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In the 4th century BC it continued its traditional policy, but in 338 was besieged by Philip II of Macedon.
With the assistance of Corinth and Athens, it escaped complete domination at Philip's hands, but was nevertheless forced to accept a Macedonian garrison.
In 294 BC, after forty-three years of semi-autonomy under Macedonian suzerainty, Ambracia was given by the son of Cassander to Pyrrhus, king of Epirus, who made it his capital, and adorned it with palace, temples and theatres.
In the wars of Philip V of Macedon and the Epirotes against the Aetolian league ( 220 – 205 ) Ambracia passed from one alliance to the other, but ultimately joined the latter confederacy.
During the struggle of the Aetolians against Rome, it stood a stubborn siege, including the first known use of poison gas against the Romans ' siege tunnels.

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