with current use more than doubling the odds of tumour development (OR: 2.09, 95 % CI 1.29–3.37). Frequency of use was also strongly associated with non-seminoma development, with those using cannabis on at least a weekly basis having two and a half times greater odds of tumour development compared those who never used cannabis (OR: 2.59, 95 % CI 1.60–4.19). Finally, those who had used cannabis for at least 10 years had nearly two and half times the odds of non-seminoma development compared to never-users (OR: 2.40, 95 % CI 1.52–3.80).

Forest plots – with odds ratios and heterogeneity statistics – for a ever-use, b current use, c > = weekly use, and d > =10 years of use. (Total = all histological types)

In terms of heterogeneity, a high level of agreement between studies was found – with I 2 values of 0 % observed for most exposure variables (Fig. 2b-d). A notable exception was the ever-use variable (Fig. 2a), for which I 2 values ranged between 59 % (non-seminoma tumour type) and 71 % (combined tumour types).


The results of this review show that current use of cannabis (pooled summary OR: 1.62, 95 % CI 1.13–2.31), using cannabis on at least a weekly basis (OR: 1.92, 95 % CI 1.35–2.72) and long duration (>10 years) of cannabis use (OR: 1.50, 95 % CI 1.08–2.09) are all associated with an increased risk of development of TGCT overall, and even more strongly with non-seminoma tumours specifically. There was insufficient evidence to conclude that there is a relationship between seminoma tumours and cannabis use.

Thus, our meta-analyses suggest that a strong association exists between TGCT development and current, chronic and/or frequent cannabis use – particularly non-seminoma development –when compared to those who have never used cannabis.

Biological plausibility of cannabis in testicular carcinogenesis

The primary psychoactive component of the cannabis plant – delta-9-tetrahydrocannabinol, or THC – stimulates neural cannabinoid receptors, mimicking the action of endogenous cannabanoids (termed endocannabanoids). The position of these cannabinoid receptors in the basal ganglia, hippocampus, cerebellum and neocortex explains the common neurophysiological effects of cannabis ingestion; however, these receptors are also expressed in peripheral locations, including the testis [22].

The biological plausibility of the link between cannabis exposure and testicular cancer is thought to be related to disruptions to the hypothalamic–pituitary–testicular axis – an endocrine feedback system which, among other actions, assists with spermatogenesis [23]. It is thought that cannabis exposure – and subsequent stimulation of cannabinoid receptors – disrupts normal hormone regulation and testicular function, and that this disruption leads to carcinogenesis [23]. However, evidence regarding the association between regulation of normal testicular function and tumour development remains inconclusive; and given the complex and multifaceted influence of cannabinoid receptor stimulation on biological processes [9], the path from cannabis exposure to testicular carcinogenesis remains unclear.

Timing of cannabis exposure

The observation of an association between cannabis use and non-seminoma TGCT development – but not seminoma development – is intriguing. As discussed by Skeldon and Goldenberg [23], this association directs our attention to puberty (rather than later in life) as the key point of exposure. Non-seminoma tumours are typically diagnosed seven [11] to ten [12] years earlier than seminoma tumours. Interestingly, one study included in the current review that asked cases and controls about the timing of their first cannabis use showed that those who first-used before the age of 18 years were substantially more likely to develop a non-seminoma TGCT compared to never-users (adjusted OR: 2.80, 95 % CI 1.60–5.10), but that those aged 18 or older were not (OR: 1.30, 95 % CI 0.60–3.20) [9]. This may suggest that any carcinogenic disruption of interest to the hypothalamic–pituitary–testicular axis occurs during (or before) puberty [23]; however it is also possible that early initiation of cannabis exposure is a marker of other mediating factors, such as duration and frequency of cannabis use later in life. Another possibility is that since those cases that developed non-seminoma tumours were younger at the time of data collection than those who developed seminoma tumours, they may have been more likely to either recall or report marijuana use. Such a scenario would have the effect of exaggerating the association between cannabis use and non-seminoma development. However, it should be noted that this exaggeration would only occur if the age-matched controls who participated in these studies were not affected by this pattern of differential reporting by age – in other words, if the cannabis use reported by controls was accurate. This is an area that warrants further exploration.

An as-yet unexplored concept regarding the timing of cannabis exposure is the period during prenatal and early childhood development. Best current evidence suggests that TC predisposition is determined prenatally; thus, it is possible that those who positively identify as current, chronic cannabis users are also more likely to have been exposed to cannabis during perinatal and/or early childhood development. In other words, it is possible that primary cannabis use could be a proxy for second-hand exposure to cannabis during the prenatal and/or early childhood period. Such exposure would be congruent with a pre-adulthood disruption to the hypothalamic-pituitary-testicular axis, albeit via a secondary rather than primary source. However this association remains speculative and further research is required regarding the role of non-primary exposure to cannabis during the prenatal and early childhood period as a risk factor for the development of TGCT.

Strengths and weaknesses of included studies

The three case–control studies examined for this review had strengths in a number of areas; however, each of the studies had acknowledged weaknesses, one of these being the ascertainment of cannabis exposure.

For all three studies, exposure to cannabis was measured using self-report – either during a face-to-face interview [8, 9] or on a written questionnaire [7]. According to the Newcastle-Ottawa Scale, one of the optimum mechanisms to measure exposure – and ostensibly minimise risk of information bias – is via a structured interview, where the interviewer is blinded to the case/control status of the participant. There is no record in any of the included studies that the interviewers were blinded to the status of the participant. The importance of this is that we do not whether (and to what extent) the association between cannabis exposure and TC was affected by interviewer bias (i.e., the interviewer knowing the case/control status of the participant, and inadvertently leading the participant toward certain answers). However, it would seem unlikely that interviewer bias could explain all or even some of the observed associations between cannabis use and TGCT development; for example, it is difficult to imagine a scenario where knowledge of case/control status would cause interviewers to inadvertently lead those with non-seminoma tumours toward one response, and those with seminoma tumours to another.

In the presence of an association between current cannabis use and testicular cancer development, it would also be desirable to validate self-reported current (or non-current) use via an appropriate specimen-based test. [24] However the absence of a valid and easily-obtainable biomarker that does not involve the participant providing a urine sample may render such an approach untenable. It is possible that the use of self-report only will underestimate current use of cannabis [24–26]; however there is also some evidence that self-report is an efficacious means of classifying current (or recent) exposure to cannabis among men of similar age to participants of the three included studies [27].

If the cases and controls are equally likely to either under- or over-report cannabis exposure, then the impact on the observed association between cannabis use and TGCT development would likely be to attenuate it. However, if TGCT cases are more likely to report/recall cannabis use than controls – because of concern that cannabis or similar exposures might be a cause of their cancer, or a similar reason – then this may serve to exaggerate the reported association away from the null. Of course, it is entirely possible that the same exaggeration could occur if cases reported their use accurately, but controls under-reported their use.

The second major weakness for two of the three included studies was low and differential response rates. In one study, the response rate was substantially lower among the controls than the cases [9]. If the reported cannabis use was different among those controls who responded compared with those who did not, and if the same differential is not present for the cases who responded and cases who did not respond, this will result in biased OR. For example, if the controls who responded had lower rates of cannabis use than non-responding controls, this will lead to an overestimate of the cannabis-TGCT association. Unusually in a second study, the control group had a substantially higher response rate than the case group [7]. In this study, the controls were friends of the cases, which may explain their willingness to participate in the study. However it is not clear why the response rate among cases was so low. For this latter study, it may be reasonable to assume that cannabis use might have been more similar between cases and controls than if unrelated controls were used. If this is true, we might expect that the ORs in this study would be biased towards the null. Reassuringly, the results of all three studies were reasonably consistent despite the different potential sources of selection bias.

Finally, when considering the role of cannabis in the development of testicular cancer we must also consider the likely pervasiveness of this exposure. For example, it was estimated in the World Drug Report that 12 % of U.S. residents aged 12 or older had used cannabis in 2012 [2], with 36 % of U.S. college students reported to have used the drug in 2013 [28]. Given this pervasiveness among young adults, it is likely that ‘ever-use’ will include many individuals with very low exposure to cannabis – meaning that ever-use is unlikely to be a true measure of meaningful cannabis exposure.

It is also worth noting that of all the exposure variables included in our meta-analysis, the greatest heterogeneity between studies was observed for the ever-use variable (I 2 > 50 %). The source of this heterogeneity is obscure and likely to be multifaceted – but could plausibly be due to heterogeneity between study populations in terms of a) pervasiveness of cannabis ever-use and/or b) willingness to report it. For example, fewer controls in the study by Trabert et al. (55 %) [7] reported ever-use of cannabis compared to the study by Daling et al. (68 %) [9].


Using meta-analysis of published studies, we observed that a) current, b) chronic, and c) frequent cannabis use is associated with the development of TGCT – particularly non-seminoma TGCT – at least when compared to never-use of the drug. We found inconclusive evidence regarding the relationship between ever- and former-use of cannabis and TGCT development. However, it must be noted that these observations were derived from only three published studies; that these studies were all conducted in the United States; and the majority of data collection occurred during the 1990’s.