About 20 prisoners are thought to have died after taking "legal highs", new research suggests.
New psychoactive substances (NPSs) are "a source of increasing concern", the Prisons and Probation Ombudsman (PPO) said on 7 July.
The research follows an investigation into 19 prison fatalities between April 2012 and September 2014 where the inmate was known, or strongly suspected, to have been taking the drugs.
Some of the prisoners died after they fell ill, while others were suicides.
At least one prisoner died after being given "spiked" cigarettes by others who wanted to test new batches of substances, the watchdog found.
Nigel Newcomen, the ombudsman, said: "The use of new psychoactive substances is a source of increasing concern, not least in prison.
"As these substances are not allowed in prison, and also because they are difficult to test for, it is possible that there are additional cases of prisoners who had used such drugs before their death."
Odourless drugs are difficult to detect
The PPO report focuses on synthetic, odourless cannabinoids such as "Spice" and "Black Mamba", which mimic the effects of cannabis.
Their use is "proving difficult to detect and to manage", the report said.
Investigations revealed examples of "erratic, violent and out of character" behaviour by prisoners suspected to have used NPSs, adding: "It is impossible, both for the prisoner and those providing medical care, to predict the consequences" of the chemical combinations in the drugs.
Newcomen said: "NPS covers a range of substances and the precise health risks are difficult to establish.
"However, there is emerging evidence that there are dangers to both physical and mental health, and there may - in some cases - be links to suicide or self-harm. Staff and other prisoners may be at risk from users reacting violently to the effects of NPS.
"Trading of these substances in prison can also lead to debt, violence and intimidation. Once again, this creates the potential to increase self-harm or suicide among the vulnerable, as well as adding to the security and control problems facing staff."
Zero tolerance to all drugs
A Prison Service spokesman said: "Not only are new psychoactive substances damaging and potentially fatal, they also lead to violence and instability in our prisons.
"That is why we take a zero tolerance approach to all drugs, with a range of robust search and security measures to detect them.
"We have already made it a criminal offence to throw drugs and other items over prison walls, and the Government's new legislation will further strengthen our powers."